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Sample records for mild osteogenesis imperfecta

  1. Osteogenesis Imperfecta

    MedlinePlus

    ... imperfecta (OI) is a genetic disorder in which bones break easily. Sometimes the bones break for no known reason. OI can also ... you make collagen, a protein that helps make bones strong. OI can range from mild to severe, ...

  2. Osteogenesis imperfecta.

    PubMed

    Forlino, Antonella; Marini, Joan C

    2016-04-16

    Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation. PMID:26542481

  3. Transgenic mouse model of the mild dominant form of osteogenesis imperfecta.

    PubMed Central

    Bonadio, J; Saunders, T L; Tsai, E; Goldstein, S A; Morris-Wiman, J; Brinkley, L; Dolan, D F; Altschuler, R A; Hawkins, J E; Bateman, J F

    1990-01-01

    Osteogenesis imperfecta type I is a mild, dominantly inherited, connective tissue disorder characterized by bone fragility. Mutations in type I collagen account for all known cases. In Mov-13 mice, integration of a murine retrovirus within the first intron of the alpha 1(I) collagen gene results in a null allele blocked at the level of transcription. This study demonstrates that mutant mice heterozygous for the null allele are a model of osteogenesis imperfecta type I. A defect in type I collagen production is associated with dominant-acting morphological and functional defects in mineralized and nonmineralized connective tissue and with progressive hearing loss. The model provides an opportunity to investigate the effect of a reduced amount of type I collagen on the structure and integrity of extracellular matrix. It also may represent a system in which therapeutic strategies to strengthen connective tissue can be developed. Images PMID:2402497

  4. Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta.

    PubMed

    Paschalis, Eleftherios P; Gamsjaeger, Sonja; Fratzl-Zelman, Nadja; Roschger, Paul; Masic, Admir; Brozek, Wolfgang; Hassler, Norbert; Glorieux, Francis H; Rauch, Frank; Klaushofer, Klaus; Fratzl, Peter

    2016-05-01

    Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ∼1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n = 11) or aberrant collagen structure (OI-Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1 PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research. PMID:26748579

  5. Osteogenesis imperfecta: cesarean deliveries in identical twins.

    PubMed

    Dinges, E; Ortner, C; Bollag, L; Davies, J; Landau, R

    2015-02-01

    Osteogenesis imperfecta is a congenital disorder resulting in multiple fractures and extremely short stature, usually necessitating cesarean delivery. Identical twins with severe osteogenesis imperfecta each of whom underwent a cesarean delivery with different anesthetic modalities are presented. A review of the literature and anesthetic options for cesarean delivery and postoperative analgesia for women with osteogenesis imperfecta are discussed. PMID:25433579

  6. Intramedullary rodding in osteogenesis imperfecta.

    PubMed

    Mulpuri, K; Joseph, B

    2000-01-01

    The results of intramedullary rodding of long bones of 16 children with osteogenesis imperfecta, over a 10-year period, were analyzed. Sheffield elongating rods or non-elongating rods were used. The frequency of fractures was dramatically reduced after implantation of either type of rod, and the ambulatory status improved in all instances. The results were significantly better after Sheffield rodding with regard to the frequency of complications requiring reoperations and the longevity of the rods. Migration of the rods, encountered frequently, appears to be related to improper placement of the rods in the bone. It seems likely that if care is taken to ensure precise placement of a rod of appropriate size, several of these complications may be avoided. PMID:10739296

  7. Heterozygous mutation of c.3521C>T in COL1A1 may cause mild osteogenesis imperfecta/Ehlers-Danlos syndrome in a Chinese family

    PubMed Central

    Shi, Xianlong; Lu, Yanqin; Wang, Yanzhou; Zhang, Yu-ang; Teng, Yuanwei; Han, Wanshui; Han, Zhenzhong; Li, Tianyou; Chen, Mei; Liu, Junlong; Fang, Fengling; Dou, Conghui; Ren, Xiuzhi; Han, Jinxiang

    2015-01-01

    Summary Osteogenesis imperfecta (OI) is an inheritable connective tissue disorder with a broad clinical heterozygosis, which can be complicated by other connective tissue disorders like Ehlers-Danlos syndrome (EDS). OI/EDS are rarely documented. Most OI/EDS mutations are located in the N-anchor region of type I procollagen and predominated by glycine substitution. We identified a c.3521C>T (p.A1174V) heterozygous mutation in COL1A1 gene in a four-generation pedigree with proposed mild OI/EDS phenotype. The affected individuals had blue sclera and dentinogenesis imperfecta (DI) was uniformly absent. The OI phenotype varied from mild to moderate, with the absence of scoliosis and increased skin extensibility. Easy bruising, joint dislocations and high Beighton score were present in some affected individuals. EDS phenotype is either mild or unremarkable in some individuals. The mutation is poorly conserved and in silico prediction support the relatively mild phenotype. The molecular mechanisms of the mutation that leads to the possible OI/EDS phenotype should be further identified by biochemical analysis of N-propeptide processing and steady state collagen analysis. PMID:25674388

  8. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: Evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta

    SciTech Connect

    Spotila, L.D.; Constantinou, C.D.; Sereda, L.; Ganguly, A.; Prockop, D.J. ); Riggs, B.L. )

    1991-06-15

    Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI), a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here, the authors show that a 52-year-old post menopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the {alpha}2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the {alpha}2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the {alpha}2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix, as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures, slightly blue sclerae, and slight hearing loss. Therefore, the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis, and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.

  9. New Perspectives on Osteogenesis Imperfecta

    PubMed Central

    Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.

    2012-01-01

    A new paradigm has emerged for osteogenesis imperfecta (OI) as a collagen-related disorder. The more prevalent autosomal dominant forms of OI are caused by primary defects in type I collagen, while autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors contributing to the mechanism of dominant OI include intracellular stress, disruption of interactions between collagen and non-collagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive OI is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex; absence of 3-hydroxylation is associated with increased modification of the collagen helix, supporting delayed collagen folding. Other causes of recessive OI include deficiency of collagen chaperones, FKBP65 or HSP47. Murine models are crucial to uncovering the common pathways in dominant and recessive OI bone dysplasia. Clinical management of OI is multidiscipinary, encompassing substantial progress in physical rehabilitation and surgical procedures, managment of hearing, dental and pulmonary abnormalities, as well as drugs such as bisphosphonates and rGH. Novel treatments using cell therapy or new drug regimens hold promise for the future. PMID:21670757

  10. Suspect osteogenesis imperfecta in a male kitten.

    PubMed

    Evason, Michelle D; Taylor, Susan M; Bebchuk, Trevor N

    2007-03-01

    A 4.5-month-old, male domestic shorthair was presented with bilateral femoral fractures after falling from a low height. Radiographs revealed reduced radio-opacity and thin cortices of all long bones. A presumptive diagnosis of osteodystrophy, secondary to osteogenesis imperfecta, was made on postmortem examination. PMID:17436908

  11. Osteogenesis imperfecta misdiagnosed as child abuse.

    PubMed

    Singh Kocher, Mininder; Dichtel, Laura

    2011-11-01

    The differential diagnosis of child abuse includes osteogenesis imperfecta (OI). Mild phenotypes of OI may be misdiagnosed as child abuse. The purpose of this study was to review the experience of families in which OI was misdiagnosed as child abuse. Sixty-one potential cases of misdiagnosis were identified from a lay support organization. Upon review of the medical records, 33 cases were identified with a confirmed diagnosis of OI (skin biopsy or DNA blood test). Questionnaires were given to families to describe their condition and experiences. There were 19 male and 14 female children. Mean age at presentation was 7.1 months (range: 1-23 months). All patients had fractures and the presenting symptoms included pain (n=14), swelling (n=7), decreased limb movement (n=5), or unusual limb position (n=2). Abnormal radiograph findings consistent with OI were found in 19 of 33 patients (58%), clinical findings of OI were present in 23 of 33 patients (70%), and a family history that could be supportive of OI was present in 18 of 33 families (55%). Children were removed from the family in 70% of cases and older siblings were removed from the family in 62% of cases. The mean age at the time of diagnosis of OI was 10.5 months (range: 3-35 months). The consequences of misdiagnosis of OI as child abuse are devastating to the family. OI should be considered in all cases of suspected child abuse. In children with any clinical, radiographic, or family history features of OI, early involvement of a bone specialist and performance of laboratory testing should be considered to establish a timely and accurate diagnosis. PMID:21716141

  12. A rare combination of amniotic constriction band with osteogenesis imperfecta.

    PubMed

    Shah, Krupa Hitesh; Shah, Hitesh

    2015-01-01

    Amniotic constriction bands and osteogenesis imperfecta are disorders arising from a collagen defect. We report a rare association of amniotic bands with osteogenesis imperfecta in a child. The child was born with multiple amniotic bands involving the right leg, both hands and both feet. Multiple fractures of long bones of lower limbs occurred in childhood due to trivial trauma. Deformities of the femur and tibia due to malunion with osteopenia and blue sclerae were present. The patient was treated with z plasty of constriction band of the right tibia and bisphosphonate for osteogenesis imperfecta. This rare association of both collagen diseases may provide further insight for the pathogenesis of these diseases. PMID:26561227

  13. How Do Health Care Providers Diagnose Osteogenesis Imperfecta?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose osteogenesis imperfecta (OI)? Skip sharing on ... Page Content If OI is moderate or severe, health care providers usually diagnose it during prenatal ultrasound at ...

  14. [Orthotic management for patients with osteogenesis imperfecta].

    PubMed

    Alguacil Diego, I M; Molina Rueda, F; Gómez Conches, M

    2011-02-01

    Osteogenesis imperfecta (OI) is a disease caused by a genetic defect in the qualitative and quantitative synthesis of type I collagen. There is a wide variation in its clinical signs, characterized by bone fragility, resulting in a bone vulnerable to external and internal forces, determining the occurrence of frequent fractures with minimal or no trauma. The therapeutic objective is directed to improve the functional capacity of the child or adult concerned, adopting those compensatory strategies to optimise their independence. In this sense, the use of different orthoses and assistive technology are important for achieving these objectives. We reviewed the main contributions to this orthotic disease and the evolution of the different devices used in different databases over the last 25 years. PMID:20880764

  15. IFITM5 mutations and osteogenesis imperfecta.

    PubMed

    Hanagata, Nobutaka

    2016-03-01

    Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed. PMID:26031935

  16. An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

    PubMed Central

    Shapiro, J R; Stover, M L; Burn, V E; McKinstry, M B; Burshell, A L; Chipman, S D; Rowe, D W

    1992-01-01

    Mutations affecting the pro alpha 1(I) or pro alpha 2(I) collagen genes have been identified in each of the major clinical types of osteogenesis imperfecta. This study reports the presence of a heritable connective tissue disorder in a family with an osteopenic syndrome which has features of mild osteogenesis imperfecta but was considered idiopathic osteoporosis in the proband. At age 38, while still premenopausal, she was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae. There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. Delayed reduction SDS-PAGE of pepsin-digested collagens from dermal fibroblast cultures demonstrated an anomalous band migrating between alpha 1(I) and alpha 1(III). This band merged with the normal alpha-chains upon prereduction, indicating an unexpected cysteine residue. Cyanogen bromide peptide mapping suggested that the mutation was in the smaller NH2-terminal peptides. cDNA was reverse transcribed from mRNA and amplified by the polymerase chain reaction. A basepair mismatch between proband and control alpha 1(I) cDNA hybrids was detected by chemical cleavage with hydroxylamine:piperidine. The cysteine substitution was thus localized to alpha 1(I) exon 9 within the cyanogen bromide 4 peptide. Nucleotide sequence analysis localized a G----T point mutation in the first position of helical codon 43, replacing the expected glycine (GGT) residue with a cysteine (TGT). The prevalence of similar NH2-terminal mutations in subjects with this phenotype which clinically overlaps idiopathic osteoporosis remains to be determined. Images PMID:1737847

  17. Prenatal diagnosis of lethal osteogenesis imperfecta in twin pregnancy.

    PubMed

    Morin, L R; Herlicoviez, M; Loisel, J C; Jacob, B; Feuilly, C; Stanescu, V

    1991-06-01

    Lethal osteogenesis imperfecta was diagnosed at 27 weeks amenorrea in one fetus of a bichorial twin pregnancy. Sonographic findings included: short-limb dwarfism, hypotrophy and hypoechoic bones. The affected fetus was so translucent that only the normal fetus could be seen on plain in utero radiography. The affected fetus died immediately after birth. Postmortem radiography and histology were typical of lethal osteogenesis imperfecta of type IIA. Aids to the etiological diagnosis of in utero dwarfism are presented. Sonographic features correlated with neonatal death are described. PMID:1863995

  18. Instability of Polymeric Skin Collagen in Osteogenesis Imperfecta

    PubMed Central

    Francis, M. J. O.; Smith, Roger; Bauze, Robert J.

    1974-01-01

    The structural polymeric collagen of the skin of 19 patients with osteogenesis imperfecta has been examined. In those with severe bone disease, who often have white sclerae, this collagen fraction is less resistant to depolymerization than that of age-matched controls, though the total amount is normal. In patients with less severe bone disease, whose sclerae are usually blue, the polymeric collagen may have normal stability but the total amount is reduced. These results suggest defective cross-linking of collagen in severe osteogenesis imperfecta. PMID:4816854

  19. A Guide to Education for Children with Osteogenesis Imperfecta. What Is OIF? Care of an Osteogenesis Imperfecta Baby and Child.

    ERIC Educational Resources Information Center

    Ostegenesis Imperfecta Foundation, Inc., Manchester, NH.

    Three pamphlets provide basic information on the care and education of children with osteogenesis imperfecta (OI) a lifelong liability to fractures due to imperfectly formed "brittle bones." The first brochure, a guide to education for children with OI, addresses the importance of attitudes, the value of early education, public school enrollment,…

  20. Recessive Osteogenesis Imperfecta Caused by Missense Mutations in SPARC

    PubMed Central

    Mendoza-Londono, Roberto; Fahiminiya, Somayyeh; Majewski, Jacek; Tétreault, Martine; Nadaf, Javad; Kannu, Peter; Sochett, Etienne; Howard, Andrew; Stimec, Jennifer; Dupuis, Lucie; Roschger, Paul; Klaushofer, Klaus; Palomo, Telma; Ouellet, Jean; Al-Jallad, Hadil; Mort, John S.; Moffatt, Pierre; Boudko, Sergei; Bächinger, Hans-Peter; Rauch, Frank

    2015-01-01

    Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans. PMID:26027498

  1. Anesthetic Management in a Gravida with Type IV Osteogenesis Imperfecta

    PubMed Central

    Vue, Elizabeth; Davila, Juan

    2016-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder of the connective tissues caused by abnormalities in collagen formation. OI may present many challenges to the anesthesiologist. A literature review reveals a wide range of implications, from basic positioning to management of the difficult airway. We present the anesthetic management of a 25-year-old gravid woman with OI, fetal demise, and possible uterine rupture, admitted for an exploratory laparotomy. PMID:27433164

  2. Infantile-onset glaucoma and anterior megalophthalmos in osteogenesis imperfecta.

    PubMed

    Bohnsack, Brenda L

    2016-04-01

    Osteogenesis imperfecta (OI) is an inherited condition in which defects in type 1 collagen cause abnormalities in many tissues and organs, including bone, teeth, heart valves, and eyes. We describe a 6-month-old boy with OI who presented with anterior megalophthalmos of the right eye and infantile-onset glaucoma of the left eye. To our knowledge, this is the first reported case of these types of congenital eye anomalies in an infant with OI. PMID:26994503

  3. Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

    PubMed

    Bregou Bourgeois, Aline; Aubry-Rozier, Bérengère; Bonafé, Luisa; Laurent-Applegate, Lee; Pioletti, Dominique P; Zambelli, Pierre-Yves

    2016-01-01

    Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development. PMID:27346233

  4. Children with Osteogenesis Imperfecta and Their Life Situation. Report and Documentation.

    ERIC Educational Resources Information Center

    Brodin, Jane

    Children with osteogenesis imperfecta form a small and relatively unknown group, with 5 to 10 children diagnosed in Sweden each year and a total of around 200 people under the age of 17 having the condition. A questionnaire was completed by families of 24 Swedish children with osteogenesis imperfecta, and three families were interviewed. The…

  5. Mandibular lengthening by distraction osteogenesis in the setting of osteogenesis imperfecta.

    PubMed

    Black, Jonathan S; Denny, Arlen D

    2015-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and deformity. The craniofacial skeleton may be involved either primarily or by result of a concomitant diagnosis. Distraction osteogenesis has emerged as a versatile reconstructive option for many craniofacial deformities. Mandibular lengthening by distraction has not been reported in a patient with OI. We present a patient in whom mandibular lengthening was successfully performed twice for hemifacial microsomia. Bilateral lengthening was initially performed with successful airway improvement. This was followed by transport distraction on the more severely affected side for condylar reconstruction. Successful mandibular lengthening by distraction is possible in the setting of OI. PMID:25565236

  6. [PREPARATIONS OF PAMIDRONOVIC ACID IN COMPLEX TREATMENT ON OSTEOGENESIS IMPERFECTA].

    PubMed

    Zyma, A M; Guk, Yu M; Magomedov, O M; Gayko, O G; Kincha-Polishchuk, T A

    2015-07-01

    Modern view of drug therapy in the complex treatment of orthopedic manifestations of osteogenesis imperfecta (OI) was submitted. Developed and tested system of drug correction of structural and functional state of bone tissue (BT) using drugs pamidronovic acid, depending on osteoporosis severity and type of disease. Such therapy is appropriate to apply both independently and in conjunction with surgery to correct deformations of long bones of the lower extremities. Effectiveness and feasibility of the proposed methods of drug therapy was proved, most patients resume features walking and support. PMID:26591224

  7. Osteogenesis Imperfecta: A Case Report and Review of Literature

    PubMed Central

    Edelu, BO; Ndu, IK; Asinobi, IN; Obu, HA; Adimora, GN

    2014-01-01

    Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. Diagnosis is mainly based on the clinical features of the disorder. We report, the case of a male neonate delivered to a 33-year-old para 2 female at University of Nigeria Teaching Hospital, Enugu with no family history suggestive of OI. He had clinical features of a type II OI and severe birth asphyxia. Multidisciplinary management was instituted, but he died on the 7th day of life. PMID:25031897

  8. Clinical perspectives on osteogenesis imperfecta versus non-accidental injury.

    PubMed

    Pereira, Elaine Maria

    2015-12-01

    Although non-accidental injuries (NAI) are more common in cases of unexplained fractures than rare disorders such as osteogenesis imperfecta (OI), ruling out OI and other medical causes of fracture is always indicated. The majority of OI patients can be diagnosed with the help of family history, physical examination, and radiographic findings. In particular, there are a few radiological findings which are seen more commonly in NAI than in OI which may help guide clinician considerations regarding the probability of either of these diagnoses. At the same time, molecular testing still merits careful consideration in cases with unexplained fractures without obvious additional signs of abuse. PMID:26492946

  9. Perinatal lethal type II osteogenesis imperfecta: a case report

    PubMed Central

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure. PMID:26401205

  10. Osteogenesis imperfecta due to compound heterozygosity for the LEPRE1 gene.

    PubMed

    Moul, Adrienne; Alladin, Amanda; Navarrete, Cristina; Abdenour, George; Rodriguez, Maria M

    2013-10-01

    Osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density. Most cases are caused by an autosomal dominant mutation in either COL1A1 or COL1A2 gene encoding type I collagen. However, autosomal recessive forms have been identified. We present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type II, born to a non-consanguineous couple with mixed African-American and African-Hispanic ethnicity. Cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the LEPRE1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type VIII, perinatal lethal type. PMID:23301918

  11. Chest compressions in an infant with osteogenesis imperfecta type II: No new rib fractures.

    PubMed

    Sewell, R D; Steinberg, M A

    2000-11-01

    The case report of a newborn female with osteogenesis imperfecta type II who underwent cardiopulmonary resuscitation (CPR) with manual chest compressions for several minutes is presented. Chest radiographs taken before and after the chest compressions were administered were reviewed by several radiologists from 3 different hospitals and demonstrated no new radiographically visible rib fractures. Collagen analysis, the patient's clinical appearance, and clinical course, as well as a consultant's opinion aided in confirmation of the diagnosis of osteogenesis imperfecta type II. A review of 4 previous studies concerning rib fractures and CPR is included. This unique case supports previous articles that have concluded that rib fractures rarely, if ever, result from CPR in pediatrics, even in children with a lethal underlying bone disease, such as osteogenesis imperfecta type II. cardiopulmonary resuscitation, chest compressions, osteogenesis imperfecta, rib fractures, bone disease. PMID:11061808

  12. Osteogenesis imperfecta : current treatment options and future prospects.

    PubMed

    Devogelaer, Jean-Pierre; Coppin, Christine

    2006-01-01

    Osteogenesis imperfecta is a heritable condition characterized by abnormally brittle bones, with an approximate prevalence of 1/20 000 births. Fractures are the main cause of suffering and disability, but owing to the abundance and wide distribution of the defective type I collagen in the body, a variety of symptoms occur. Several types of osteogenesis imperfecta (I-VII) have been described that vary in severity. For many years, therapy consisted of rehabilitation and orthopedic surgery. Presently, pharmacologic therapies aimed at strengthening bone are available, which decrease the pain and fracture rate associated with this condition, and allow more appropriate rehabilitation programs that will hopefully result in a less marked failure to thrive in affected children. In particular, the bisphosphonates, especially pamidronate, have been used for several years. They have been successful in increasing bone mineral density (BMD) and improving bone resistance, leading to a decrease in the fracture rate. Various regimens have been proposed, but it is the therapeutic regimen first used by Glorieux and co-workers in Montreal that has been the most frequently applied.However, as yet there is no definite consensus regarding the indications for therapy, the osteogenesis imperfecta types that are of the greatest concern, the appropriate age at the outset of therapy, and the treatment duration, without yet speaking about the best bisphosphonate regimen for use. The authors have proposed some personal recommendations for the clinical use of bisphosphonates, based on their own experience with the management of patients with this condition; these include the indications for therapy, based on the clinical status, and the treatment duration. These recommendations will certainly not be unanimously endorsed, but they should help to stimulate discussion. Ameliorating BMD is an important step, but will not prevent all fractures because bisphosphonate therapy does not correct the

  13. Cochlear implantation in a child with osteogenesis imperfecta.

    PubMed

    Migirov, Lela; Henkin, Yael; Hildesheimer, Minka; Kronenberg, Jona

    2003-06-01

    Osteogenesis imperfecta (OI) is a hereditary disease of connective tissue and affects bone, dentine, sclera, joint, tendon, blood vessels, heart valves, and skin. Approximately 50% of the adult patients with OI have associated hearing impairment. To date, only three cases of cochlear implantation in adults with OI have been reported, but none in children. We present a case of cochlear implantation in a congenitally deaf 6-year-old boy with OI. The Nucleus 24 Contour device was successfully implanted using the suprameatal approach (SMA). At 6 months post-initial stimulation there was no evidence of non-acoustic nerve excitation (i.e. facial twitching) or discomfort, and significant progress in auditory abilities was manifested by open set word identification. PMID:12745164

  14. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta

    PubMed Central

    Chan, Jerry K. Y.; Götherström, Cecilia

    2014-01-01

    Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI. PMID:25346689

  15. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

    PubMed Central

    Brizola, Evelise; Mattos, Eduardo P.; Ferrari, Jessica; Freire, Patricia O.A.; Germer, Raquel; Llerena Jr, Juan C.; Félix, Têmis M.

    2015-01-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5′UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID:26648832

  16. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V.

    PubMed

    Brizola, Evelise; Mattos, Eduardo P; Ferrari, Jessica; Freire, Patricia O A; Germer, Raquel; Llerena, Juan C; Félix, Têmis M

    2015-10-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID:26648832

  17. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases.

    PubMed

    Pepin, Melanie G; Byers, Peter H

    2015-12-01

    Non-accidental injury (NAI) is a major medical concern in the United States. One of the challenges in evaluation of children with unexplained fractures is that genetic forms of bone fragility are one of the differential diagnoses. Infants who present with fractures with mild forms of osteogenesis imperfecta (OI) (OI type I or OI type IV), the most common genetic form of bone disease leading to fractures might be missed if clinical evaluation alone is used to make the diagnosis. Diagnostic clinical features (blue sclera, dentinogenesis imperfecta, Wormian bones on X-rays or positive family history) may not be present or apparent at the age of evaluation. The evaluating clinician faces the decision about whether genetic testing is necessary in certain NAI cases. In this review, we outline clinical presentations of mild OI and review the history of genetic testing for OI in the NAI versus OI setting. We summarize our data of molecular testing in the Collagen Diagnostic Laboratory (CDL) from 2008 to 2014 where NAI was noted on the request for DNA sequencing of COL1A1 and COL1A2. We provide recommendations for molecular testing in the NAI versus OI setting. First, DNA sequencing of COL1A1, COL1A2, and IFITM5 simultaneously and duplication/deletion testing is recommended. If a causative variant is not identified, in the absence of a pathologic clinical phenotype, no additional gene testing is indicated. If a VUS is found, parental segregation studies are recommended. PMID:26566591

  18. Clinical manifestations and dental management of dentinogenesis imperfecta associated with osteogenesis imperfecta: Case report.

    PubMed

    Abukabbos, Halima; Al-Sineedi, Faisal

    2013-10-01

    Dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta (OI) is a genetic disorder that affects the connective tissues and results in dentine dysplasia. This case report discusses the systemic and dental manifestations of OI and DI in a 4-year-old child, with moderate presentation of both disorders, who was treated at King Fahd Military Medical Complex in Dhahran. Dental treatment included the use of strip and stainless-steel crowns under local anesthesia, as well as behavior modification techniques. Rigorous home care instructions, including reinforcement of the oral hygiene practice and avoidance of any episode that may lead to bone fracture, were discussed with the parents. The case was reevaluated at 3-month follow-up visits, wherein the medical and dental histories were updated, the child's growth was monitored, periodic clinical and radiographic examinations were performed, and the oral hygiene was evaluated via the debris index score and caries risk assessment. Further treatment of the permanent dentition may be needed in the future. PMID:24371383

  19. Clinical manifestations and dental management of dentinogenesis imperfecta associated with osteogenesis imperfecta: Case report

    PubMed Central

    Abukabbos, Halima; Al-Sineedi, Faisal

    2013-01-01

    Dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta (OI) is a genetic disorder that affects the connective tissues and results in dentine dysplasia. This case report discusses the systemic and dental manifestations of OI and DI in a 4-year-old child, with moderate presentation of both disorders, who was treated at King Fahd Military Medical Complex in Dhahran. Dental treatment included the use of strip and stainless-steel crowns under local anesthesia, as well as behavior modification techniques. Rigorous home care instructions, including reinforcement of the oral hygiene practice and avoidance of any episode that may lead to bone fracture, were discussed with the parents. The case was reevaluated at 3-month follow-up visits, wherein the medical and dental histories were updated, the child’s growth was monitored, periodic clinical and radiographic examinations were performed, and the oral hygiene was evaluated via the debris index score and caries risk assessment. Further treatment of the permanent dentition may be needed in the future. PMID:24371383

  20. Cesarean delivery and colon resection in a patient with type III osteogenesis imperfecta.

    PubMed

    Fiegel, Matthew J

    2011-09-01

    OBJECTIVE. Osteogenesis imperfecta is a connective tissue disorder that results from the inability to produce normal collagen. Eight types are described; type II is considered the lethal variant. Because of abnormal collagen production, these patients possess many anatomic and functional abnormalities. In addition to the obvious brittle bones, osteogenesis imperfecta patients may also possess respiratory, cardiac, spinal, endocrine, and hematologic abnormalities. These numerous derangements can lead to a challenging perioperative course. CASE REPORT. This report describes a case of a 27-year-old woman, G1P0 with history of type III osteogenesis imperfecta presenting at 31+ weeks with preterm premature rupture of membranes, lower extremity edema, and constipation. Because of progressive labor and cephalopelvic disproportion, an urgent cesarean section was performed under general anesthesia. Intraoperative coagulopathy was noted. After hemostasis was achieved, a colonic mass below the splenic flexure that measured 20 × 10 cm was revealed. General surgery was consulted intraoperatively, and a rectosigmoid resection was performed for a presumed colonic pseudo-obstruction. Patient tolerated the procedure well and was extubated at the completion of the case. The patient was discharged home on postoperative day 5. CLINICAL CHALLENGES. (a) Preoperative assessment of an osteogenesis imperfecta patient, (b) determination of anesthetic type, (c) management of hemorrhage/cardiovascular instability, and (d) management of hyperthermia. CONCLUSIONS. This case report illustrates that, with proper knowledge of this disease state, osteogenesis imperfecta patients can undergo a safe anesthetic during a potentially challenging combined cesarean section/colonic resection. PMID:21813546

  1. Clinical Application of Antenatal Genetic Diagnosis of Osteogenesis Imperfecta Type IV

    PubMed Central

    Yuan, Jing; Li, Song; Xu, YeYe; Cong, Lin

    2015-01-01

    Background Clinical analysis and genetic testing of a family with osteogenesis imperfecta type IV were conducted, aiming to discuss antenatal genetic diagnosis of osteogenesis imperfecta type IV. Material/Methods Preliminary genotyping was performed based on clinical characteristics of the family members and then high-throughput sequencing was applied to rapidly and accurately detect the changes in candidate genes. Results Genetic testing of the III5 fetus and other family members revealed missense mutation in c.2746G>A, pGly916Arg in COL1A2 gene coding region and missense and synonymous mutation in COL1A1 gene coding region. Conclusions Application of antenatal genetic diagnosis provides fast and accurate genetic counseling and eugenics suggestions for patients with osteogenesis imperfecta type IV and their families. PMID:25835785

  2. Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI

    PubMed Central

    Homan, Erica P; Rauch, Frank; Grafe, Ingo; Lietman, Caressa; Doll, Jennifer A; Dawson, Brian; Bertin, Terry; Napierala, Dobrawa; Morello, Roy; Gibbs, Richard; White, Lisa; Miki, Rika; Cohn, Daniel H; Crawford, Susan; Travers, Rose; Glorieux, Francis H; Lee, Brendan

    2011-01-01

    Abstract Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF 1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. © 2011 American Society for Bone and Mineral Research PMID:21826736

  3. Cochlear implantation in a patient with osteogenesis imperfecta.

    PubMed

    Makizumi, Yoshimi; Kashio, Akinori; Sakamoto, Takashi; Karino, Shotaro; Kakigi, Akinobu; Iwasaki, Shinichi; Yamasoba, Tatsuya

    2013-10-01

    Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by a deficit in the synthesis of type I collagen. Hearing loss affects 42-58% of OI patients and progresses to deafness in 35-60% of these patients. For OI patients, cochlear implantation (CI) is the only promising treatment option. However, literature on CI in patients with OI is relatively rare. After CI, speech perception is generally good. However, among patients with severe demineralization of the cochlea, most patients are reported to have complications of facial nerve stimulation (FNS), preventing some patients from using the cochlear implant on a daily basis. Here we report a successful CI using a Nucleus CI24 Contour Advance cochlear implant in a patient with OI. Although high-resolution computed tomography (HRCT) showed extensive demineralization of the cochlea, intracochlear electrodes were inserted properly. The use of a modiolus-hugging device and the advance off-stylet technique contributed to the successful implantation, with no complications such as FNS or misplacement of electrodes. Therefore, CI can be used for treating deaf patients with OI. PMID:23219154

  4. Anisotropic properties of human cortical bone with osteogenesis imperfecta.

    PubMed

    Katti, Kalpana S; Gu, Chunju; Katti, Dinesh R

    2016-02-01

    The heterogeneity of bone shape and size variation is modulated by genetic, mechanical, nutritional, and hormonal patterning throughout its lifetime. Microstructural changes across cross sections are a result of mechanistic optimization that results over the years of evolution while being based on universal, time-invariant ingredients and patterns. Here we report changes across anatomical sections of bone with osteogenesis imperfecta (OI) that undermines the work of evolution through genetic mutation. This work examines the microstructure and molecular composition of different anatomical positions (anterior, medial, posterior, and lateral regions) in the diaphysis of an OI human tibia. The study shows that although there is no significant microstructural difference, molecular changes are observed using FTIR revealing differences in molecular composition of the four anatomical positions. In addition, the nanomechanical properties of anterior section of OI bone seem more heterogeneous. The nanomechanical properties of interstitial lamellae in all these bone samples are consistently greater than those of osteonal lamellae. The nanomechanical properties of bone depend on its anatomical section and on the measurement direction as well. Variations in molecular structure with anatomical positions and also corresponding differences in nanomechanical properties are reported. These are compared to those observed typically in healthy bone illustrating the unique influence of OI on bone multiscale behavior which results from an evolutionary process lasting for many years. PMID:26399513

  5. Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.

    PubMed

    Ward, Leanne; Bardai, Ghalib; Moffatt, Pierre; Al-Jallad, Hadil; Trejo, Pamela; Glorieux, Francis H; Rauch, Frank

    2016-06-01

    Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis. PMID:26815784

  6. Excessive TGFβ signaling is a common mechanism in Osteogenesis Imperfecta

    PubMed Central

    Grafe, Ingo; Yang, Tao; Alexander, Stefanie; Homan, Erica; Lietman, Caressa; Jiang, Ming Ming; Bertin, Terry; Munivez, Elda; Chen, Yuqing; Dawson, Brian; Ishikawa, Yoshihiro; Weis, Mary Ann; Sampath, T. Kuber; Ambrose, Catherine; Eyre, David; Bächinger, Hans Peter; Lee, Brendan

    2014-01-01

    Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations1. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms2. Here, we show that excessive transforming growth factor-beta (TGFβ) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) OI mouse models. In the skeleton, we find higher expression of TGFβ target genes, ratio of pSmad2/Smad2 protein, and in vivo Smad2 reporter activity. Anti-TGFβ treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI, and improves the lung abnormalities in Crtap−/− mice. Moreover, type I collagen of Crtap−/− mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGFβ activity3–4. Hence, altered TGFβ matrix-cell signaling is a primary mechanism in the pathogenesis of OI, and could be a promising target for the treatment of OI. PMID:24793237

  7. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment

    PubMed Central

    Van Dijk, FS; Sillence, DO

    2014-01-01

    Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID:24715559

  8. AB129. Osteogenesis imperfecta: clinical features and bisphosphonate treatment outcome

    PubMed Central

    Can, Ngoc Thi Bich; Vu, Dung Chi; Bui, Thao Phuong; Nguyen, Khanh Ngoc

    2015-01-01

    Background and objective Osteogenesis imperfecta (OI) comprises a group of disorders principally affecting type I collagen which result in increased bone fragility. Children with severe OI suffer recurrent fractures, resulting in severe deformity and growth stunting in many cases, with loss of independent ambulation by the teenage years in over 50% of cases. Recently, cyclical intravenous treatment with pamidronate has proven of benefit to children with severe forms of OI. This article aims to describle clinical features and laboratory manifestations of patient with OI and evaluate outcome of bisphosphonate management. Methods Clinical features, biochemical finding, and management outcome of 104 cases were study. The patients were classified into four major subtypes of Sillience et al. 1979. Patients with severe types were treatment with pamidronate (Aredia) used Rauch protocol 2003. Results Now we have 196 patients (87 females and 109 males) but we studied focus on 104 patients from 98 families (60 males, 44 females) onset at 2.1±3.0 years (median 0.35) with the average fracture bone of 5.9±4.4 times. In there, 17% type I, 8% type II, 63% type III, and 12% type IV. Clinical features include of intrauterine fracture visible on ultrasound 35%, bone deformation after birth 68%, triangle face 76%, long bone deformation 91%, chest deformation 46%, scoliosis 27%, short status 90%, blue sclera 83%, dentinogenesis imperfecta 20%, hearing loss 6%. Thirty patients have been treated with pamidronate at 3.2±3.7 years (4 months to 8 years) during 13±0.8 months (6-30 months). Fourteen patients had fracture bone after 6 months of treatment but no patients had fracture bone after 12 months. Seven patients had been treatment after 1.6±0.5 years, BMD increase from 0.39±0.311 to 0.79±0.105 g/cm2 (P<0.05). One patient had fever reaction after first pamidronate infusion but controlled with standard antipyretic therapy, and do not recur in later treatments. Conclusions OI has

  9. Pamidronate Affects the Mandibular Cortex of Children with Osteogenesis Imperfecta

    PubMed Central

    Apolinário, A.C.; Figueiredo, P.T.; Guimarães, A.T.; Acevedo, A.C.; Castro, L.C.; Paula, A.P.; Paula, L.M.; Melo, N.S.; Leite, A.F.

    2015-01-01

    We hypothesized that mandibular cortical width (MCW) is smaller in children with osteogenesis imperfecta (OI) than in healthy children and that pamidronate can improve the cortical mandibular thickness. The aim of this study was to assess changes in the MCW on dental panoramic radiographs (DPRs) of children with normal bone mineral density (BMD) and with OI. We also compared the MCW of children with different types of OI regarding the number of pamidronate cycles and age at the beginning of treatment. MCW measurements were retrospectively obtained from 197 DPRs of 66 children with OI types I, III, and IV who were in treatment with a comparable dosage of cyclical intravenous pamidronate between 2007 and 2013. The control group had 92 DPRs from normal BMD children. Factorial analysis of variance was used to compare MCW measurements among different age groups and between sexes and also to compare MCW measurements of children with different types of OI among different pamidronate cycles and age at the beginning of treatment. No significant differences in results were found between male and female subjects in both OI and healthy children, so they were evaluated altogether (P > 0.05). There was an increase of MCW values related to aging in all normal BMD and OI children but on a smaller scale in children with OI types I and III. Children with OI presented lower mean MCW values than did children with normal BMD at the beginning of treatment (P < 0.05). A linear model estimated the number of pamidronate cycles necessary to achieve mean MCW values equivalent to those of healthy children. The thinning of the mandibular cortex depended on the number of pamidronate cycles, the type of OI, and the age at the beginning of treatment. DPRs could thus provide a way to identify cyclic pamidronate treatment outcomes in patients with OI. PMID:25608973

  10. Mutations in patients with osteogenesis imperfecta from consanguineous Indian families.

    PubMed

    Stephen, Joshi; Girisha, Katta Mohan; Dalal, Ashwin; Shukla, Anju; Shah, Hitesh; Srivastava, Priyanka; Kornak, Uwe; Phadke, Shubha R

    2015-01-01

    Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families. PMID:25450603

  11. CRTAP AND LEPRE1 MUTATIONS IN RECESSIVE OSTEOGENESIS IMPERFECTA

    PubMed Central

    Baldridge, Dustin; Schwarze, Ulrike; Morello, Roy; Lennington, Jennifer; Bertin, Terry K.; Pace, James M.; Pepin, Melanie G.; Weis, MaryAnn; Eyre, David R.; Walsh, Jennifer; Lambert, Deborah; Green, Andrew; Robinson, Haynes; Michelson, Melonie; Houge, Gunnar; Lindman, Carl; Martin, Judith; Ward, Jewell; Lemyre, Emmanuelle; Mitchell, John J.; Krakow, Deborah; Rimoin, David L.; Cohn, Daniel H.; Byers, Peter H.; Lee, Brendan

    2009-01-01

    Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, CRTAP, or cartilage-associated protein, and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and sixteen with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations. PMID:18566967

  12. Osteogenesis Imperfecta and non-accidental injury: problems in diagnosis and management.

    PubMed

    Kasim, M S; Cheah, I; Sameon, H

    1995-06-01

    It has been noted in the literature that Osteogenesis Imperfecta is frequently mistaken for non-accidental injury. This article serves to illustrate the difficulty in differentiating between the two conditions and that they can occur concomitantly in one patient. PMID:7565189

  13. Children with Osteogenesis Imperfecta and Their Daily Living. Handicap Research Group Report No. 4.

    ERIC Educational Resources Information Center

    Brodin, Jane

    The study examined aspects of daily living of Swedish children with osteogenesis imperfecta, a mineral deficiency in the skeleton which results in stunted growth and frequent fractures. A questionnaire was administered to 24 families with children under the age of 18 and 3 families were interviewed. The study found the families in great need of…

  14. Fracture of mandible during yawning in a patient with osteogenesis imperfecta

    PubMed Central

    Ram, Hari; Shadab, Mohammad; Vardaan, Ajay; Aga, Pallavi

    2014-01-01

    Osteogenesis imperfecta is a genetic disorder characterised by fragility and multiple fractures of bones. Clinical signs and symptoms vary depending on the type of disease. Fractures of facial bones are rare compared with load-bearing long bones. We report a case of fracture of the mandible during yawning which was managed by open reduction and internal fixation. PMID:25103485

  15. Traumatic and spontaneous scleral rupture and uveal prolapse in osteogenesis imperfecta.

    PubMed

    Pirouzian, Amir; O'Halloran, Henry; Scher, Colin; Jockin, Yvett; Yaghmai, Reza

    2007-01-01

    Three cases of severe globe injuries due to scleral fragility in osteogenesis imperfecta patients between the ages of 4 and 15 years are reported. Patient 1 had complete loss of vision. Patients 2 and 3 suffered non-sight-threatening scleral perforation. All 3 patients had no previous knowledge of recommendation for eyewear protection. PMID:17913179

  16. Osteogenesis imperfecta and clubfoot—a rare combination

    PubMed Central

    Persiani, Pietro; Ranaldi, Filippo Maria; Martini, Lorena; Zambrano, Anna; Celli, Mauro; D’Eufemia, Patrizia; Villani, Ciro

    2016-01-01

    Abstract Background: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-α type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. Methods: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. Results: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. Conclusion: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes

  17. A rare case of osteogenesis imperfecta combined with complete tooth loss.

    PubMed

    Lu, Yanqin; Zhao, Fei; Ren, Xiuzhi; Li, Zhiliang; Yang, Xiaomeng; Han, Jinxiang

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue characterized by blue sclerae, osteoporosis and bone fragility. Dentinogenesis imperfecta type I is commonly seen in OI patients, but other dental impairments, such as tooth agenesis or complete tooth loss, are rarely reported for these patients. Here, we report the case of a 37-year-old female Chinese OI patient who experienced complete tooth loss before puberty. The patient has a family history of OI and her father has a history of tooth loss. She showed obvious OI phenotypes, including a dwarfed stature, blue sclerae, scoliosis, pigeon chest and a history of fractures. Tooth loss began at the age of 6 years and continued until complete tooth loss at 20 years; this occurred in the absence of dental decay, gum disease, accidents or drug usage. Radiological studies revealed osteoporosis of the lower limbs and an underdeveloped scapula. Type I collagen gene analysis identified a known c.2314G>A (p.Gly772Ser) substitution in the COL1A2 gene, which we suggest affects the interaction between type I collagen and extracellular matrix proteins, including cartilage oligomeric matrix protein, phosphophoryn and SPARC (secreted protein acidic and rich in cysteine). In silico prediction indicated a relatively mild effect of the mutation, so it is conceivable that the severity of the clinical phenotype may result from additional mutations in candidate genes responsible for abnormal dental phenotypes in this family. To our knowledge, this is the first report of an OI patient with a phenotype of complete tooth loss at a young age. PMID:23934635

  18. A rare presentation of a child with osteogenesis imperfecta and congenital laryngomalacia for herniotomy

    PubMed Central

    Chandran, Roshith; Dave, Nandini; Padvi, Amit; Garasia, Madhu

    2011-01-01

    Sometimes anaesthesiologists come across rare congenital anomalies in their practice. The inherent complications associated with the disorder necessitate tailor-made approaches for providing anaesthesia to even seemingly simple surgical interventions. Here, we share our experience of anaesthesia management of an infant with congenital laryngomalacia and recently diagnosed osteogenesis imperfecta type 1 who had presented to us with an acute abdomen for a semi-emergency herniotomy. PMID:22174477

  19. A rare presentation of a child with osteogenesis imperfecta and congenital laryngomalacia for herniotomy.

    PubMed

    Chandran, Roshith; Dave, Nandini; Padvi, Amit; Garasia, Madhu

    2011-09-01

    Sometimes anaesthesiologists come across rare congenital anomalies in their practice. The inherent complications associated with the disorder necessitate tailor-made approaches for providing anaesthesia to even seemingly simple surgical interventions. Here, we share our experience of anaesthesia management of an infant with congenital laryngomalacia and recently diagnosed osteogenesis imperfecta type 1 who had presented to us with an acute abdomen for a semi-emergency herniotomy. PMID:22174477

  20. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients

    PubMed Central

    Ríos-Rodenas, Mercedes; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-01-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID:25810828

  1. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients.

    PubMed

    Ríos-Rodenas, Mercedes; de Nova, Joaquín; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-02-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID:25810828

  2. Effect of osteogenesis imperfecta mutations in tropocollagen molecule on strength of biomimetic tropocollagen-hydroxyapatite nanocomposites

    NASA Astrophysics Data System (ADS)

    Dubey, Devendra K.; Tomar, Vikas

    2010-01-01

    Osteogenesis Imperfecta (OI) is a genetic disorder that affects cellular synthesis of Type-I collagen fibrils and causes extreme bone fragility. This study reports the effects of OI mutations in Tropocollagen (TC) molecules on strength of model Tropocollagen-Hydroxyapatite biomaterials with two different mineral [hydroxyapatite (HAP)] distributions using three dimensional atomistic simulations. Results show that the effect of TC mutations on the strength of TC-HAP biomaterials is insignificant. Instead, change in mineral distribution showed significant impact on the overall strength of TC-HAP biomaterials. Study suggests that TC mutations manifest themselves by changing the mineral distribution during hydroxyapatite growth and nucleation period.

  3. Surgical technique of double valve replacement in a patient with osteogenesis imperfecta.

    PubMed

    Sumi, Mizuki; Ariyoshi, Tsuneo; Matsukuma, Seiji; Nakaji, Shun; Hashizume, Koji; Kinoshita, Naoe; Eishi, Kiyoyuki

    2016-04-01

    Osteogenesis imperfecta (OI) is an inherited connective tissue disorder. Left ventricle dilation and valve insufficiency are complications in patients with OI and such patients are at high risk of mortality and complications related to bleeding and tissue friability during cardiac surgery. Valve dehiscence due to extreme friability of the annulus is a major complication of cardiac valve replacement with OI. We describe OI in a male patient who underwent double valve replacement with mechanical valves using a tissue protective method to prevent valve dehiscence. PMID:25028093

  4. The role of dual energy x-ray absorptiometry in aiding the diagnosis of pediatric osteogenesis imperfecta.

    PubMed

    Moore, M S; Minch, C M; Kruse, R W; Harcke, H T; Jacobson, L; Taylor, A

    1998-12-01

    The role of dual energy x-ray absorptiometry (DEXA) in the evaluation of the pediatric patient with multiple fractures has not been well established. We retrospectively examined the medical records of 45 patients who had presented to our institution with multiple fractures of unknown cause, who were not known to have osteogenesis imperfecta, and who had obtained DEXA as part of their evaluation. Of these, 26 patients had sufficient clinical data for inclusion in this study. Patients underwent DEXA of the anteroposterior spine and whole body. A z score was calculated to normalize the DEXA values for age. The diagnosis of osteogenesis imperfecta was correlated with the outcome of each DEXA scan to assess the validity of DEXA as a diagnostic tool. The DEXA of the anteroposterior spine had the highest sensitivity at 91.7%, while DEXA of the whole body had the highest specificity at 100.0%. Decreased bone mineral density may be associated with osteogenesis imperfecta, and DEXA is helpful in detecting low bone mineral density that may be missed on plain radiographs of children with milder forms of osteogenesis imperfecta. PMID:9880097

  5. Investigation of the Human Disease Osteogenesis Imperfecta: A Research-Based Introduction to Concepts and Skills in Biomolecular Analysis

    ERIC Educational Resources Information Center

    Mate, Karen; Sim, Alistair; Weidenhofer, Judith; Milward, Liz; Scott, Judith

    2013-01-01

    A blended approach encompassing problem-based learning (PBL) and structured inquiry was used in this laboratory exercise based on the congenital disease Osteogenesis imperfecta (OI), to introduce commonly used techniques in biomolecular analysis within a clinical context. During a series of PBL sessions students were presented with several…

  6. Bulbous epiphysis and popcorn calcification as related to growth plate differentiation in osteogenesis imperfecta

    PubMed Central

    Brizola, Evelise; McCarthy, Edward; Shapiro, Jay Robert

    2015-01-01

    Summary Background Osteogenesis Imperfecta (OI) is an heritable systemic disorder of connective tissue due to different sequence variants in genes affecting both the synthesis of type I collagen and osteoblast function. Dominant and recessive inheritance is recognized. Approximately 90% of the OI cases are due to mutations in COL1A1/A2 genes. We clinically and radiologically describes an adult male with type III osteogenesis imperfecta who presents a rare bone dysplasia termed bulbous epiphyseal deformity in association with popcorn calcifications. Popcorn calcifications may occur with bulbous epiphyseal deformity or independently. Methods Molecular analysis was performed for COL1A1, COL1A2, LEPRE1 and WNT1 genes. Results An uncommon COL1A1 mutation was identified. Clinical and radiological exams confirmed a distinctive bulbous epiphyseal deformity with popcorn calcifications in distal femurs. We have identified four additional OI patients reported in current literature, whose X-rays show bulbous epiphyseal deformity related to mutations in CR-TAP, LEPRE1 and WNT1 genes. Conclusion The mutation identified here had been previously described twice in OI patients and no previous correlation with bulbous epiphyseal deformity was described. The occurrence of this bone dysplasia focuses attention on alterations in normal growth plate differentiation and the subsequent effect on endochondral bone formation in OI. PMID:26604951

  7. Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice.

    PubMed

    Árvai, Kristóf; Horváth, Péter; Balla, Bernadett; Tobiás, Bálint; Kató, Karina; Kirschner, Gyöngyi; Klujber, Valéria; Lakatos, Péter; Kósa, János P

    2016-01-01

    Next generation sequencing (NGS) is a rapidly developing area in genetics. Utilizing this technology in the management of disorders with complex genetic background and not recurrent mutation hot spots can be extremely useful. In this study, we applied NGS, namely semiconductor sequencing to determine the most significant osteogenesis imperfecta-related genetic variants in the clinical practice. We selected genes coding collagen type I alpha-1 and-2 (COL1A1, COL1A2) which are responsible for more than 90% of all cases. CRTAP and LEPRE1/P3H1 genes involved in the background of the recessive forms with relatively high frequency (type VII and VIII) represent less than 10% of the disease. In our six patients (1-41 years), we identified 23 different variants. We found a total of 14 single nucleotide variants (SNV) in COL1A1 and COL1A2, 5 in CRTAP and 4 in LEPRE1. Two novel and two already well-established pathogenic SNVs have been identified. Among the newly recognized mutations, one results in an amino acid change and one of them is a stop codon. We have shown that a new full-scale cost-effective NGS method can be developed and utilized to supplement diagnostic process of osteogenesis imperfecta with molecular genetic data in clinical practice. PMID:27335225

  8. Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice

    PubMed Central

    Árvai, Kristóf; Horváth, Péter; Balla, Bernadett; Tobiás, Bálint; Kató, Karina; Kirschner, Gyöngyi; Klujber, Valéria; Lakatos, Péter; Kósa, János P.

    2016-01-01

    Next generation sequencing (NGS) is a rapidly developing area in genetics. Utilizing this technology in the management of disorders with complex genetic background and not recurrent mutation hot spots can be extremely useful. In this study, we applied NGS, namely semiconductor sequencing to determine the most significant osteogenesis imperfecta-related genetic variants in the clinical practice. We selected genes coding collagen type I alpha-1 and-2 (COL1A1, COL1A2) which are responsible for more than 90% of all cases. CRTAP and LEPRE1/P3H1 genes involved in the background of the recessive forms with relatively high frequency (type VII and VIII) represent less than 10% of the disease. In our six patients (1–41 years), we identified 23 different variants. We found a total of 14 single nucleotide variants (SNV) in COL1A1 and COL1A2, 5 in CRTAP and 4 in LEPRE1. Two novel and two already well-established pathogenic SNVs have been identified. Among the newly recognized mutations, one results in an amino acid change and one of them is a stop codon. We have shown that a new full-scale cost-effective NGS method can be developed and utilized to supplement diagnostic process of osteogenesis imperfecta with molecular genetic data in clinical practice. PMID:27335225

  9. How tough is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone††

    PubMed Central

    Carriero, A.; Zimmermann, E. A.; Paluszny, A.; Tang, S. Y.; Bale, H.; Busse, B.; Alliston, T.; Kazakia, G.

    2015-01-01

    The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level we attribute the loss in toughness to a decrease in the stabilizing enzymatic crosslinks and an increase in non-enzymatic crosslinks, which may break prematurely inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales. PMID:24420672

  10. Bone tissue ultrastructural defects in a mouse model for osteogenesis imperfecta: a Raman spectroscopy study

    NASA Astrophysics Data System (ADS)

    Chen, Tsoching; Kozloff, Kenneth M.; Goldstein, Steven A.; Morris, Michael D.

    2004-07-01

    Osteogenesis imperfecta (OI) is genetic defect in which the genes that code for the α1(I) or α2(I) chains of type I collagen are defective. The defects often result in substitution of a bulky amino acid for glycine, causing formation of collagen that can not form the normal triple helix. Depending on the details of the defects, the outcomes range from controllable to lethal. This study focuses on OI type IV, a more common and moderately severe form of the disease. People with the disease have a substantial increase in the risk and rate of fracture. We examine the spectroscopic consequences of these defects, using a mouse model (BRTL) that mimics OI type IV. We compare Raman images from tibial cortical tissue of wild-type mice and BRTL mice with single copy of mutation and show that both mineral to matrix ratios and collagen inter-fibril cross-links are different in wild-type and mutant mice.

  11. Osteogenesis Imperfecta Diagnosed from Mandibular and Lower Limb Fractures: A Case Report.

    PubMed

    Kobayashi, Yoshikazu; Satoh, Koji; Mizutani, Hideki

    2016-06-01

    Osteogenesis imperfecta (OI) is a congenital disease characterized by bone fragility and low bone mass. Despite the variety of its manifestation and severity, facial fractures occur very infrequently. Here, we report a case of an infant diagnosed with OI after mandibular and lower limb fractures. A boy aged 1 year and 3 months was brought to his neighboring hospital with a complaint of facial injury. He was transferred to our hospital to undergo operation 3 days later. Computed tomography images revealed multiple mandibular fractures including complete fracture in the symphysis and dislocated condylar fracture on the right side. Open reduction and internal fixation with absorbable implants was performed 7 days after injury. He fractured his right lower limb 2 months later. He was diagnosed with OI type IA by an orthopedist. He will be administered bone-modifying agents if he suffers from frequent fractures. PMID:27162570

  12. Osteogenesis imperfecta type III in South Africa: Psychosocial challenges.

    PubMed

    Stephen, L X G; Roberts, T; Van Hayden, E; Chetty, M

    2016-01-01

    Individuals with osteogenesis imperfecta type III (OI III) are severely physically disabled due to frequent fracturing. Their disability poses numerous barriers that challenge their social development. Despite these limitations, several affected persons are able to rise above these problems and achieve success in their personal and professional life. This outcome is directly relevant to their psychosocial development.The achievements of five individuals with OI III living in Cape Town are highlighted in this article, as well as the challenges that they have experienced and continue to experience in their daily lives. The authors intend to promulgate understanding of the psychosocial circumstances of affected persons, thereby facilitating the deployment of appropriate efforts and resources to address these challenges. PMID:27245537

  13. [Sliding centro-medullary nailing. Application to the treatment of severe forms of osteogenesis imperfecta].

    PubMed

    Metaizeau, J P

    1987-01-01

    In osteogenesis Imperfecta, the bowing of bones concures to increase their fragility. In order to avoid bowing of bones, Sofield, followed by Bailey have proposed centro medullary nailing. The pins used by Sofield do not expand and repeated changes are necessary. The expanding rods used by Bailey are to large and they can't be used in neonates. The author describe a new technique of bipolar centro medullary pinning. Two bowed K. Wires are introduced in the centromedullary canal, the first one through the proximal epiphysis, the second one through the distal epiphysis. During growth, each pin migrates distally and the osteosynthesis expand regularly. The technique can be used in the neonates and protects their bone from progressive bowing. PMID:3442930

  14. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.

    PubMed

    Lindert, Uschi; Cabral, Wayne A; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N; Janecke, Andreas R; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  15. Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.

    PubMed

    Cho, Sung Yoon; Asharani, P V; Kim, Ok-Hwa; Iida, Aritoshi; Miyake, Noriko; Matsumoto, Naomichi; Nishimura, Gen; Ki, Chang-Seok; Hong, Geehay; Kim, Su Jin; Sohn, Young Bae; Park, Sung Won; Lee, Jieun; Kwun, Younghee; Carney, Thomas J; Huh, Rimm; Ikegawa, Shiro; Jin, Dong-Kyu

    2015-02-01

    Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay. PMID:25402547

  16. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

    PubMed Central

    Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  17. Osteogenesis imperfecta: determining the demographics and the predictors of death from an inpatient population.

    PubMed

    Vitale, Michael G; Matsumoto, Hiroko; Kessler, Michael W; Hoffmann, William; Roye, David P

    2007-03-01

    Osteogenesis imperfecta is a heritable disease that may result in bone fragility, increased joint laxity, decreased muscle tone, thinning of the skin, a bluish appearance of the sclerae, and scoliosis in as many as 60% of cases. The purpose of this study was to examine the impact of patient and hospital characteristics on mortality rate during inpatient stays. Data was collected retrospectively from the Healthcare Cost and Utilization Project Kids' Inpatient Database, a resource designed to analyze pediatric hospital usage. Data were collected from 1793 patients in the 27 states. Overall, 3% of this population died during hospitalization. Self-pay patients, patients in hospitals with small bed sizes, patients in non pediatric hospitals, and younger patients all had higher mortality rates than did their counterparts. In addition, black patients were 3.7 times more likely to die than did patients of any other race, and women were more likely to die than did men, although more than half of the number of patients were classified as white and 52% were men. Although these trends suggest that the mortality of younger patients may be reduced by admittance to children's hospitals, the children who are hospitalized younger tend to have more severe forms of the disease and are therefore more deformed and more difficult to treat. Overall, the results of this study indicate that children with osteogenesis imperfecta who need hospitalization may benefit from being referred to a large children's hospital, and that there is further research needed into the significant differences in the mortality of black patients and female patients. PMID:17314652

  18. Increased intra-cortical porosity reduces bone stiffness and strength in pediatric patients with osteogenesis imperfecta.

    PubMed

    Vardakastani, V; Saletti, D; Skalli, W; Marry, P; Allain, J M; Adam, C

    2014-12-01

    Osteogenesis imperfecta (OI) is a heritable disease occurring in one out of every 20,000 births. Although it is known that Type I collagen mutation in OI leads to increased bone fragility, the mechanism of this increased susceptibility to fracture is not clear. The aim of this study was to assess the microstructure of cortical bone fragments from patients with osteogenesis imperfecta (OI) using polarized light microscopy, and to correlate microstructural observations with the results of previously performed mechanical compression tests on bone from the same source. Specimens of cortical bone were harvested from the lower limbs of three (3) OI patients at the time of surgery, and were divided into two groups. Group 1 had been subjected to previous micro-mechanical compression testing, while Group 2 had not been subjected to any prior testing. Polarized light microscopy revealed disorganized bone collagen architecture as has been previously observed, as well as a large increase in the areal porosity of the bone compared to typical values for healthy cortical bone, with large (several hundred micron sized), asymmetrical pores. Importantly, the areal porosity of the OI bone samples in Group 1 appears to correlate strongly with their previously measured apparent Young's modulus and compressive strength. Taken together with prior nanoindentation studies on OI bone tissue, the results of this study suggest that increased intra-cortical porosity is responsible for the reduction in macroscopic mechanical properties of OI cortical bone, and therefore that in vivo imaging modalities with resolutions of ~100 μm or less could potentially be used to non-invasively assess bone strength in OI patients. Although the number of subjects in this study is small, these results highlight the importance of further studies in OI bone by groups with access to human OI tissue in order to clarify the relationship between increased porosity and reduced macroscopic mechanical integrity. PMID

  19. Mutations in FKBP10 Cause Recessive Osteogenesis Imperfecta and Bruck Syndrome

    PubMed Central

    Kelley, Brian P; Malfait, Fransiska; Bonafe, Luisa; Baldridge, Dustin; Homan, Erica; Symoens, Sofie; Willaert, Andy; Elcioglu, Nursel; Van Maldergem, Lionel; Verellen-Dumoulin, Christine; Gillerot, Yves; Napierala, Dobrawa; Krakow, Deborah; Beighton, Peter; Superti-Furga, Andrea; De Paepe, Anne; Lee, Brendan

    2011-01-01

    Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research. PMID:20839288

  20. COL1A1 mutation analysis in Lithuanian patients with osteogenesis imperfecta.

    PubMed

    Benusiené, Egle; Kucinskas, Vaidutis

    2003-01-01

    Osteogenesis imperfecta (OI) is a generalised disorder of connective tissue characterised by an increased fragility of bones and also manifested in other tissues containing collagen type I, by blue sclera, hearing loss, dentinogenesis imperfecta, hyperextensible joints, hernias and easy bruising. OI is dominantly inherited and results in >90% OI cases, caused by mutations in one of the two genes COL1A1 or COL1A2 coding for type I procollagen. The Lithuanian OI database comprises 147 case records covering the period of 1980 - 2001. Clinical and genealogical analysis of OI cases/families from Lithuania available for examination revealed 18 familial cases of OI type I and 22 sporadic cases: OI type II (3 cases), OI type III (11 cases) and OI type I (8 cases). As a result of their molecular genetic investigation, 11 mutations were identified in the COL1A1 gene in 13 unrelated patients. Of them, nine mutations (E500X, G481A, c.2046insCTCTCTAG, c.1668delT, c.1667insC, c.4337insC, IVS19+1G > A, IVS20-2A > G, IVS22-1G > T) appeared to be novel, i.e. not yet registered in the Human Type I and Type III Collagen Mutations Database (http://www.le.ac.uk/genetics/collagen). PMID:12590186

  1. Craniofacial and Dental Defects in the Col1a1Jrt/+ Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Eimar, H; Tamimi, F; Retrouvey, J-M; Rauch, F; Aubin, J E; McKee, M D

    2016-07-01

    Certain mutations in the COL1A1 and COL1A2 genes produce clinical symptoms of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) that include abnormal craniofacial growth, dental malocclusion, and dentinogenesis imperfecta. A mouse model (Col1a1(Jrt)/+) was recently developed that had a skeletal phenotype and other features consistent with moderate-to-severe OI and also with EDS. The craniofacial phenotype of 4- and 20-wk-old Col1a1(Jrt)/+ mice and wild-type littermates was assessed by micro-computed tomography (µCT) and morphometry. Teeth and the periodontal ligament compartment were analyzed by µCT, light microscopy/histomorphometry, and electron microscopy. Over time, at 20 wk, Col1a1(Jrt)/+ mice developed smaller heads, a shortened anterior cranial base, class III occlusion, and a mandibular side shift with shorter morphology in the masticatory region (maxilla and mandible). Col1a1(Jrt)/+ mice also had changes in the periodontal compartment and abnormalities in the dentin matrix and mineralization. These findings validate Col1a1(Jrt)/+ mice as a model for OI and EDS in humans. PMID:26951553

  2. Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms

    PubMed Central

    Thiele, Frank; Cohrs, Christian M.; Flor, Armando; Lisse, Thomas S.; Przemeck, Gerhard K. H.; Horsch, Marion; Schrewe, Anja; Gailus-Durner, Valerie; Ivandic, Boris; Katus, Hugo A.; Wurst, Wolfgang; Reisenberg, Catherine; Chaney, Hollis; Fuchs, Helmut; Hans, Wolfgang; Beckers, Johannes; Marini, Joan C.; Hrabé de Angelis, Martin

    2012-01-01

    Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings such as cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and, especially, cardiac fibroblast of perinatal lethal Aga2/+ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in a loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue support a bone-independent vicious cycle of heart dysfunction, including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline in pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on the heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients. PMID:22589248

  3. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with osteogenesis imperfecta.

    PubMed

    Albert, Carolyne; Jameson, John; Smith, Peter; Harris, Gerald

    2014-09-01

    Osteogenesis imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64-68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3 and 42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (P≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight toward understanding bone fragility and the role of intracortical porosity on the strength of bone

  4. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with Osteogenesis Imperfecta

    PubMed Central

    Jameson, John; Smith, Peter; Harris, Gerald

    2015-01-01

    Osteogenesis Imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64–68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3–42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (p≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight towards understanding bone fragility and the role of intracortical porosity on the strength of bone

  5. Osteogenesis imperfecta

    MedlinePlus

    ... baby has the condition. However, because so many different mutations can cause OI, some forms cannot be diagnosed with a genetic test. The severe form of type II OI can be seen on ultrasound when the fetus is as young as 16 weeks.

  6. Osteogenesis imperfecta

    MedlinePlus

    ... defect in the gene that produces type 1 collagen, an important building block of bone. There are ... fractures Early hearing loss ( deafness ) Because type I collagen is also found in ligaments, people with OI ...

  7. Burnei’s technique of femoral neck variation and valgisation by using the intramedullary rod in Osteogenesis imperfecta

    PubMed Central

    Georgescu, I; Gavriliu, Șt; Nepaliuc, I; Munteanu, L; Țiripa, I; Ghiță, R; Japie, E; Hamei, S; Dughilă, C; Macadon, M

    2014-01-01

    Background: Varus or valgus deviations of the femoral neck in osteogenesis imperfecta have been an ignored chapter because the classic correction procedures were applied in medical practice with unsatisfying results. Until the use of telescopic rods, coronal deviations remained unsolved and the distal configuration of the proximal femoral extremity remained uncorrected or partially corrected, which required an extensive use of the wheel chair or bed immobilization of the patient. The concomitant correction of the complex deformities, coxa vara/valga and femoral integrated configuration, have been a progress which allowed the patients to walk with or without support. Purpose: The purpose of this study is to present the Burnei’s technique, a therapeutic alternative in deformity corrections of the varus or valgus hip in children with osteogenesis imperfecta. Study design: The paper is about a retrospective study done in a single center, which analyses Burnei technique and other procedures described in literature. Patient sample: The content of the article is based on a 12 years experience on a batch of 51 patients with osteogenesis imperfecta from which 10 patients (13 hips) presented frontal plane deviations of the femoral neck. Outcome measures: All the patients with osteogenesis imperfecta who presented coxa vara or valga were submitted to investigations with the purpose of measuring blood loss, the possibility of extending the surgical intervention to the leg, the association of severe deformities of the proximal extremity of the femur and the necessity of postoperative intensive care. Burnei’s technique: The operation was first performed in 2002. A subtrochanteric osteotomy was made in an oblique cut, from the internal side to the external side and from proximal to distal for coxa vara, or by using a cuneiform resection associated with muscular disinsertions. Only telescopic rods were used for osteosynthesis. Discussions: There are a few articles in

  8. AB069. Effect of osteogenesis imperfecta on children and their families

    PubMed Central

    Dung, Vu Chi; Armstrong, Kate; Ngoc, Can Thi Bich; Thao, Bui Phuong; Khanh, Nguyen Ngoc; Trang, Nguyen Thu; Hoan, Nguyen Thi; Dat, Nguyen Phu; Munns, Craig

    2015-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder, with features that include increased bone fragility, pathological fractures, blue sclera, dentinogenesis imperfecta and conductive or mixed hearing loss. Clinical variability is wide from children with few fractures and normal stature to children with multiple fractures, long bone deformity, scoliosis and extreme short stature. Although there is no curative treatment, there are several therapeutic tools capable of improving the course of the condition and patient quality of life. We aim to evaluate the effect of OI on the well-being of children with the disorder and their families through a family-centered questionnaire. Sixty children with OI from the Vietnam National Hospital of Pediatrics and/or their parent(s), who attended the first annual family support group in 2011, completed a child and parent questionnaire. Sixty patients participated, 26 female and 34 male. The median age was 6.0 years [interquartile range (IQR), 0.25-18 years]. Of these, 36 (60%) had dentinogenesis imperfect and 23 (38.3%) had a scoliosis. The median number of fractures was 6.0 (IQR 0-30) and median number of hospitalizations due to OI was 5.0 (IQR 0-30). Among patients of school age, 9 (15%) could not go to school due to OI. Almost all parents (93.7%) worried about school social communication of the patients. Among these parents, 100% fear of inferiority with friends and 98.3% fear of broken bones. Most parents (76.2%) were significantly concerned about their child’s health. The parents’ themselves reported psychological concerns, with feelings of desperation (58.4%), anxiety (81.7%) and depression (56.7%). OI appeared to have a significant deleterious effect on the life of the patients and their families. These data provide a baseline from which to evaluate the effectiveness of interventions to improve the medical and psychological needs of this cohort and their families.

  9. Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

    PubMed Central

    Brooks, Peter; Marcaillou, Charles; Vanpeene, Maud; Saraiva, Jean-Paul; Stockholm, Daniel; Francke, Stephan; Favis, Reyna; Cohen, Nadine; Rousseau, Francis; Tores, Frédéric; Lindenbaum, Pierre; Hager, Jörg; Philippi, Anne

    2009-01-01

    Background The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI. Results We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis. Conclusion Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing. PMID:19331686

  10. Homozygous sequence variants in the FKBP10 gene underlie osteogenesis imperfecta in consanguineous families.

    PubMed

    Umair, Muhammad; Hassan, Annum; Jan, Abid; Ahmad, Farooq; Imran, Muhammad; Samman, Muhammad I; Basit, Sulman; Ahmad, Wasim

    2016-03-01

    Osteogenesis imperfecta (OI, MIM 610968) is a genetically and clinically heterogeneous disorder characterized by bone fragility. It is one of the rare forms of skeletal deformity caused by sequence variants in at least 14 different genes, including FKBP10 (MIM 607063) encoding protein FKBP65. Here we present three consanguineous families of Pakistani origin segregating OI in an autosomal-recessive pattern. Genotyping using either single-nucleotide polymorphism markers by Affymetrix GeneChip Human Mapping 250K Nsp array or polymorphic microsatellite markers revealed a homozygous region, containing a candidate gene FKBP10, among affected members on chromosome 17q21.2. Sequencing the FKBP10 gene revealed a homozygous novel nonsense variant (c.1490G>A, p.Trp497*) in the family A and two previously reported variants, including a missense (c.344G>A, p.Arg115Gln), in the family B and duplication of a nucleotide C (c.831dupC, p.Gly278ArgfsX295) in the family C. Our findings further extend the body of evidence that supports the importance of FKBP10 gene in the development of skeletal system. PMID:26538303

  11. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix

    PubMed Central

    Valli, M; Barnes, AM; Gallanti, A; Cabral, WA; Viglio, S; Weis, MA; Makareeva, E; Eyre, D; Leikin, S; Antoniazzi, F; Marini, JC; Mottes, M

    2013-01-01

    Deficiency of any component of the ER-resident collagen prolyl 3-hydroxylation complex causes recessive osteogenesis imperfecta (OI). The complex modifies the α1(I)Pro986 residue and contains cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (CyPB). Fibroblasts normally secrete about 10% of CRTAP. Most CRTAP mutations cause a null allele and lethal type VII OI. We identified a 7-year-old Egyptian boy with non-lethal type VII OI and investigated the effects of his null CRTAP mutation on collagen biochemistry, the prolyl 3-hydroxylation complex, and collagen in extracellular matrix. The proband is homozygous for an insertion/deletion in CRTAP (c.118_133del16insTACCC). His dermal fibroblasts synthesize fully overmodified type I collagen, and 3-hydroxylate only 5% of α1(I)Pro986. CRTAP transcripts are 10% of control. CRTAP protein is absent from proband cells, with residual P3H1 and normal CyPB levels. Dermal collagen fibril diameters are significantly increased. By immunofluorescence of long-term cultures, we identified a severe deficiency (10–15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborate deficiency of matrix deposition, rather than increased matrix turnover. We conclude that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of type VII OI. PMID:21955071

  12. Muscle force sensitivity of a finite element fracture risk assessment model in osteogenesis imperfecta - biomed 2009.

    PubMed

    Fritz, Jessica M; Guan, Yabo; Wang, Mei; Smith, Peter A; Harris, Geald F

    2009-01-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder characterized by skeletal deformities and increased bone fragility. There is currently no established clinical method for quantifying fracture risk in OI patients. A method for developing a finite element model of the femur to assist in fracture risk assessment of a selected patient with OI type I was created. The material properties were based on nanoindentation testing of OI bone specimens collected during routine surgery. Dynamic data from clinical gait analysis was used to prescribe joint reaction forces and moments in a quasi-static model. Muscle forces were prescribed according to current literature. Von Mises stresses were analyzed across all seven phases of the gait cycle and analyzed for sensitivity to changes in muscle forces. The model showed that the patient with OI was not at current risk for fracture during normal gait. The highest stress levels occurred during mid stance and loading response. Maximum von Mises stresses were most sensitive to the gluteal muscles. Insight provided by the model may be useful for similar clinical applications, more refined model development and an improved ability for fracture prediction. PMID:19369782

  13. Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report

    PubMed Central

    D’Eufemia, Patrizia; Palombaro, Marta; Lodato, Valentina; Zambrano, Anna; Celli, Mauro; Persiani, Pietro; De Bari, Maria Pia; Sangiorgi, Luca

    2012-01-01

    Summary Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns. The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities’ attention as a suspected child abuse. However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI. Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture. In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI. PMID:23289038

  14. Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report.

    PubMed

    D'Eufemia, Patrizia; Palombaro, Marta; Lodato, Valentina; Zambrano, Anna; Celli, Mauro; Persiani, Pietro; De Bari, Maria Pia; Sangiorgi, Luca

    2012-09-01

    Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns.The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities' attention as a suspected child abuse.However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI.Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture.In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI. PMID:23289038

  15. Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging

    PubMed Central

    Carter, Erin M.; Lin, Ping-Chang; Pleshko, Nancy; Raggio, Cathleen L.; Spencer, Richard G.

    2016-01-01

    The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T1, T2, km, MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T2 and km. These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI. PMID:27416032

  16. Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model.

    PubMed

    Andriotis, O G; Chang, S W; Vanleene, M; Howarth, P H; Davies, D E; Shefelbine, S J; Buehler, M J; Thurner, P J

    2015-10-01

    The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry. PMID:26468064

  17. The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI.

    PubMed

    Al-Jallad, Hadil; Palomo, Telma; Roughley, Peter; Glorieux, Francis H; McKee, Marc D; Moffatt, Pierre; Rauch, Frank

    2015-07-01

    Osteogenesis imperfecta type VI is caused by mutations in SERPINF1, which codes for pigment-epithelium derived factor (PEDF). Most of the reported SERPINF1 mutations lead to premature termination codons, but three in-frame insertion or deletion mutations have also been reported. It is not clear how such in-frame mutations lead to OI type VI. In the present study we therefore investigated how SERPINF1 in-frame mutations affect the intracellular localization and secretion of PEDF. Skin fibroblasts affected by SERPINF1 in-frame mutations transcribed SERPINF1 at slightly reduced levels but secretion of PEDF was markedly diminished. Two deletions (p.F277del and the deletion of SERPINF1 exon 5) were associated with retention of PEDF in the endoplasmic reticulum and a stress response in osteoblastic cells. A recurrent in-frame duplication of three amino acids (p.Ala91_Ser93dup) appeared to lead to intracellular degradation but no retention in the endoplasmic reticulum or stress response. Immunofluorescence imaging in transiently transfected osteoblastic MC3T3-E1 cells suggested that PEDF affected by in-frame mutations was not transported along the secretory pathway. MC3T3-E1 osteoblasts stably overexpressing SERPINF1 with the p.Ala91_Ser93dup mutation had decreased collagen type I deposition and mineralization. Thus, the assessed homozygous in-frame deletions or insertions lead to retention or degradation within cellular compartments and thereby interfere with PEDF secretion. PMID:25868797

  18. Structure–mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model

    PubMed Central

    Andriotis, O. G.; Chang, S. W.; Vanleene, M.; Howarth, P. H.; Davies, D. E.; Shefelbine, S. J.; Buehler, M. J.; Thurner, P. J.

    2015-01-01

    The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry. PMID:26468064

  19. Microstructural and Photoacoustic Infrared Spectroscopic Studies of Human Cortical Bone with Osteogenesis Imperfecta

    NASA Astrophysics Data System (ADS)

    Gu, Chunju; Katti, Dinesh R.; Katti, Kalpana S.

    2016-04-01

    The molecular basis of bone disease osteogenesis imperfecta (OI) and the mineralization of hydroxyapatite in OI bone have been of significant research interest. To further investigate the mechanism of OI disease and bone mineralization, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, and x-ray diffraction (XRD) are used in the present study to describe the structural and compositional differences between OI and healthy bone. OI bone exhibits more porous, fibrous features, abnormal collagen fibrils, and abnormal mineral deposits. Likewise, photoacoustic-FTIR experiments indicate an aberrant collagen structure and an altered mineral structure in OI. In contrast, there is neither significant difference in the non-collagenous proteins (NCPs) composition observed nor apparent change in the crystal structure between OI and healthy bone minerals as shown in XRD and energy-dispersive x-ray spectroscopy (EDS) results. This observation indicates that the biomineralization process is more controlled by the bone cells and non-collagenous phosphorylated proteins. The present study also confirms that there is an orientational influence on the stoichiometry of the mineral in OI bone. Also, a larger volume of the hydrated layer in the transverse plane than the longitudinal plane of the mineral crystal structure is proposed. The appearance of a new C-S band in the FTIR spectra in OI bone suggests the substitution of glycine by cysteine in collagen molecules or/and an increased amount of cysteine-rich osteonectin that relates to mineral nucleation and mineral crystal formation.

  20. Gait characteristics and functional assessment of children with type I osteogenesis imperfecta.

    PubMed

    Graf, Adam; Hassani, Sahar; Krzak, Joseph; Caudill, Angela; Flanagan, Ann; Bajorunaite, Ruta; Harris, Gerald; Smith, Peter

    2009-09-01

    The purpose of this study was to improve the evaluation process of children with type I Osteogenesis Imperfecta (OI) by providing a quantitative comparison of gait and selected functional assessments to age-matched controls. A 14-camera Vicon Motion Analysis System was used for gait analysis along with selected functional assessments (Pediatric Outcomes Data Collection Instrument [PODCI], Functional Assessment Questionnaire [FAQ], Faces Pain Scale-Revised [FPS-R]) conducted on 10 subjects with type I OI and 22 age-matched healthy controls. The results of the OI group demonstrated abnormal gait parameters including increased double support, delayed foot off, reduced ankle range of motion and plantarflexion during third rocker, along with greater ankle power absorption during terminal stance and reduced ankle power generation during push off. The functional assessment scores of the OI group were similar to the control group for basic mobility and function, but were lower than their peers in the sports and physical function category. The evaluation of individuals with OI by means of gait analysis and selected functional assessments, along with an accurate biomechanical model of the lower extremities, is proposed to better understand and predict OI disability and improve quality of life. PMID:19242979

  1. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations.

    PubMed

    Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming; Bertin, Terry K; Chen, Yuqing; Abraham, Annie M; Ding, Hao; Bi, Xiaohong; Ambrose, Catherine G; Lee, Brendan H

    2014-08-01

    Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1(sw/sw)) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1(sw/sw) mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations. PMID:24634143

  2. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations

    PubMed Central

    Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming; Bertin, Terry K.; Chen, Yuqing; Abraham, Annie M.; Ding, Hao; Bi, Xiaohong; Ambrose, Catherine G.; Lee, Brendan H.

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1sw/sw) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1sw/sw mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1sw/sw mouse is a murine model of OI caused by WNT1 mutations. PMID:24634143

  3. Quantitative changes in human epithelial cancers and osteogenesis imperfecta disease detected using nonlinear multicontrast microscopy

    NASA Astrophysics Data System (ADS)

    Adur, Javier; Pelegati, Vitor B.; de Thomaz, Andre A.; D'Souza-Li, Lilia; Assunção, Maria do Carmo; Bottcher-Luiz, Fátima; Andrade, Liliana A. L. A.; Cesar, Carlos L.

    2012-08-01

    We show that combined multimodal nonlinear optical (NLO) microscopies, including two-photon excitation fluorescence, second-harmonic generation (SHG), third harmonic generation, and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation during the progression of cancer and osteogenesis imperfecta (OI) disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for different types of human breast cancer, mucinous ovarian tumors, and skin dermis of patients with OI. Using a set of scoring methods (anisotropy, correlation, uniformity, entropy, and lifetime components), we found significant differences in the content, distribution and organization of collagen fibrils in the stroma of breast and ovary as well as in the dermis of skin. We suggest that our results provide a framework for using NLO techniques as a clinical diagnostic tool for human cancer and OI. We further suggest that the SHG and FLIM metrics described could be applied to other connective or epithelial tissue disorders that are characterized by abnormal cells proliferation and collagen assembly.

  4. Deep tissue single cell MSC ablation using a fiber laser source to evaluate therapeutic potential in osteogenesis imperfecta

    NASA Astrophysics Data System (ADS)

    Tehrani, Kayvan F.; Pendleton, Emily G.; Lin, Charles P.; Mortensen, Luke J.

    2016-04-01

    Osteogenesis imperfecta (OI) is a currently uncurable disease where a mutation in collagen type I yields brittle bones. One potential therapy is transplantation of mesenchymal stem cells (MSCs), but controlling and enhancing transplanted cell survival has proven challenging. Therefore, we use a 2- photon imaging system to study individual transplanted cells in the living bone marrow. We ablated cells deep in the bone marrow and observed minimal collateral damage to surrounding tissue. Future work will evaluate the local impact of transplanted MSCs on bone deposition in vivo.

  5. [Early use of BiPAP in the management of respiratory failure in an infant with osteogenesis imperfecta: case report].

    PubMed

    Vega-Briceño, Luis; Contreras, Ilse; Sánchez, Ignacio; Bertrand, Pablo

    2004-07-01

    Osteogenesis imperfecta (OI) is an heterogeneous group of genetic disorders that affect connective tissue integrity. Severe forms cause chest deformities, sometimes associated to alveolar hypoventilation. We report a 4 months old infant with OI type III, who developed respiratory failure (RF) due to a bronchiolitis and required mechanical ventilation. Weaning progressed successfully to a nasal bi-level Positive Airway Pressure (n-BiPAP) device. Clinical follow up showed a normal cognitive development and growth. Respiratory condition, blood gases and ventilation status were in normal ranges. Non invasive ventilation, associated to careful monitoring may avoid tracheostomy and its complications in infants with OI. PMID:15379335

  6. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype–phenotype relationships

    PubMed Central

    Bodian, Dale L.; Chan, Ting-Fung; Poon, Annie; Schwarze, Ulrike; Yang, Kathleen; Byers, Peter H.; Kwok, Pui-Yan; Klein, Teri E.

    2009-01-01

    Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype–phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of ∼5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen α1(I) chains predicted lethality with ∼90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes. PMID:18996919

  7. Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.

    PubMed

    Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

    2016-05-01

    Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage-associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1-week-old and 6-week-old Crtap(-/-) mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of "pediatric" and "young adult" recessive OI. Vehicle-treated Crtap(-/-) and wild-type (WT) mice served as controls. Compared with control Crtap(-/-) mice, micro-computed tomography (μCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab-treated Crtap(-/-) mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole-bone strength in Crtap(-/-) mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research. PMID:26716893

  8. Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta.

    PubMed

    Berman, Alycia G; Wallace, Joseph M; Bart, Zachary R; Allen, Matthew R

    2016-01-01

    Osteogenesis imperfecta (OI) is a genetic disease of Type I collagen and collagen-associated pathways that results in brittle bone behavior characterized by fracture and reduced mechanical properties. Based on previous work in our laboratory showing that raloxifene (RAL) can significantly improve bone mechanical properties through non-cellular mechanisms, we hypothesized that raloxifene would improve the mechanical properties of OI bone. In experiment 1, tibiae from female wild type (WT) and homozygous oim mice were subjected to in vitro soaking in RAL followed by mechanical tests. RAL soaking resulted in significantly higher post-yield displacement (+75% in WT, +472% in oim; p<0.004), with no effect on ultimate load or stiffness, in both WT and oim animals. In experiment 2, eight-week old WT and oim male mice were treated for eight weeks with saline vehicle (VEH) or RAL. Endpoint measures included assessment of in vivo skeletal fractures, bone density/geometry and mechanical properties. In vivo skeletal fractures of the femora, assessed by micro CT imaging, were significantly lower in oim-RAL (20%) compared to oim-VEH (48%, p=0.047). RAL led to significantly higher DXA-based BMD (p<0.01) and CT-based trabecular BV/TV in both WT and oim animals compared to those treated with VEH. Fracture toughness of the femora was lower in oim mice compared to WT and improved with RAL in both genotypes. These results suggest that raloxifene reduces the incidence of fracture in this mouse model of oim. Furthermore, they suggest that raloxifene's effects may be the result of both cellular (increased bone mass) and non-cellular (presumably changes in hydration) mechanisms, raising the possibility of using raloxifene, or related compounds, as a new approach for treating bone fragility associated with OI. PMID:26707242

  9. Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Shi, Changgui; Hu, Bo; Guo, Lei; Cao, Peng; Tian, Ye; Ma, Jun; Chen, Yuanyuan; Wu, Huiqiao; Hu, Jinquan; Deng, Lianfu; Zhang, Ying; Yuan, Wen

    2016-05-01

    Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (μCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research. PMID:26679066

  10. Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta

    PubMed Central

    Eyre, David R.; Ann Weis, Mary

    2013-01-01

    Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90% of OI cases. Since then a growing list of mutant genes causing the 5–10% of recessive cases has rapidly emerged. They include CRTAP, LEPRE1 and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode respectively lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPIN H1, which encodes the collagen chaperone HSP47; SERPIN F1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include over-mineralization or under-mineralization defects as well as abnormal collagen post-translational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen. These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen post-translational modification, chaperoning of newly synthesized collagen chains into native molecules or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on post-translational features of bone collagen that have evolved to optimize it as a biomineral template. PMID:23508630

  11. Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice

    PubMed Central

    Muir, Alison M.; Ren, Yinshi; Butz, Delana Hopkins; Davis, Nicholas A.; Blank, Robert D.; Birk, David E.; Lee, Se-Jin; Rowe, David; Feng, Jian Q.; Greenspan, Daniel S.

    2014-01-01

    Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1−/− and Tll1−/− lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures—defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI. PMID:24419319

  12. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

    SciTech Connect

    Orioli, I.M.; Castilla, E.E.; Scarano, G.; Mastroiacovo, P.

    1995-11-06

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC) series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 {plus_minus} 6.74 years in the IPIMC, and 37.19 {plus_minus} 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 {plus_minus} 7.08 years in the IPIMC, and 36.41 {plus_minus} 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 {plus_minus} 9.25 years, but not in the IPIMC, 32.26 {plus_minus} 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area. 28 refs., 1 fig., 6 tabs.

  13. Quality of life in osteogenesis imperfecta: A mixed-methods systematic review.

    PubMed

    Dahan-Oliel, N; Oliel, S; Tsimicalis, A; Montpetit, K; Rauch, F; Dogba, M J

    2016-01-01

    Clinical interventions and research have mostly focused on the orthopedic, genetic, and pharmacological outcomes of individuals with osteogenesis imperfecta (OI), and although quality of life (QoL) has gained recognition as an important patient-outcome, it has received little attention in individuals with OI. This mixed-methods systematic review of the literature included five search engines and identified a total of 212 articles. Once study eligibility was reviewed, 10 studies met the inclusion criteria and were included in this mixed-methods review (9 quantitative and 1 qualitative). Among the 10 included QoL studies, six reported on children with OI, three on adults with OI, and one on the parents of children with OI. Physical QoL in children and adults with OI appears to be less than that of the general population, with individuals with more severe OI types reporting worse QoL. On the other hand, mental and psychosocial QoL is the same or better in individuals with OI than that of the general population. Pain, scoliosis activity limitations and participation restrictions due to decreased function are associated with lower levels of physical QoL. Researchers must agree on a definition of QoL as it relates to OI and use validated measures appropriate for evaluating QoL in OI. Pediatric studies should consider both the child and the parent's QOL perceptions as these may differ. QoL in the adult population should not be dismissed in order to offer proper client-centered interventions throughout the lifespan. PMID:26365089

  14. Allelic background of LEPRE1 mutations that cause recessive forms of osteogenesis imperfecta in different populations

    PubMed Central

    Pepin, Melanie G; Schwarze, Ulrike; Singh, Virendra; Romana, Marc; Jones-LeCointe, Altheia; Byers, Peter H

    2013-01-01

    Biallelic mutations in LEPRE1 result in recessively inherited forms of osteogenesis imperfecta (OI) that are often lethal in the perinatal period. A mutation (c.1080+1G>T, IVS5+1G>T) in African Americans has a carrier frequency of about 1/240. The mutant allele originated in West Africa in tribes of Ghana and Nigeria where the carrier frequencies are 2% and 5%. By examining 200 samples from an African-derived population in Tobago and reviewing hospital neonatal death records, we determined that the carrier frequency of c.1080+1G>T was about one in 200 and did not contribute to the neonatal deaths recorded over a 3-year period of time in Trinidad. In the course of sequence analysis, we found surprisingly high LEPRE1 allelic diversity in the Tobago DNA samples in which there were 11 alleles distinguished by a single basepair variant in or near exon 5. All the alleles found in the Tobago population that were within the sequence analysis region were found in the African American population in the Exome Variant Project. This diversity appeared to reflect the geographic origin of the original population in Tobago. In 44 individuals with biallelic LEPRE1 mutations identified by clinical diagnostic testing, we found the sequence alterations occurred on seven of the 11 variant alleles. All but one of the mutations identified resulted in mRNA or protein instability for the majority of the transcripts from the altered allele. These findings suggest that the milder end of the clinical spectrum could be due to as yet unidentified missense mutations in LEPRE1. PMID:24498616

  15. Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta.

    PubMed

    Balasubramanian, Meena; Cartwright, Ashley; Smith, Kath; Arundel, Paul; Bishop, Nicholas J

    2016-02-01

    We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI. PMID:26471105

  16. Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta

    PubMed Central

    Al-Senaidi, Khalfan S.; Ullah, Irfan; Javad, Hashim; Al-Khabori, Murtadha; Al-Yaarubi, Saif

    2015-01-01

    Objectives: Structural and functional cardiovascular abnormalities have been reported in adults with osteogenesis imperfecta (OI); however, there is a lack of paediatric literature on this topic. This study aimed to investigate cardiovascular abnormalities in children with OI in comparison to a control group. Methods: This case-control study was conducted at the Sultan Qaboos University Hospital in Muscat, Oman, between May 2013 and August 2014. Data from eight patients with OI and 24 healthy controls were compared using conventional and tissue Doppler echocardiography (TDE). Results: The OI group had significantly lower peak early mitral valve flow velocity (P = 0.027), peak a-wave reversal in the pulmonary vein (P = 0.030) and peak early diastolic velocity of the mitral valve and upper septum (P = 0.001 each). The peak late diastolic velocities of the mitral valve (P = 0.002) and the upper septum (P = 0.037) were significantly higher in the OI group; however, the peak early/late diastolic velocity ratios of the mitral valve (P = 0.002) and upper septum (P = 0.001) were significantly lower. Left ventricular dimensions and aortic and pulmonary artery diameters were larger in the OI group when indexed for body surface area. Both groups had normal systolic cardiac function. Conclusion: Children with OI had normal systolic cardiac function. However, changes in myocardial tissue Doppler velocities were suggestive of early diastolic cardiac dysfunction. They also had increased left ventricular dimensions and greater vessel diameters. These findings indicate the need for early and detailed structural and functional echocardiographic assessment and follow-up of young patients with OI. PMID:26629370

  17. Osteogenesis imperfecta caused by PPIB mutation with severe phenotype and congenital hearing loss

    PubMed Central

    Rush, Eric T.; Caldwell, Kathleen S.; Kreikemeier, Rose M.; Lutz, Richard E.; Esposito, Paul W.

    2014-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder of connective tissue typically caused by defects in either COL1A1 or COL1A2. A number of other genes causative of this disorder have been found, including PPIB, which forms one subunit of the prolyl 3-hydroxylase enzyme complex. Patients with homozygous or compound heterozygous mutations in this gene have OI with a trend toward lethal or severe phenotype. We present a Native American female with prenatal diagnosis of OI. Long bones were shortened with significant rhizomelia. At birth, fractures were present in ribs, humerii, and femurs. She had significant respiratory disease at birth, and required oxygen throughout her life. She also had recurrent pneumonias, one of which ultimately caused her death at age 16 mo. She also had significant bilateral sensorineural hearing loss. Molecular testing showed that the patient was homozygous for a single nucleotide substitution in PPIB (c. 136-2A>G). Patients with OI caused by PPIB mutations have had variable disease, but with majority of either with perinatal lethality or progressively deforming severe disease. Patients with OI due to PPIB mutation have shown some differences in phenotype. There appears to be a trend toward rhizomelic shortening and less severe bowing of the extremities, as compared to patients with comparably severe OI caused by COL1A1 or COL1A2 mutation. Congenital hearing loss may be an inconsistent feature of this condition, or may have co-occurred in our patient for unrelated reasons. Still, patients with OI caused by PPIB mutation should have appropriate early and regular management of their hearing.

  18. Digital stereophotogrammetry as a new technique to quantify truncal deformity: a pilot study in persons with osteogenesis imperfecta.

    PubMed

    Gabor, Lisa R; Chamberlin, Andrew P; Levy, Ellen; Perry, Monique B; Cintas, Holly; Paul, Scott M

    2011-10-01

    The objective of this pilot study was to determine the usability of stereophotogrammetry (SP) as a noninvasive technique for obtaining linear measures and anatomical data of the torso in people with osteogenesis imperfecta in comparison with clinical observations. Ten participants were recruited from subjects enrolled in ongoing institutional review board-approved osteogenesis imperfecta protocols at the National Institute of Child Health and Human Development. Using a Gulick tape measure, anthropometer, and the SP system proprietary software, linear measurements of the torso were taken. In addition, the presence or absence of specific torso deformities was documented from both clinical observation and evaluation of SP images. Measurements of torso diameter and circumference by SP demonstrated strong agreement with the manual measurements (intraclass correlation coefficient = 0.995 and 0.964, respectively). Substantial and statistically significant agreement was present between SP image evaluation and clinical observation for pectus carinatum (κ = 0.52 ± 0.23) and thoracic scoliosis (κ = 0.72 ± 0.12). The kappa values between clinical observation and SP evaluations of other torso deformities were not significant. The strong correlations and P values determined by this study demonstrate the potential value of SP in studying persons with truncal deformities. However, the weak agreement between SP and some clinical observations suggests that further development of SP image analysis tools is required before SP can be used as a standard method of diagnosis or assessment of treatment success. PMID:21862911

  19. Right ventricular and pulmonary arterial dimensions in adults with osteogenesis imperfecta.

    PubMed

    Radunovic, Zoran; Wekre, Lena L; Steine, Kjetil

    2012-06-15

    We examined right ventricular (RV) and ascending pulmonary artery (PA1) dimensions in adults with osteogenesis imperfecta (OI). The survey included 99 adults with OI divided in 3 clinical types (I, III, and IV) and 52 controls. RV and PA1 dimensions were measured by echocardiography and indexed for body surface area. Scoliosis was registered, and spirometry was performed in 75 patients with OI. All RV dimensions indexed by body surface area were significantly larger in the OI group compared to controls (RV basal dimension 1.9 ± 0.5 vs 1.7 ± 0.3 cm/m(2), p <0.05; RV midcavity dimension 1.7 ± 0.5 vs 1.5 ± 0.3 cm/m(2), p <0.05; RV longitudinal dimension 4.3 ± 1.1 vs 4.0 ± 0.9 cm/m(2), p <0.05). RV outflow tract (RVOT) proximal diameter (1.8 ± 0.4 vs 1.5 ± 0.2 cm/m(2), p <0.05), RVOT distal diameter (1.2 ± 0.2 vs 1.0 ± 0.1 cm/m(2), p <0.05), and PA1 (1.2 ± 0.3 vs 1.0 ± 0.2 cm/m(2), p <0.05) were also significantly larger in the OI group. Furthermore, all RV dimensions and PA1 were significantly larger in patients with OI type III compared to patients with OI types I and IV and controls. There were no differences in RV, RVOT, or PA1 dimensions between patients presenting a restrictive ventilatory pattern (n = 11) and patients a normal ventilatory pattern. Scoliosis was registered in 42 patients. Patients with OI type III had greater RV and PA1 dimensions compared to controls and patients with OI types I and IV. Impaired ventilatory patterns and scoliosis did not have any impact on RV dimensions in these patients. In conclusion, patients with OI had increased RV and PA1 dimensions compared to the control group. PMID:22459302

  20. Thermal stability of type I and type III procollagens from normal human fibroblasts and from a patient with osteogenesis imperfecta.

    PubMed

    Peltonen, L; Palotie, A; Hayashi, T; Prockop, D J

    1980-01-01

    Type I and type III procollagens were isolated from the medium of human fibroblast cultures in amounts adequate for examination by circular dichroism. Type I procollagen had a spectrum similar to that of type I procollagen and collagen from chicken embryos. The human type III procollagen showed a red shift not seen in type III collagen from calf skin. The midpoint (tm) for the helix-to-coil transition for both human procollagens was 40 degrees C. the same tm values were obtained with type I and type III procollagens synthesized by fibroblasts from a patient with osteogenesis imperfecta. Type I procollagen synthesized by the patient's fibroblasts, however, tended to aggregate more readily than type I procollagen from normal human fibroblasts, apparently because of a structural alteration of the protein. PMID:6928611

  1. Microstructure and compressive mechanical properties of cortical bone in children with osteogenesis imperfecta treated with bisphosphonates compared with healthy children.

    PubMed

    Imbert, Laurianne; Aurégan, Jean-Charles; Pernelle, Kélig; Hoc, Thierry

    2015-06-01

    Osteogenesis imperfecta (OI) is a genetic disorder characterized by a change in bone tissue quality, but little data are available to describe the factors involved at the macroscopic scale. To better understand the effect of microstructure alterations on the mechanical properties at the sample scale, we studied the structural and mechanical properties of six cortical bone samples from children with OI treated with bisphosphonates and compared them to the properties of three controls. Scanning electron microscopy, high resolution computed tomography and compression testing were used to assess these properties. More resorption cavities and a higher osteocyte lacunar density were observed in OI bone compared with controls. Moreover, a higher porosity was measured for OI bones along with lower macroscopic Young's modulus, yield stress and ultimate stress. The microstructure was impaired in OI bones; the higher porosity and osteocyte lacunar density negatively impacted the mechanical properties and made the bone more prone to fracture. PMID:25828157

  2. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review.

    PubMed

    Sinikumpu, Juha-Jaakko; Ojaniemi, Marja; Lehenkari, Petri; Serlo, Willy

    2015-08-01

    Osteogenesis imperfecta (OI) is a group of genetic disorders, of which Type III is the most severe among survivors. The disease is characterised in particular by bone fragility, decreased bone mass and increased incidence of fractures. Other usual findings are muscle hypotonia, joint hypermobility and short stature. Fractures and weak bones may consequently cause limb and spinal deformity and chronic physical disability. Bisphosphonates have revolutionised the treatment of newborn children with severe OI type III. Surgery is still needed in most patients due to high frequency of the fractures. In this systematic review we describe the present state-of-art in treating the most severe type of OI in newborn and preschool children with their bone fractures. PMID:25943292

  3. Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

    PubMed Central

    Stover, M L; Primorac, D; Liu, S C; McKinstry, M B; Rowe, D W

    1993-01-01

    Osteogenesis imperfecta (OI) type I is the mildest form of heritable bone fragility resulting from mutations within the COL1A1 gene. We studied fibroblasts established from a child with OI type I and demonstrated underproduction of alpha 1 (I) collagen chains and alpha 1 (I) mRNA. Indirect RNase protection suggested two species of alpha 1 (I) mRNA, one of which was not collinear with fully spliced alpha 1 (I) mRNA. The noncollinear population was confined to the nuclear compartment of the cell, and contained the entire sequence of intron 26 and a G-->A transition in the first position of the intron donor site. The G-->A transition was also identified in the genomic DNA. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably account for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but inframe RNA transcript, this mutation did not result in production of a defective collagen pro alpha 1 (I) chain. Instead, the mild nature of the disease in this case reflects failure to process the defective mRNA and thus the absence of a protein product from the mutant allele. Images PMID:8408653

  4. Current Practices and the Provider Perspectives on Inconclusive Genetic Test Results for Osteogenesis Imperfecta in Children with Unexplained Fractures: ELSI Implications.

    PubMed

    Youngblom, Emily; Murray, Mitzi Leah; Byers, Peter H

    2016-09-01

    Genetic testing can be used to determine if unexplained fractures in children could have resulted from a predisposition to bone fractures, e.g., osteogenesis imperfecta. However, uncertainty is introduced if a variant of unknown significance (VUS) is identified. Proper interpretation of VUS in these situations is critical because of its influence on clinical care and in court rulings. This study sought to understand how VUS are interpreted and used by practitioners when there is a differential diagnosis including both osteogenesis imperfecta and non-accidental injury.A 15-question survey was emailed to physicians who requested analysis of two genes, COL1A1 and COL1A2, from the University of Washington from 2005-2013 for patient cases involving suspicion of child abuse.Among the 89 participants, responses differed about when genetic testing should be ordered for osteogenesis imperfecta, who should be consulted about utilization of VUS test results, follow-up procedures, and who should receive the VUS results.There are no clear guidelines for how to interpret and follow up on VUS. In the legal setting, misinterpreted VUS could lead to unintended consequences and deleterious ramifications for family members. The need for better practice guidelines to help promote more equitable handling of these sensitive legal cases is clear. PMID:27587455

  5. OI Issues: Type I - Understanding the Mildest Form of Osteogenesis Imperfecta

    MedlinePlus

    ... counseling can address both types of problems. A nutritionist can design a diet that is rich in ... with Type I OI recommend developing an effective personal support network. Resources For more information about osteogenesis ...

  6. An unusual case of atrophic mandible fracture in a patient with osteogenesis imperfecta and on oral bisphosphonate therapy: Case report.

    PubMed

    Al-Osaimi, Abdulrahman; Samman, Mahmood; Al-Shakhs, Mohammad; Al-Suhaim, Faisal; Ramalingam, Sundar

    2014-04-01

    Fractures of severely atrophic (height < 10 mm) edentulous mandibles are infrequent and challenging to manage. Factors such as sclerotic bone and decreased vascularity combined with systemic diseases complicate the management of such fractures. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of type I collagen metabolism. Patients with OI characteristically present with histories of long bone fractures, deformities, blue sclerae, and opalescent dentin. However, fractures of the facial skeleton are rare. Bisphosphonate therapy has been proven to effectively reduce the fracture risk in patients with OI. The purpose of this clinical report is to present an unusual case of spontaneous fracture of the atrophic mandible in a patient with OI. Despite open reduction and internal fixation (ORIF) with miniplate osteosynthesis, the patient developed a second fracture at a screw placement site distal to the first fracture. The patient was successfully treated with ORIF using locking reconstruction plates fixed in the symphyseal and angle regions. Bone healing following ORIF was normal, and no clinical sign of osteonecrosis as a result of bisphosphonate therapy was observed. Patients with OI can present with spontaneous fractures of already weakened mandibles. Although such fractures can be managed with care using established protocols, further research is required to examine the effects of concomitant medication, such as bisphosphonates. PMID:25408599

  7. Osteogenesis Imperfecta Missense Mutations in Collagen: Structural consequences of a glycine to alanine replacement at a highly charged site

    PubMed Central

    Xiao, Jianxi; Cheng, Haiming; Silva, Teresita; Baum, Jean; Brodsky, Barbara

    2011-01-01

    Glycine is required as every third residue in the collagen triple-helix, and a missense mutation leading to the replacement of even one Gly in the repeating (Gly-Xaa-Yaa)n sequence by a larger residue leads to a pathological condition. Gly to Ala missense mutations are highly underrepresented in osteogenesis imperfecta (OI) and other collagen diseases, suggesting that the smallest replacement residue Ala might cause the least structural perturbation and mildest clinical consequences. The relatively small number of Gly to Ala mutation sites that do lead to OI must have some unusual features, such as greater structural disruption due to local sequence environment or location at a biologically important site. Here, peptides are used to model a severe OI case where a Gly to Ala mutation is found within a highly stabilizing Lys-Gly-Asp sequence environment. NMR, CD and DSC studies indicate this Gly to Ala replacement leads to a substantial loss in triple-helix stability and non-equivalence of the Ala residues in the three chains such that only one of the three Ala residues is capable of form a good backbone hydrogen bond. Examination of reported OI Gly to Ala mutations suggests preferential location at known collagen binding sites, and we propose that structural defects due to Ala replacements may lead to pathology when interfering with interactions. PMID:22054507

  8. Delivery by Cesarean Section is not Associated With Decreased at-Birth Fracture Rates in Osteogenesis Imperfecta

    PubMed Central

    Bellur, S; Jain, M; Cuthbertson, D; Krakow, D; Shapiro, JR; Steiner, RD; Smith, PA; Bober, MB; Hart, T; Krischer, J; Mullins, M; Byers, PH; Pepin, M; Durigova, M; Glorieux, FH; Rauch, F; Sutton, VR; Lee, B; Nagamani, SC

    2015-01-01

    Purpose Osteogenesis imperfecta (OI) predisposes to recurrent fractures. The moderate-to-severe forms of OI present with antenatal fractures and the mode of delivery that would be safest for the fetus is not known. Methods We conducted systematic analyses on the largest cohort of individuals (n=540) with OI enrolled to-date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared in individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates including method of delivery on fracture-related outcomes. Results When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean section (CS). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CS for delivery. Conclusion Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI shows that delivery by CS is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CS should be performed only for other maternal or fetal indications, but not for the sole purpose of fracture prevention in OI. PMID:26426884

  9. Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI.

    PubMed

    Belinsky, Glenn S; Ward, Leanne; Chung, Chuhan

    2016-01-01

    Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions. PMID:27579219

  10. An unusual case of atrophic mandible fracture in a patient with osteogenesis imperfecta and on oral bisphosphonate therapy: Case report

    PubMed Central

    Al-Osaimi, Abdulrahman; Samman, Mahmood; Al-Shakhs, Mohammad; Al-Suhaim, Faisal; Ramalingam, Sundar

    2014-01-01

    Fractures of severely atrophic (height < 10 mm) edentulous mandibles are infrequent and challenging to manage. Factors such as sclerotic bone and decreased vascularity combined with systemic diseases complicate the management of such fractures. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of type I collagen metabolism. Patients with OI characteristically present with histories of long bone fractures, deformities, blue sclerae, and opalescent dentin. However, fractures of the facial skeleton are rare. Bisphosphonate therapy has been proven to effectively reduce the fracture risk in patients with OI. The purpose of this clinical report is to present an unusual case of spontaneous fracture of the atrophic mandible in a patient with OI. Despite open reduction and internal fixation (ORIF) with miniplate osteosynthesis, the patient developed a second fracture at a screw placement site distal to the first fracture. The patient was successfully treated with ORIF using locking reconstruction plates fixed in the symphyseal and angle regions. Bone healing following ORIF was normal, and no clinical sign of osteonecrosis as a result of bisphosphonate therapy was observed. Patients with OI can present with spontaneous fractures of already weakened mandibles. Although such fractures can be managed with care using established protocols, further research is required to examine the effects of concomitant medication, such as bisphosphonates. PMID:25408599

  11. The Impact of Psycho-Educational Trainingon the Psychosocial Adjustment of Caregivers ofOsteogenesis Imperfecta Patients

    PubMed Central

    Bozkurt, Satı; Arabacı, Leyla Baysan; Vara, Şenay; Özen, Samim; Gökşen, Damla; Darcan, Şükran

    2014-01-01

    Ob­jec­ti­ve: To investigate the impact of a psycho-educational program developed for the caregivers of patients diagnosed with osteogenesis imperfecta (OI). Methods: The participants consisted of 16 caregivers. The study was designed as a quasi-experimental pre-test/post-test type study consisting of 10 semi-structured three-hour training sessions. The data were collected using the “Introductory Information Form” and appropriate scales (Burden Interview, Coping Strategies Scale, Problem-Solving Inventory and Psychosocial Adjustment to Illness Scale). The results were evaluated by descriptive statistics, correlation analysis, one-way variance analysis and Bonferroni analysis. Results: Psychosocial adjustment levels of the caregivers of OI patients before their participation in the educational program were found to be associated with styles of coping with stress, problem-solving skills and care burden. After the psycho-educational training, the majority of the participants reported favorable changes in their lives. Following the offered psycho-education resulted in positive changes in the mean scores of the caregivers (p<0.05). Conclusion: Before the education program, the participants were not able to deal efficiently with many aspects of their caregiver responsibilities and suffered from an emotional burden due to lack of knowledge. The program appears to have provided them both with support to achieve significant psychosocial transformation and with an opportunity to reconsider their lives in multiple dimensions. PMID:24932601

  12. Rapidly Growing Brtl/+ Mouse Model of Osteogenesis Imperfecta Improves Bone Mass and Strength with Sclerostin Antibody Treatment

    PubMed Central

    Sinder, Benjamin P.; Salemi, Joseph D.; Ominsky, Michael S.; Caird, Michelle S.; Marini, Joan C.; Kozloff, Kenneth M.

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3 week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly->Cys substitution on col1a1, for 5 weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI. PMID:25445450

  13. Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

    PubMed Central

    DiGirolamo, Douglas J.; Singhal, Vandana; Chang, Xiaoli; Lee, Se-Jin; Germain-Lee, Emily L.

    2015-01-01

    Osteogenesis imperfecta (OI) comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI, many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B (ACVR2B) in a mouse model of type III OI (oim). Treatment of 12-week-old oim mice with ACVR2B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy, wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system. PMID:26161291

  14. Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI

    PubMed Central

    Belinsky, Glenn S.; Ward, Leanne; Chung, Chuhan

    2016-01-01

    ABSTRACT Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions. PMID:27579219

  15. Osteochondritis dissecans of the lateral femoral condyle in a patient affected by osteogenesis imperfecta: a case report.

    PubMed

    Persiani, Pietro; Di Domenica, Marica; Martini, Lorena; Ranaldi, Filippo M; Zambrano, Anna; Celli, Mauro; Villani, Ciro

    2015-11-01

    Osteochondritis dissecans is a very uncommon phenomenon in osteogenesis imperfecta (OI). A 14-year-old boy, affected by OI and followed in our Center for Congenital Osteodystrophies, had a knee trauma and MRI indicated a hollowed area of 2.5×1.5 cm in the lateral femoral condyle, which was classified as grade III. The patient underwent surgery, performed as a one-step surgical treatment: the osteochondral fragment was removed, curettage of lesion's bottom was performed, and a biphasic scaffold was used to fill the defect, implanted with a press-fit technique. MRI at 12 and 24 months after surgery showed scaffold integration. At the final follow-up, the patient did not feel any pain or articular limitations. It is difficult to provide a guideline on osteochondritis dissecans in patients affected by OI because of the lack of literature reports on this rare disorder in a rare disease. According to our experience, in these patients, osteosynthesis of the bone fragment and the use of autograft are not recommended because of the patient's bone weakness and osteoporosis. Moreover, compared with two-step surgery, one-step surgery is preferred to reduce the risk related to anesthesia, often observed to be higher in these patients. PMID:25919806

  16. Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.

    PubMed

    Syx, Delfien; Guillemyn, Brecht; Symoens, Sofie; Sousa, Ana Berta; Medeira, Ana; Whiteford, Margo; Hermanns-Lê, Trinh; Coucke, Paul J; De Paepe, Anne; Malfait, Fransiska

    2015-08-01

    Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization. PMID:25656619

  17. Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.

    PubMed

    Xiao, Jianxi; Yang, Zhangfu; Sun, Xiuxia; Addabbo, Rayna; Baum, Jean

    2015-10-01

    Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy. PMID:25980613

  18. The recurrent causal mutation for osteogenesis imperfecta type V occurs at a highly methylated CpG dinucleotide within the IFITM5 gene

    PubMed Central

    Corradi, Massimiliano; Monti, Elena; Venturi, Giacomo; Gandini, Alberto; Mottes, Monica; Antoniazzi, Franco

    2014-01-01

    Recent studies have identified the molecular defect underlying autosomal dominant osteogenesis imperfecta (OI) type V. Unlike all other OI types, which are characterized by high genetic heterogeneity, OI type V appears consistently associated to a unique de novo C>T transition within the 5′ UTR of the IFITM5 gene. Although the precise frequency of OI type V is not known, this recurrent base substitution may well represent a mutational hotspot in the human genome. We show that it occurs at a CpG dinucleotide that is highly methylated in several tissues and particularly in the sperm DNA, suggesting a mutational mechanism common to other de novo recurrent dominant mutations.

  19. Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: clues to pathogenesis.

    PubMed

    Arundel, Paul; Offiah, Amaka; Bishop, Nicholas J

    2011-04-01

    We present the first report of the development of characteristic radiologic appearances of long bones during the first year of life in an infant with type V osteogenesis imperfecta (OI). We show the evolution of metaphyseal abnormalities from a rickets-like appearance to the classically described dense metaphyseal bands. These abnormalities suggest that the underlying defect in type V OI may involve a molecule common to both bone and cartilage that is involved in the regulation of growth plate development and metadiaphyseal ossification. Our findings provide new insights into skeletal development in type V OI and potentially yield useful clues to the identity of the defect underpinning the condition. PMID:20872883

  20. [Contradictions of public health policies geared to rare disorders: the example of the Osteogenesis Imperfecta Treatment Program in the Brazilian Unified Health System (SUS)].

    PubMed

    Lima, Maria Angelica de Faria Domingues de; Horovitz, Dafne Dain Gandelman

    2014-02-01

    The scope of this paper is to examine the process of consolidation of a public health policy in Brazil geared to a rare disorder, namely osteogenesis imperfecta, the treatment for which has fallen under the responsibility of the Brazilian Unified Health System (SUS) after the publication of Ministerial Ruling GM/MS2305/2001. The implementation of this law has been accompanied by many contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition. These attitudes are clearly shown both by the drafting process and the final text of the new law (Ministerial Ruling 714/2010). PMID:24863824

  1. Pre- and Postnatal Transplantation of Fetal Mesenchymal Stem Cells in Osteogenesis Imperfecta: A Two-Center Experience

    PubMed Central

    Westgren, Magnus; Shaw, S.W. Steven; Åström, Eva; Biswas, Arijit; Byers, Peter H.; Mattar, Citra N.Z.; Graham, Gail E.; Taslimi, Jahan; Ewald, Uwe; Fisk, Nicholas M.; Yeoh, Allen E.J.; Lin, Ju-Li; Cheng, Po-Jen; Choolani, Mahesh; Le Blanc, Katarina; Chan, Jerry K.Y.

    2014-01-01

    Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 × 106 same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 × 106 hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 × 106 MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required. PMID:24342908

  2. The Effects of RANKL Inhibition on Fracture Healing and Bone Strength in a Mouse Model of Osteogenesis Imperfecta

    PubMed Central

    Delos, D.; Yang, X.; Ricciardi, B.F.; Myers, E.R.; Bostrom, M.P.G.; Pleshko Camacho, N.

    2009-01-01

    Summary Currently, the standard treatment for osteogenesis imperfecta (OI) is bisphosphonate therapy. Recent studies, however, have shown delayed healing of osteotomies in a subset of OI patients treated with such agents. The current study sought to determine the effects of another therapy, RANKL inhibition, on bone healing and bone strength in the growing oim/oim mouse, a model of moderate-to-severe OI. Mice (73 oim/oim and 69 wildtype (WT)) were injected twice weekly with either soluble murine RANK (RANK-Fc) (1.5mg/kg) or saline beginning at 6 weeks of age. At 8 weeks of age, the animals underwent transverse mid-diaphyseal osteotomies of the right femur. Therapy was continued until sacrifice at 2, 3, 4 or 6 weeks post-fracture. At 6 weeks post-fracture, greater callus area (6.59±3.78mm2 vs 2.67±2.05mm2, p=0.003) and increased radiographic intensity (mineral density) (0.48 ± 0.14 vs. 0.30 ± 0.80, p=0.005) were found in the RANK-Fc vs saline oim/oim group, indicating a delay in callus remodeling. Despite this delay, mechanical tests at 6 weeks post-fracture revealed no significant differences in whole bone properties of stiffness and failure moment. Further, RANKL inhibition resulted in a greater failure moment and greater work to failure for the non-fractured contralateral WT bones compared to the non-fractured saline WT bones. Together, these results demonstrate that RANKL-inhibition does not adversely affect the mechanical properties of healing bone in the oim/oim mice, and is associated with increased strength in intact bone in the WT mice. PMID:17729310

  3. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

    PubMed Central

    Garbes, Lutz; Kim, Kyungho; Rieß, Angelika; Hoyer-Kuhn, Heike; Beleggia, Filippo; Bevot, Andrea; Kim, Mi Jeong; Huh, Yang Hoon; Kweon, Hee-Seok; Savarirayan, Ravi; Amor, David; Kakadia, Purvi M.; Lindig, Tobias; Kagan, Karl Oliver; Becker, Jutta; Boyadjiev, Simeon A.; Wollnik, Bernd; Semler, Oliver; Bohlander, Stefan K.; Kim, Jinoh; Netzer, Christian

    2015-01-01

    As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish). PMID:25683121

  4. Tissue level material composition and mechanical properties in Brtl/+ mouse model of Osteogenesis Imperfecta after sclerostin antibody treatment

    NASA Astrophysics Data System (ADS)

    Lloyd, William R.; Sinder, Benjamin P.; Salemi, Joseph; Ominsky, Michael S.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2015-02-01

    Osteogenesis imperfecta (OI) is a genetic disorder resulting in defective collagen or collagen-associated proteins and fragile, brittle bones. To date, therapies to improve OI bone mass, such as bisphosphonates, have increased bone mass in the axial skeleton of OI patients, but have shown limited effects at reducing long bone fragility. Sclerostin antibody (Scl- Ab), currently in clinical trials for osteoporosis, stimulates bone formation and may have the potential to reduce long bone fracture rates in OI patients. Scl-Ab has been investigated as an anabolic therapy for OI in the Brtl/+ mouse model of moderately severe Type IV OI. While Scl-Ab increases long bone mass in the Brtl/+ mouse, it is not known whether material properties and composition changes also occur. Here, we report on the effects of Scl-Ab on wild type and Brtl/+ young (3 week) and adult (6 month) male mice. Scl-Ab was administered over 5 weeks (25mg/kg, 2x/week). Raman microspectroscopy and nanoindentation are used for bone composition and biomechanical bone property measurements in excised bone. Fluorescent labels (calcein and alizarin) at 4 time points over the entire treatment period are used to enable measurements at specific tissue age. Differences between wild type and Brtl/+ groups included variations in the mineral and matrix lattices, particularly the phosphate v1, carbonate v1, and the v(CC) proline and hydroxyproline stretch vibrations. Results of Raman spectroscopy corresponded to nanoindentation findings which indicated that old bone (near midcortex) is stiffer (higher elastic modulus) than new bone. We compare and contrast mineral to matrix and carbonate to phosphate ratios in young and adult mice with and without treatment.

  5. Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

    PubMed

    Vasanwala, Rashida F; Sanghrajka, Anish; Bishop, Nicholas J; Högler, Wolfgang

    2016-07-01

    Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment

  6. Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial.

    PubMed

    Plante, Laura; Veilleux, Louis-Nicolas; Glorieux, Francis H; Weiler, Hope; Rauch, Frank

    2016-05-01

    Osteogenesis imperfecta (OI) is a heritable condition characterized by fragile bones. Our previous studies indicated that serum 25-hydroxyvitamin D (25OHD) concentrations were positively associated with lumbar spine areal bone mineral density (LS-aBMD) in children and adolescents with OI. Here we assessed whether one year of high-dose vitamin D supplementation results in higher LS-aBMD z-scores in youth with OI. A one-year double-blind randomized controlled trial conducted at a pediatric orthopedic hospital in Montreal, Canada. Sixty patients (age: 6.0 to 18.9years; 35 female) were randomized in equal numbers to receive either 400 or 2000international units (IU) of vitamin D, stratified according to baseline bisphosphonate treatment status and pubertal stage. At baseline, the average serum 25OHD concentration was 65.6nmol/L (SD 20.4) with no difference between treatment groups (p=0.77); 21% of patients had results <50nmol/L. Vitamin D supplementation was associated with higher serum 25OHD concentrations in 90% of participants. The increase in mean 25OHD was significantly higher (p=0.02) in the group receiving 2000IU of vitamin D (mean [95% CI]=30.5nmol/L [21.3; 39.6]) than in the group receiving 400IU (15.2nmol/L [6.4; 24.1]). No significant differences in LS-aBMD z-score changes were detected between treatment groups. Thus, supplementation with vitamin D at 2000IU increased serum 25OHD concentrations in children with OI more than supplementation with 400IU. However, in this study where about 80% of participants had baseline serum 25OHD concentrations ≥50nmol/L, this difference had no detectable effect on LS-aBMD z-scores. PMID:26924265

  7. Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome

    PubMed Central

    McInerney-Leo, Aideen M; Marshall, Mhairi S; Gardiner, Brooke; Coucke, Paul J; Van Laer, Lut; Loeys, Bart L; Summers, Kim M; Symoens, Sofie; West, Jennifer A; West, Malcolm J; Paul Wordsworth, B; Zankl, Andreas; Leo, Paul J; Brown, Matthew A; Duncan, Emma L

    2013-01-01

    Osteogenesis imperfecta (OI) and Marfan syndrome (MFS) are common Mendelian disorders. Both conditions are usually diagnosed clinically, as genetic testing is expensive due to the size and number of potentially causative genes and mutations. However, genetic testing may benefit patients, at-risk family members and individuals with borderline phenotypes, as well as improving genetic counseling and allowing critical differential diagnoses. We assessed whether whole exome sequencing (WES) is a sensitive method for mutation detection in OI and MFS. WES was performed on genomic DNA from 13 participants with OI and 10 participants with MFS who had known mutations, with exome capture followed by massive parallel sequencing of multiplexed samples. Single nucleotide polymorphisms (SNPs) and small indels were called using Genome Analysis Toolkit (GATK) and annotated with ANNOVAR. CREST, exomeCopy and exomeDepth were used for large deletion detection. Results were compared with the previous data. Specificity was calculated by screening WES data from a control population of 487 individuals for mutations in COL1A1, COL1A2 and FBN1. The target capture of five exome capture platforms was compared. All 13 mutations in the OI cohort and 9/10 in the MFS cohort were detected (sensitivity=95.6%) including non-synonymous SNPs, small indels (<10 bp), and a large UTR5/exon 1 deletion. One mutation was not detected by GATK due to strand bias. Specificity was 99.5%. Capture platforms and analysis programs differed considerably in their ability to detect mutations. Consumable costs for WES were low. WES is an efficient, sensitive, specific and cost-effective method for mutation detection in patients with OI and MFS. Careful selection of platform and analysis programs is necessary to maximize success. PMID:24501682

  8. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation.

    PubMed

    Balasubramanian, M; Sobey, G J; Wagner, B E; Peres, L C; Bowen, J; Bexon, J; Javaid, M K; Arundel, P; Bishop, N J

    2016-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses. PMID:26863094

  9. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

    PubMed

    Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2016-09-01

    Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. PMID:27297606

  10. An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.

    PubMed

    Mackenroth, Luisa; Fischer-Zirnsak, Björn; Egerer, Johannes; Hecht, Jochen; Kallinich, Tilmann; Stenzel, Werner; Spors, Birgit; von Moers, Arpad; Mundlos, Stefan; Kornak, Uwe; Gerhold, Kerstin; Horn, Denise

    2016-04-01

    Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype. PMID:26799614

  11. Involving Families with Osteogenesis Imperfecta in Health Service Research: Joint Development of the OI/ECE Questionnaire

    PubMed Central

    Dogba, Maman Joyce; Dahan-Oliel, Noémi; Snider, Laurie; Glorieux, Francis H.; Durigova, Michaela; Palomo, Telma; Cordey, Michel; Bédard, Marie-Hélène; Bedos, Christophe; Rauch, Frank

    2016-01-01

    Background Despite the growing interest in understanding the psycho-social impact of rare genetic diseases, few studies examine this concept and even fewer seek to obtain feedback from families who have lived the experience. The aim of this project was to involve families of children living with osteogenesis imperfecta (OI) in the development of a tool to assess the impact of OI on the lives of patients and their families. Methods This project used an integrated knowledge translation approach in which knowledge users (clinicians and people living with OI and their families) were consulted throughout the four steps of development, that is: content mapping, item generation, tool appraisal and pre-testing of the questionnaires. The International Classification of Functioning and Health was used as a framework for content mapping. Based on a scoping review we selected two validated tools to use as a basis for developing the questionnaire. The final parent self-report version measured six domains: experience of diagnosis; use of health services; use of social and psychological support services; expectations about tertiary specialized centers; and socio-demographic information. Results A total of 27 out of 40 families receiving care at the Shriners Hospital for Children-Canada and invited to participate in the pre-test returned the completed questionnaires. In more than two-thirds of families (69%; n = 18) OI was suspected either at or within the first 3 months after birth. Up to 46% of families consulted between 3 and 5 doctors (46%; n = 12) prior to final diagnosis. The use of services by families varied from 0 to 16 consultations, 0 to 9 exploratory examinations and 1 to 10 types of allied health services. In the 12 months prior to the study, fewer than a quarter of children had been admitted, for treatment, for hospital stays of longer than 8 hours or to an emergency department (24% and 9% respectively). Only 29% of parents received psychological support. Conclusion

  12. Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels - a Novel Therapeutic Approach in Osteogenesis Imperfecta

    PubMed Central

    Lindahl, Katarina; Kindmark, Andreas; Laxman, Navya; Åström, Eva; Rubin, Carl-Johan; Ljunggren, Östen

    2013-01-01

    Osteogenesis imperfecta, also known as “brittle bone disease”, is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis

  13. Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta.

    PubMed

    Masci, Marco; Wang, Min; Imbert, Laurianne; Barnes, Aileen M; Spevak, Lyudmila; Lukashova, Lyudmila; Huang, Yihe; Ma, Yan; Marini, Joan C; Jacobsen, Christina M; Warman, Matthew L; Boskey, Adele L

    2016-06-01

    The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP(+/A214V) high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1(a2+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+). FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution

  14. What Is Osteogenesis Imperfecta?

    MedlinePlus

    ... and Other Related Conditions: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 AMS Circle Bethesda, MD ... FDA-approved drug products. NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 AMS Circle Bethesda, MD ...

  15. Osteogenesis Imperfecta Foundation

    MedlinePlus

    ... taking place on November 12, 2016! Learn More Current Research Opportunities Click below to learn more about the OIF's current research opportunities including the Michael Geisman Fellowship and ...

  16. Learning about Osteogenesis Imperfecta

    MedlinePlus

    ... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education ... Subjects Research Informed Consent for Genomics Research Intellectual ...

  17. Osteogenesis Imperfecta Overview

    MedlinePlus

    ... is extremely rare slightly elevated activity level of alkaline phosphatase (an enzyme linked to bone formation), which ... for people with OI. This treatment involves inserting metal rods through the length of the long bones ...

  18. Osteogenesis Imperfecta Issues: Constipation

    MedlinePlus

    ... cultures that contain the bacteria lactobacillus acidophilus. • Limit soft drinks and drinks containing caffeine such as colas or tea. • Drink water throughout the day. Strive for a diet that keeps the stool soft. Too much fiber has the secondary effect of ...

  19. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

    PubMed

    Belinsky, Glenn S; Sreekumar, Bharath; Andrejecsk, Jillian W; Saltzman, W Mark; Gong, Jingjing; Herzog, Raimund I; Lin, Samantha; Horsley, Valerie; Carpenter, Thomas O; Chung, Chuhan

    2016-08-01

    Null mutations in for pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF-knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt/β-catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume/total volume by 52% in 6-mo-old PEDF-KO mice but not in wild-type mice. In young (19-d-old) PEDF-KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt-green fluorescent protein reporter demonstrated dynamic changes in Wnt/β-catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34-mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.-Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. PMID:27127101

  20. Burnei’s procedure in the treatment of long bone pseudarthrosis in patients having osteogenesis imperfecta or congenital pseudarthrosis of tibia – preliminary report

    PubMed Central

    Vlad, C; Georgescu, I; Gavriliu, TS; Hodorogea, DI; El Nayef, T; Dan, D

    2012-01-01

    Rationale: given the recalcitrant behaviour of pseudarthrosis in osteogenesis imperfecta (OI) and congenital pseudarthrosis of the tibia (CPT), there is no ideal solution to treat such challenging deformities. The reconsideration of the already known principles, by using the modern technology, may generate new treatment methods. Aim: the present paper presents the preliminary results of an original reconstruction procedure used to treat large bone defects in paediatric orthopaedics. A case series study, the surgical technique, complications and illustrative cases are presented. Methods and results: 3 cases of pseudarthrosis in OI and 2 cases of CPT were operated by using this technique. The principles of the method are to create an optimal osteoconductive and osteoinductive environment by using a bone autograft, bone allograft and bone graft substitutes and to provide a good stabilisation of the bones. We operated 3 patients with OI and 2 patients with CPT. Four patients had multiple previous surgeries. The follow-up period ranged from 3 to 28 months. Four of the five patients are able to ambulate independently at the moment this paper was written. Discussion: we believe that the present technique could be a reliable alternative to other procedures, especially in cases of repeated failures. PMID:22802896

  1. Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in α2(I)-G610C Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Mirigian, Lynn S; Makareeva, Elena; Mertz, Edward L; Omari, Shakib; Roberts-Pilgrim, Anna M; Oestreich, Arin K; Phillips, Charlotte L; Leikin, Sergey

    2016-08-01

    Glycine (Gly) substitutions in collagen Gly-X-Y repeats disrupt folding of type I procollagen triple helix and cause severe bone fragility and malformations (osteogenesis imperfecta [OI]). However, these mutations do not elicit the expected endoplasmic reticulum (ER) stress response, in contrast to other protein-folding diseases. Thus, it has remained unclear whether cell stress and osteoblast malfunction contribute to the bone pathology caused by Gly substitutions. Here we used a mouse with a Gly610 to cysteine (Cys) substitution in the procollagen α2(I) chain to show that misfolded procollagen accumulation in the ER leads to an unusual form of cell stress, which is neither a conventional unfolded protein response (UPR) nor ER overload. Despite pronounced ER dilation, there is no upregulation of binding immunoglobulin protein (BIP) expected in the UPR and no activation of NF-κB signaling expected in the ER overload. Altered expression of ER chaperones αB crystalline and HSP47, phosphorylation of EIF2α, activation of autophagy, upregulation of general stress response protein CHOP, and osteoblast malfunction reveal some other adaptive response to the ER disruption. We show how this response alters differentiation and function of osteoblasts in culture and in vivo. We demonstrate that bone matrix deposition by cultured osteoblasts is rescued by activation of misfolded procollagen autophagy, suggesting a new therapeutic strategy for OI. © 2016 American Society for Bone and Mineral Research. PMID:26925839

  2. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

    PubMed

    Panaroni, Cristina; Gioia, Roberta; Lupi, Anna; Besio, Roberta; Goldstein, Steven A; Kreider, Jaclynn; Leikin, Sergey; Vera, Juan Carlos; Mertz, Edward L; Perilli, Egon; Baruffaldi, Fabio; Villa, Isabella; Farina, Aurora; Casasco, Marco; Cetta, Giuseppe; Rossi, Antonio; Frattini, Annalisa; Marini, Joan C; Vezzoni, Paolo; Forlino, Antonella

    2009-07-01

    Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases. PMID:19414862

  3. A case of fetal osteogenesis imperfecta type 2A: longitudinal observation of natural course in utero and pitfalls for prenatal ultrasound diagnosis.

    PubMed

    Kimura, Ibuki; Araki, Ryota; Yoshizato, Toshiyuki; Miyamoto, Shingo

    2015-10-01

    We present a case of osteogenesis imperfecta (OI) type 2A in which a natural course in utero was observed from 23 weeks' gestation to term. At 23 weeks' gestation, a sonographic examination showed a cloverleaf skull-like head, a narrow thorax, and marked shortening of the long bones with bowing of the femurs and humeri. Follow-up examinations showed that the cloverleaf skull-like head was not evident at 28 weeks' gestation. Discontinuity of the ribs and femurs was observed at 26 and 30 weeks' gestation, respectively. This finding suggested bone fractures, which were confirmed by three-dimensional computed tomography at 32 weeks' gestation. Ultrasonographic findings of bones, including the long bones and calvarium, changed with advancing gestation during the second trimester. Characteristic features of OI type 2A were evident during the late second to early third trimesters. Repeated ultrasonographic examinations together with three-dimensional computed tomography are necessary for the definitive diagnosis of OI type 2A in the second trimester. PMID:26576983

  4. Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype

    PubMed Central

    Salazar, Valerie S.; Zarkadis, Nicholas; Huang, Lisa; Norris, Jin; Grimston, Susan K.; Mbalaviele, Gabriel; Civitelli, Roberto

    2013-01-01

    Summary To examine interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-β–BMP pathway, in Osx1+ cells in mice. We show that loss of Smad4 causes stunted growth, spontaneous fractures and a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia and Wnt-deficiency syndromes. Bones of Smad4 mutant mice exhibited markers of fully differentiated osteoblasts but lacked multiple collagen-processing enzymes, including lysyl oxidase (Lox), a BMP2-responsive gene regulated by Smad4 and Runx2. Accordingly, the collagen matrix in Smad4 mutants was disorganized, but also hypomineralized. Primary osteoblasts from these mutants did not mineralize in vitro in the presence of BMP2 or Wnt3a, and Smad4 mutant mice failed to accrue new bone following systemic inhibition of the Dickkopf homolog Dkk1. Consistent with impaired biological responses to canonical Wnt, ablation of Smad4 causes cleavage of β-catenin and depletion of the low density lipoprotein receptor Lrp5, subsequent to increased caspase-3 activity and apoptosis. In summary, Smad4 regulates maturation of skeletal collagen and osteoblast survival, and is required for matrix-forming responses to both BMP2 and canonical Wnt. PMID:24006258

  5. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N.; Sargent, Brandi M.; Weis, MaryAnn; Barnes, Aileen M.; Webb, Emma A.; Shaw, Nicholas J.; Ala-Kokko, Leena; Lacbawan, Felicitas L.; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S.; Zimmerberg, Joshua; Eyre, David R.; Yamada, Yoshihiko; Marini, Joan C.

    2016-01-01

    Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. PMID:27441836

  6. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.

    PubMed

    Sykes, B; Ogilvie, D; Wordsworth, P; Wallis, G; Mathew, C; Beighton, P; Nicholls, A; Pope, F M; Thompson, E; Tsipouras, P

    1990-02-01

    The segregation of COL1A1 and COL1A2, the two genes which encode the chains of type I collagen, was analyzed in 38 dominant osteogenesis imperfecta (OI) pedigrees by using polymorphic markers within or close to the genes. This was done in order to estimate the consistency of linkage of OI genes to these two loci. None of the 38 pedigrees showed evidence of recombination between the OI gene and both collagen loci, suggesting that the frequency of unlinked loci in the population must be low. From these results, approximate 95% confidence limits for the proportion of families linked to the type I collagen genes can be set between .91 and 1.00. This is high enough to base prenatal diagnosis of dominantly inherited OI on linkage to these genes even in families which are too small for the linkage to be independently confirmed to high levels of significance. When phenotypic features were compared with the concordant collagen locus, all eight pedigrees with Sillence OI type IV segregated with COL1A2. On the other hand, Sillence OI type I segregated with both COL1A1 (17 pedigrees) and COL1A2 (7 pedigrees). The concordant locus was uncertain in the remaining six OI type I pedigrees. Of several other features, the presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature. PMID:1967900

  7. A Novel DHPLC-Based Procedure for the Analysis of COL1A1 and COL1A2 Mutations in Osteogenesis Imperfecta

    PubMed Central

    Fuccio, Antonella; Iorio, Mariangela; Amato, Felice; Elce, Ausilia; Ingino, Rosaria; Filocamo, Mirella; Castaldo, Giuseppe; Salvatore, Francesco; Tomaiuolo, Rossella

    2011-01-01

    Approximately 90% of patients with osteogenesis imperfecta (OI) exhibit dominant COL1A1 or COL1A2 mutations; however, molecular analysis is difficult because these genes span 51 and 52 exons, respectively. We devised a PCR-denaturing high-performance liquid chromatography (DHPLC) procedure to analyze the COL1A1 or COL1A2 coding regions and validated it using 130 DNA samples from individuals without OI, 25 DNA samples from two cells to investigate the procedure's potential for preimplantation diagnosis, and DNA samples from 10 patients with OI. Three novel intronic variants in vitro were expressed using a minigene assay to assess their effects on splicing. The procedure is rapid, inexpensive, and reproducible. Analysis of samples from individuals without OI revealed six novel and some known polymorphisms useful for linkage diagnosis because of high heterozygosity. Analysis of two-cell samples confirmed the known genotype in 24 of 25 experiments; DNA failed to amplify in only one case. No incidence of allele dropout was recorded. DHPLC revealed six novel mutations, three of which were intronic, in all patients with OI, and these results were confirmed by means of COL1A1 and COL1A2 direct sequencing. Expression of intronic mutations demonstrated that variant 804 + 2_804 + 3delTG in intron 11 disrupts normal splicing, thereby leading to formation of two alternative products. Variants c.3046-4_3046-5dupCT (COL1A1) and c.891 + 77A>T (COL1A2) did not affect splicing. The described DHPLC protocol combined with the minigene assay may contribute to molecular diagnosis in OI. Moreover, this protocol will aid in counseling about prenatal and preimplantation diagnosis. PMID:21884818

  8. Characterization of skin abnormalities in a mouse model of osteogenesis imperfecta using high resolution magnetic resonance imaging and Fourier transform infrared imaging spectroscopy.

    PubMed

    Canuto, H C; Fishbein, K W; Huang, A; Doty, S B; Herbert, R A; Peckham, J; Pleshko, N; Spencer, R G

    2012-01-01

    Evaluation of the skin phenotype in osteogenesis imperfecta (OI) typically involves biochemical measurements, such as histologic or biochemical assessment of the collagen produced from biopsy-derived dermal fibroblasts. As an alternative, the current study utilized non-invasive magnetic resonance imaging (MRI) microscopy and optical spectroscopy to define biophysical characteristics of skin in an animal model of OI. MRI of skin harvested from control, homozygous oim/oim and heterozygous oim/+ mice demonstrated several differences in anatomic and biophysical properties. Fourier transform infrared imaging spectroscopy (FT-IRIS) was used to interpret observed MRI signal characteristics in terms of chemical composition. Differences between wild-type and OI mouse skin included the appearance of a collagen-depleted lower dermal layer containing prominent hair follicles in the oim/oim mice, accounting for 55% of skin thickness in these. The MRI magnetization transfer rate was lower by 50% in this layer as compared to the upper dermis, consistent with lower collagen content. The MRI transverse relaxation time, T2, was greater by 30% in the dermis of the oim/oim mice compared to controls, consistent with a more highly hydrated collagen network. Similarly, an FT-IRIS-defined measure of collagen integrity was 30% lower in the oim/oim mice. We conclude that characterization of phenotypic differences between the skin of OI and wild-type mice by MRI and FT-IRIS is feasible, and that these techniques provide powerful complementary approaches for the analysis of the skin phenotype in animal models of disease. PMID:21845737

  9. Strategy for prenatal diagnosis of osteogenesis imperfecta by linkage analysis to the type I collagen loci COL1A1 and COL1A2.

    PubMed

    Benušienė, E; Kučinskas, V

    2000-01-01

    To improve prenatal diagnosis of osteogenesis imperfecta (OI) in Lithuania, possibilities of indirect molecular genetic diagnosis were investigated in 11 families with dominant OI. Segregation of polymorphic DNA markers closely linked to COL1A1 and COL1A2 genes with OI phenotype was investigated. Polymorphic DNA markers applied were individual haplotypes constructed using a set of restriction enzyme sites within or close to the genes. Comparison of phenotypic features with the concordant collagen locus showed that in four pedigrees with OI Sillence type I segregated with COL1A1, while two pedigrees with OI Sillence type I and OI type IV segregated with COL1A2. Out of six remaining pedigrees with OI Sillence type I, three were concordant at both loci, two pedigrees were discordant at the locus COL1A2 and non-informative at the locus COL1A1 and one pedigree was concordant at the locus COL1A1 and non-informative at the locus COL1A2. Informativity of DNA markers applied was also investigated in the Lithuanian OI families. The frequencies of six restriction enzyme site dimorphisms in type I collagen loci were estimated and polymorphism information content (PIC) values were calculated for each restriction site and for a combination of three sites. COL1A1 locus dimorphisms A/MspI, B/RsaI and F/MnlI, showed PIC values of 0.327, 0.191 and 0.366, respectively, giving a combined PIC of 0.656 at the locus, while COL1A2 locus dimorphisms C/EcoRI, D/MspI and E/RsaI RFLPs had PIC values of 0.357, 0.168 and 0.331, respectively, giving a combined PIC of 0.655 at the locus. PMID:11208313

  10. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta.

    PubMed

    Cabral, Wayne A; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N; Sargent, Brandi M; Weis, MaryAnn; Barnes, Aileen M; Webb, Emma A; Shaw, Nicholas J; Ala-Kokko, Leena; Lacbawan, Felicitas L; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S; Zimmerberg, Joshua; Eyre, David R; Yamada, Yoshihiko; Marini, Joan C

    2016-07-01

    Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. PMID:27441836

  11. A Novel IFITM5 Mutation in Severe Atypical Osteogenesis Imperfecta Type VI Impairs Osteoblast Production of Pigment Epithelium-Derived Factor

    PubMed Central

    Farber, Charles R; Reich, Adi; Barnes, Aileen M; Becerra, Patricia; Rauch, Frank; Cabral, Wayne A; Bae, Alison; Quinlan, Aaron; Glorieux, Francis H; Clemens, Thomas L; Marini, Joan C

    2015-01-01

    Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5′-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and

  12. Efficacy of Bisphosphonates on Bone Mineral Density and Fracture Rate in Patients With Osteogenesis Imperfecta: A Systematic Review and Meta-analysis.

    PubMed

    Shi, Chang Gui; Zhang, Ying; Yuan, Wen

    2016-01-01

    Epidemiological evidence suggests that bisphosphonates are the most promising drugs for patients with osteogenesis imperfecta (OI). However, data on this issue are controversial. We conducted a meta-analysis to assess the efficacy of bisphosphonates on bone mineral density (BMD) and fracture rate in patients with OI. Electronic databases were searched to find relevant studies. Two reviewers independently identified relevant randomized controlled trials, which evaluated the efficacy of bisphosphonates in patients with OI. Outcome measures were fracture incidence and BMD changes in different skeletal sites. A total of 9 randomized controlled trials including 557 patients were identified. Meta-analysis demonstrated a beneficial effect of bisphosphonates on spine BMD Z-score and area BMD (in grams per square centimeter) %. Patients treated with bisphosphonates had a lower risk of fracture [risk ratio (RR) = 0.80; 95% confidence interval (CI): 0.66-0.97] compared with those in control groups. In children, bisphosphonates were efficacious in reducing fractures (RR = 0.80; 95% CI: 0.66-0.97), where in adults, bisphosphonates seemed equivalent to placebo in that respect (RR = 0.82; 95% CI: 0.42-1.59), although no significant difference was noted between these 2 RRs (test of interaction, z = -0.07; P = 0.94). There was also no significant difference in reducing fractures between oral and intravenous bisphosphonates (P = 0.23). This study showed that bisphosphonates could increase the BMD and reduce the risk of facture in patients with OI. There was no enough evidence to identify any differences in efficacy between oral and intravenous bisphosphonates on fracture reduction, as well as between children and adults. PMID:25844482

  13. COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients

    PubMed Central

    2014-01-01

    Background The majority of Osteogenesis Imperfecta (OI) cases are caused by mutations in one of the two genes, COL1A1 and COL1A2 encoding for the two chains that trimerize to form the procollagen 1 molecule. However, alterations in gene expression and microRNAs (miRNAs) are responsible for the regulation of cell fate determination and may be evolved in OI phenotype. Methods In this work, we analyzed the coding region and intron/exon boundaries of COL1A1 and COL1A2 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. COL1A1 and miR-29b expression were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System. Results We have identified eight novel mutations, where of four may be responsible for OI phenotype. COL1A1 and miR-29b showed lower expression values in OI type I and type III samples. Interestingly, one type III OI sample from a patient with Bruck Syndrome showed COL1A1 and miR-29b expressions alike those from normal samples. Conclusions Results suggest that the miR-29b mechanism directed to regulate collagen protein accumulation during mineralization is dependent upon the amount of COL1A1 mRNA. Taken together, results indicate that the lower levels observed in OI samples were not sufficient for the induction of miR-29b. PMID:24767406

  14. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes

    PubMed Central

    Pyott, Shawna M.; Schwarze, Ulrike; Christiansen, Helena E.; Pepin, Melanie G.; Leistritz, Dru F.; Dineen, Richard; Harris, Catharine; Burton, Barbara K.; Angle, Brad; Kim, Katherine; Sussman, Michael D.; Weis, MaryAnn; Eyre, David R.; Russell, David W.; McCarthy, Kevin J.; Steiner, Robert D.; Byers, Peter H.

    2011-01-01

    Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis–trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis–trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis–trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI. PMID:21282188

  15. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    PubMed

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. PMID:26927310

  16. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

    PubMed

    Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

    2016-03-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

  17. Abnormal Type I Collagen Post-translational Modification and Crosslinking in a Cyclophilin B KO Mouse Model of Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Perdivara, Irina; Weis, MaryAnn; Terajima, Masahiko; Blissett, Angela R.; Chang, Weizhong; Perosky, Joseph E.; Makareeva, Elena N.; Mertz, Edward L.; Leikin, Sergey; Tomer, Kenneth B.; Kozloff, Kenneth M.; Eyre, David R.; Yamauchi, Mitsuo; Marini, Joan C.

    2014-01-01

    Cyclophilin B (CyPB), encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that functions independently and as a component of the collagen prolyl 3-hydroxylation complex. CyPB is proposed to be the major PPIase catalyzing the rate-limiting step in collagen folding. Mutations in PPIB cause recessively inherited osteogenesis imperfecta type IX, a moderately severe to lethal bone dysplasia. To investigate the role of CyPB in collagen folding and post-translational modifications, we generated Ppib−/− mice that recapitulate the OI phenotype. Knock-out (KO) mice are small, with reduced femoral areal bone mineral density (aBMD), bone volume per total volume (BV/TV) and mechanical properties, as well as increased femoral brittleness. Ppib transcripts are absent in skin, fibroblasts, femora and calvarial osteoblasts, and CyPB is absent from KO osteoblasts and fibroblasts on western blots. Only residual (2–11%) collagen prolyl 3-hydroxylation is detectable in KO cells and tissues. Collagen folds more slowly in the absence of CyPB, supporting its rate-limiting role in folding. However, treatment of KO cells with cyclosporine A causes further delay in folding, indicating the potential existence of another collagen PPIase. We confirmed and extended the reported role of CyPB in supporting collagen lysyl hydroxylase (LH1) activity. Ppib−/− fibroblast and osteoblast collagen has normal total lysyl hydroxylation, while increased collagen diglycosylation is observed. Liquid chromatography/mass spectrometry (LC/MS) analysis of bone and osteoblast type I collagen revealed site-specific alterations of helical lysine hydroxylation, in particular, significantly reduced hydroxylation of helical crosslinking residue K87. Consequently, underhydroxylated forms of di- and trivalent crosslinks are strikingly increased in KO bone, leading to increased total crosslinks and decreased helical hydroxylysine- to lysine-derived crosslink ratios. The altered

  18. Child Abuse or Osteogenesis Imperfecta?

    MedlinePlus

    ... Most cases involve a defect in type 1 collagen—the protein “scaffolding” of bone and other connective ... bodies to make either too little type 1 collagen or poor quality type 1 collagen. The result ...

  19. Genetics Home Reference: osteogenesis imperfecta

    MedlinePlus

    ... proteins that are used to assemble type I collagen. This type of collagen is the most abundant protein in bone, skin, ... genetic changes reduce the amount of type I collagen produced in the body, which causes bones to ...

  20. Fast Facts on Osteogenesis Imperfecta

    MedlinePlus

    ... IV in appearance and symptoms of OI. The alkaline phosphatase (an enzyme linked to bone formation) activity ... for people with OI. This treatment involves inserting metal rods through the length of the long bones ...

  1. Myths about OI (Osteogenesis Imperfecta)

    MedlinePlus

    ... Support Groups Glossary Links of Interest Clinic Directory Child Abuse Allegations Adoption Brittle Bone Disorders Rare Disease Consortium ... can be easily distinguished from those caused by child abuse. FACT: Children with OI can have all types ...

  2. G to A substitution in 5{prime} donor splice site of introns 18 and 48 of COL1A1 gene of type I collagen results in different splicing alternatives in osteogenesis imperfecta type I cell strains

    SciTech Connect

    Willing, M.; Deschenes, S.

    1994-09-01

    We have identified a G to A substitution in the 5{prime} donor splice site of intron 18 of one COL1A1 allele in two unrelated families with osteogenesis imperfecta (OI) type I. A third OI type I family has a G to A substitution at the identical position in intron 48 of one COL1A1 allele. Both mutations abolish normal splicing and lead to reduced steady-state levels of mRNA from the mutant COL1A1 allele. The intron 18 mutation leads to both exon 18 skipping in the mRNA and to utilization of a single alternative splice site near the 3{prime} end of exon 18. The latter results in deletion of the last 8 nucleotides of exon 18 from the mRNA, a shift in the translational reading-frame, and the creation of a premature termination codon in exon 19. Of the potential alternative 5{prime} splice sites in exon 18 and intron 18, the one utilized has a surrounding nucleotide sequence which most closely resembles that of the natural splice site. Although a G to A mutation was detected at the identical position in intron 48 of one COL1A1 allele in another OI type I family, nine complex alternative splicing patterns were identified by sequence analysis of cDNA clones derived from fibroblast mRNA from this cell strain. All result in partial or complete skipping of exon 48, with in-frame deletions of portions of exons 47 and/or 49. The different patterns of RNA splicing were not explained by their sequence homology with naturally occuring 5{prime} splice sites, but rather by recombination between highly homologous exon sequences, suggesting that we may not have identified the major splicing alternative(s) in this cell strain. Both G to A mutations result in decreased production of type I collagen, the common biochemical correlate of OI type I.

  3. Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.

    PubMed

    Cabral, Wayne A; Makareeva, Elena; Letocha, Anne D; Scribanu, Nina; Fertala, Andrzej; Steplewski, Andrzej; Keene, Douglas R; Persikov, Anton V; Leikin, Sergey; Marini, Joan C

    2007-04-01

    The most common mutations in type I collagen causing types II-IV osteogenesis imperfecta (OI) result in substitution for glycine in a Gly-Xaa-Yaa triplet by another amino acid. We delineated a Y-position substitution in a small pedigree with a combined OI/Ehlers-Danlos Syndrome (EDS) phenotype, characterized by moderately decreased DEXA z-score (-1.3 to -2.6), long bone fractures, and large-joint hyperextensibility. Affected individuals have an alpha1(I)R888C (p.R1066C) substitution in one COL1A1 allele. Polyacrylamide gel electrophoresis (PAGE) of [(3)H]-proline labeled steady-state collagen reveals slight overmodification of the alpha1(I) monomer band, much less than expected for a substitution of a neighboring glycine residue, and a faint alpha1(I) dimer. Dimers form in about 10% of proband type I collagen. Dimer formation is inefficient compared to a possible 25%, probably because the SH-side chains have less proximity in this Y-position than when substituting for a glycine. Theoretical stability calculations, differential scanning calorimetry (DSC) thermograms, and thermal denaturation curves showed only weak local destabilization from the Y-position substitution in one or two chains of a collagen helix, but greater destabilization is seen in collagen containing dimers. Y-position collagen dimers cause kinking of the helix, resulting in a register shift that is propagated the full length of the helix and causes resistance to procollagen processing by N-proteinase. Collagen containing the Y-position substitution is incorporated into matrix deposited in culture, including immaturely and maturely cross-linked fractions. In vivo, proband dermal fibrils have decreased density and increased diameter compared to controls, with occasional aggregate formation. This report on Y-position substitutions in type I collagen extends the range of phenotypes caused by nonglycine substitutions and shows that, similar to X- and Y-position substitutions in types II and III

  4. What Are the Symptoms of Osteogenesis Imperfecta?

    MedlinePlus

    ... deformities worsen over time The bone deformities and collagen defects common to OI can affect various internal ... be less space for the lungs to expand. Collagen also is an important building block of connective ...

  5. What Are the Treatments for Osteogenesis Imperfecta?

    MedlinePlus

    ... articles, clinical trials, resources Clinical Trials & Clinical Research Find clinical trials, guidance for clinical researchers Health Education Campaigns & Programs Safe to Sleep, Media-Smart Youth, Maternal/Child Health Education Program NICHD Publications ...

  6. Planning for Your Child's Surgery (Osteogenesis Imperfecta)

    MedlinePlus

    ... when something hurts. Common reactions to pain include anger, whining, uncooperativeness, regression to babyish behavior previously outgrown, ... It is normal to experience feelings of guilt, anger, sorrow, depression, fatigue, and stress. The hospital routine ...

  7. Genetics Home Reference: amelogenesis imperfecta

    MedlinePlus

    ... Amelogenesis imperfecta Encyclopedia: Tooth - Abnormal Colors Health Topic: Tooth Disorders Genetic and Rare Diseases Information Center (1 link) ... amelogenesis imperfecta Merck Manual Consumer Version: Overview of Tooth Disorders Orphanet: Amelogenesis imperfecta School of Dentistry, University of ...

  8. [Cytokines and osteogenesis].

    PubMed

    Fujiwara, Makoto; Ozono, Keiichi

    2014-06-01

    Many cytokines associate with proliferation, differentiation and activation of osteoblasts which have an important role in osteogenesis. TGF-β, BMP, IGF, FGF, Hedgehog, Notch, IL and WNT signaling pathways and their inhibitors have been revealed to correlate to osteogenesis, and those gene mutations have been shown to cause various bone disorders. It has been suggested that there are common pathways or crosstalk in these cytokine signaling each other, but mechanism of their complicated regulation on osteogenesis has been unclear. It was expected that the knowledge about these cytokines will apply to clinical therapies of bone diseases. PMID:24870835

  9. Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia

    PubMed Central

    Barron, Martin J; McDonnell, Sinead T; MacKie, Iain; Dixon, Michael J

    2008-01-01

    The hereditary dentine disorders, dentinogenesis imperfecta (DGI) and dentine dysplasia (DD), comprise a group of autosomal dominant genetic conditions characterised by abnormal dentine structure affecting either the primary or both the primary and secondary dentitions. DGI is reported to have an incidence of 1 in 6,000 to 1 in 8,000, whereas that of DD type 1 is 1 in 100,000. Clinically, the teeth are discoloured and show structural defects such as bulbous crowns and small pulp chambers radiographically. The underlying defect of mineralisation often results in shearing of the overlying enamel leaving exposed weakened dentine which is prone to wear. Currently, three sub-types of DGI and two sub-types of DD are recognised but this categorisation may change when other causative mutations are found. DGI type I is inherited with osteogenesis imperfecta and recent genetic studies have shown that mutations in the genes encoding collagen type 1, COL1A1 and COL1A2, underlie this condition. All other forms of DGI and DD, except DD-1, appear to result from mutations in the gene encoding dentine sialophosphoprotein (DSPP), suggesting that these conditions are allelic. Diagnosis is based on family history, pedigree construction and detailed clinical examination, while genetic diagnosis may become useful in the future once sufficient disease-causing mutations have been discovered. Differential diagnoses include hypocalcified forms of amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann's disease, cyclic neutropenia, Chediak-Hegashi syndrome, histiocytosis X, Papillon-Lefevre syndrome), permanent teeth discolouration due to tetracyclines, Vitamin D-dependent and vitamin D-resistant rickets. Treatment involves removal of sources of infection or pain, improvement of aesthetics and protection of the posterior teeth from wear. Beginning in infancy, treatment usually continues into adulthood with a number of options including

  10. Biomimetic Scaffolds for Osteogenesis

    PubMed Central

    Yuan, Nance; Rezzadeh, Kameron S.; Lee, Justine C.

    2015-01-01

    Skeletal regenerative medicine emerged as a field of investigation to address large osseous deficiencies secondary to congenital, traumatic, and post-oncologic conditions. Although autologous bone grafts have been the gold standard for reconstruction of skeletal defects, donor site morbidity remains a significant limitation. To address these limitations, contemporary bone tissue engineering research aims to target delivery of osteogenic cells and growth factors in a defined three dimensional space using scaffolding material. Using bone as a template, biomimetic strategies in scaffold engineering unite organic and inorganic components in an optimal configuration to both support osteoinduction as well as osteoconduction. This article reviews the various structural and functional considerations behind the development of effective biomimetic scaffolds for osteogenesis and highlights strategies for enhancing osteogenesis. PMID:26413557

  11. Combined Treatment with Laser Sintering and Zirconium: A Case Report of Dentinogenesis Imperfecta

    PubMed Central

    Sahin, Cem; Akgün, Özlem Marti; Basak, Feridun

    2013-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous disorder of connective tissue that manifests mainly as skeletal deformity and bone fragility. Dentinogenesis imperfecta (DI) is sometimes an accompanying symptom of OI. The treatment protocol of these patients varies according to the clinical appearance. The case report here describes complete mouth rehabilitation of an 18-year-old male patient with OI and DI using direct metal laser sintering (DMLS) technique of metal-ceramic restorations and zirconium all-ceramic crowns. DMLS is an additive metal fabrication technology that is simpler, more precise, and healthier than conventional manufacturing and can be remarkably cost effective. Moreover, the technique affords highly accurate production of fixed partial dentures with ideal marginal fit and excellent mechanical properties. The patient was treated using a multidisciplinary strategy that focused on controlling caries, protecting teeth from further wear, obtaining an appropriate vertical dimension, and providing soft tissue support to return the facial profile to a normal appearance using new technology in the field of prosthetics. PMID:23533828

  12. Pharmacological management of osteogenesis

    PubMed Central

    Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

    2014-01-01

    Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

  13. Distraction Osteogenesis Update: Introduction of Multidirectional Cranial Distraction Osteogenesis.

    PubMed

    Gomi, Akira; Sunaga, Ataru; Kamochi, Hideaki; Oguma, Hirofumi; Sugawara, Yasushi

    2016-05-01

    In this review, we discuss in detail our current procedure for treating craniosynostosis using multidirectional cranial distraction osteogenesis (MCDO). The MCDO method allows all phenotypes of skull deformity to be reshaped by distraction osteogenesis, except in patients who are 5 months of age or younger and patients with posterior cranial vault problems. We report the results of clinical data of 36 children with craniosynostosis who underwent MCDO between 2005 and 2014 in our institute. This method has the following benefits, such as a high flexibility of reshaping, shorter treatment period and less invasive secondary intervention. We also discuss the other distraction osteogenesis techniques that are used to treat craniosynostosis and compare them with MCDO. The preferred procedure for correction of craniosynostosis may depend on the patient's age, the extent of deformity, and the extent of correction achievable by surgery. We can arrange the combinations of various methods according to the advantage and disadvantage of each technique. PMID:27226854

  14. Distraction Osteogenesis Update: Introduction of Multidirectional Cranial Distraction Osteogenesis

    PubMed Central

    Sunaga, Ataru; Kamochi, Hideaki; Oguma, Hirofumi; Sugawara, Yasushi

    2016-01-01

    In this review, we discuss in detail our current procedure for treating craniosynostosis using multidirectional cranial distraction osteogenesis (MCDO). The MCDO method allows all phenotypes of skull deformity to be reshaped by distraction osteogenesis, except in patients who are 5 months of age or younger and patients with posterior cranial vault problems. We report the results of clinical data of 36 children with craniosynostosis who underwent MCDO between 2005 and 2014 in our institute. This method has the following benefits, such as a high flexibility of reshaping, shorter treatment period and less invasive secondary intervention. We also discuss the other distraction osteogenesis techniques that are used to treat craniosynostosis and compare them with MCDO. The preferred procedure for correction of craniosynostosis may depend on the patient's age, the extent of deformity, and the extent of correction achievable by surgery. We can arrange the combinations of various methods according to the advantage and disadvantage of each technique. PMID:27226854

  15. Intranuclear Actin Regulates Osteogenesis

    PubMed Central

    Sen, Buer; Xie, Zhihui; Uzer, Gunes; Thompson, William R.; Styner, Maya; Wu, Xin; Rubin, Janet

    2016-01-01

    Depolymerization of the actin cytoskeleton induces nuclear trafficking of regulatory proteins and global effects on gene transcription. We here show that in mesenchymal stem cells (MSCs), cytochalasin D treatment causes rapid cofilin-/importin-9-dependent transfer of G-actin into the nucleus. The continued presence of intranuclear actin, which forms rod-like structures that stain with phalloidin, is associated with induction of robust expression of the osteogenic genes osterix and osteocalcin in a Runx2-dependent manner, and leads to acquisition of osteogenic phenotype. Adipogenic differentiation also occurs, but to a lesser degree. Intranuclear actin leads to nuclear export of Yes-associated protein (YAP); maintenance of nuclear YAP inhibits Runx2 initiation of osteogenesis. Injection of cytochalasin into the tibial marrow space of live mice results in abundant bone formation within the space of 1 week. In sum, increased intranuclear actin forces MSC into osteogenic lineage through controlling Runx2 activity; this process may be useful for clinical objectives of forming bone. PMID:26140478

  16. Laser effects on osteogenesis

    NASA Astrophysics Data System (ADS)

    Freitas, I. G. F.; Baranauskas, V.; Cruz-Höfling, M. A.

    2000-02-01

    The traumatic or surgical cutting of a long bone is immediately followed by a sequence of repair processes in which the osteogenic cells of the periosteum start to proliferate and differentiate in osteoblast cells. In this work, we explored the influence of a He-Ne laser on osteogenesis after a controlled surgical fracture. We used young male adult Wistar rats (of mass between 250 and 300 g). The fracture was provoked by piercing a 2-mm-diameter hole in just one cortical tibia surface. Laser treatment was started 24 h after the surgery. The animals were separated into three groups, for different radiation doses, and after daily applications, they were sacrificed at 8 or 15 days. Light and electron microscopies revealed that the laser treatment of the lesion with doses of 31.5 and 94.7 J cm -2 resulted in the formation of thicker bony trabeculae, which indicates a greater synthesis of collagen fibers and therefore that the osteoblastic activity was increased by the low-energy laser radiation.

  17. Study in Mice Links Key Signaling Molecule to Underlying Cause of Osteogenesis Imperfecta

    MedlinePlus

    ... by mutations in a gene that codes for collagen, an abundant structural component of bone. This type ... linked to defects in enzymes that help process collagen to its mature form. These types of OI ...

  18. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta

    PubMed Central

    Pereira, Ruth F.; O’Hara, Michael D.; Laptev, Alexey V.; Halford, Kenneth W.; Pollard, Marea D.; Class, Reiner; Simon, Daniela; Livezey, Kristin; Prockop, Darwin J.

    1998-01-01

    Marrow stromal cells from wild-type mice were infused into transgenic mice that had a phenotype of fragile bones resembling osteogenesis imperfecta because they expressed a human minigene for type I collagen. In mice that were irradiated with potentially lethal levels (700 cGy) or sublethal levels (350 cGy), DNA from the donor marrow stromal cells was detected consistently in marrow, bone, cartilage, and lung either 1 or 2.5 mo after the infusions. The DNA also was detected but less frequently in the spleen, brain, and skin. There was a small but statistically significant increase in both collagen content and mineral content of bone 1 mo after the infusion. Similar results were obtained with infusion of relatively large amounts of wild-type whole marrow cells into the transgenic mice. In experiments in which male marrow stromal cells were infused into a female osteogenesis imperfecta-transgenic mouse, fluorescense in situ hybridization assays for the Y chromosome indicated that, after 2.5 mo, donor male cells accounted for 4–19% of the fibroblasts or fibroblast-like cells obtained in primary cultures of the lung, calvaria, cartilage, long bone, tail, and skin. In a parallel experiment in which whole marrow cells from a male mouse were infused into a female immunodeficient rag-2 mouse, donor male cells accounted for 4–6% of the fibroblasts or fibroblast-like cells in primary cultures. The results support previous suggestions that marrow stromal cells or related cells in marrow serve as a source for continual renewal of cells in a number of nonhematopoietic tissues. PMID:9448299

  19. Transcriptional Repression of the Dspp Gene Leads to Dentinogenesis Imperfecta Phenotype in Col1a1-Trps1 Transgenic Mice

    PubMed Central

    Napierala, Dobrawa; Sun, Yao; Maciejewska, Izabela; Bertin, Terry K; Dawson, Brian; D'Souza, Rena; Qin, Chunlin; Lee, Brendan

    2012-01-01

    Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro–computed tomography (µCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI. © 2012 American Society for Bone and Mineral Research. PMID:22508542

  20. A Case of Dentinogenesis Imperfecta Treated with Submerged Root Technique

    PubMed Central

    Chandar, Bhanu; Srilakshmi, J.; Khaitan, Tanya; Babu, B. Balaji

    2015-01-01

    Dentinogenesis imperfecta (DGI), an autosomal dominant trait, is one of the most common hereditary disorders affecting both the formation and mineralization of dentin. Either or both primary and permanent dentition is affected by it. Here, we present a case report of a 13-year-old female patient affected with DGI who had undergone prosthetic rehabilitation with submerged root technique. PMID:26501025

  1. Treatment considerations for patient with Amelogenesis Imperfecta: a review

    PubMed Central

    Chen, Chiung-Fen; Hu, Jan CC; Bresciani, Eduardo; Peters, Mathilde C; Estrella, Maria Regina

    2016-01-01

    Objectives Amelogenesis imperfecta (AI) is a group of inherited disorders primary affecting the structural of enamel. Patients with AI experience poor esthetic, excessive tooth sensitivity and compromised chewing function that dental treatments are frequently required at early age. This review describes the non-enamel implications, stage-specific management strategies and outcomes of selected restorative materials based on literature evidence.

  2. Sclerostin Antibody Improves Skeletal Parameters in a Brtl/+ Mouse Model of Osteogenesis Imperfecta†

    PubMed Central

    Sinder, Benjamin P.; Eddy, Mary M.; Ominsky, Michael S; Caird, Michelle S.; Marini, Joan C.; Kozloff, Kenneth M.

    2012-01-01

    Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although anti-resorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials showed improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly->Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in Brtl/+ and WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI. PMID:22836659

  3. Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification.

    PubMed

    de La Dure-Molla, Muriel; Philippe Fournier, Benjamin; Berdal, Ariane

    2015-04-01

    Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners. PMID:25118030

  4. Vertical Alveolar Ridge Augmentation by Distraction Osteogenesis

    PubMed Central

    Kumar, N. Nanda; Ravindran, C.

    2015-01-01

    Introduction Compromised alveolar ridge in vertical and horizontal dimension is a common finding in patients visiting practitioners for dental prosthesis. Various treatment modalities are available for correction of deficient ridges among which alveolar distraction osteogenesis is one. Aim To study the efficacy of alveolar distraction osteogenesis in augmentation of alveolar ridges deficient in vertical dimension. Materials and Methods Ten patients aged 16 to 46 years with deficient alveolar ridge underwent ridge augmentation in 11 alveolar segments using the distraction osteogenesis method. For each patient a custom made distraction device was fabricated. The device was indigenously manufactured with SS-316 (ISO 3506). Results The vertical bone gain reached more than 10mm without the use of bone transplantation. Certain complications like incorrect vector of distraction, paresthesia, pain and loss of transport segment were encountered during the course of the study. Conclusion Alveolar vertical distraction osteogenesis is a reliable and predictable technique for both hard and soft tissue genesis. Implant placement is feasible with primary stability in neogenerated bone at the level of the distracted areas. PMID:26816991

  5. Nuclear sequestration of COL1A1 mRNA transcript associated with type I osteogenesis imperfecta (OI)

    SciTech Connect

    Primorac, D.; Stover, M.L.; McKinstry, M.B.

    1994-09-01

    Previously we identified an OI type I patient with a splice donor mutation that resulted in intron 26 retention instead of exon skipping and sequestration of normal levels of the mutant transcript in the nuclear compartment. Intron retention was consistent with the exon definition hypothesis for splice site selection since the size of the exon-intron-exon unit was less than 300 bp. Furthermore, the retained intron contained in-frame stop codons which is thought to cause the mutant RNA to remain within the nucleus rather than appearing in the cytoplasm. To test these hypotheses, genomic fragments containing the normal sequence or the donor mutation were cloned into a collagen minigene and expressed in stably tansfected NIH 3T3 cells. None of the modifications to the normal intron altered the level of RNA that accumulated in the cytoplasm, as expected. However none of the modifications to the mutant intron allowed accumulation of normal levels of mRNA in the cytoplasm. Moreover, in contrast to our findings in the patient`s cells only low levels of mutant transcript were found in the nucleus; a fraction of the transcript did appear in the cytoplasm which had spliced the mutant donor site correctly. Nuclear run-on experiments demonstrated equal levels of transcription from each transgene. Expression of another donor mutation known to cause in-frame exon skipping in OI type IV was accurately reproduced in the minigene in transfected 3T3 cells. Our experience suggests that either mechanism can lead to formation of a null allele possibly related to the type of splicing events surrounding the potential stop codons. Understanding the rules governing inactivation of a collagen RNA transcript may be important in designing a strategy to inactivate a dominate negative mutation associated with the more severe forms of OI.

  6. Callus stimulation in distraction osteogenesis.

    PubMed

    Mofid, Mehrdad M; Inoue, Nozomu; Atabey, Atay; Marti, Guy; Chao, Edmund Y S; Manson, Paul N; Vander Kolk, Craig A

    2002-04-15

    Distraction osteogenesis has been described as in vivo tissue engineering. The ability to stimulate this process for the repair of bony defects or lengthening of congenitally shortened facial structures is likely to significantly impact the field of craniofacial surgery. The purpose of this study was to determine whether mechanical stimulation of the distracted rabbit mandible would accelerate the maturation of the bony callus when applied during the early consolidation period. Twenty adult New Zealand White rabbits underwent unilateral mandibular osteotomy. A uni-directional internal distractor device (Synthes, Paoli, Pa.) was positioned along a plane perpendicular to the line of osteotomy. After a 7-day latency period, distraction was commenced at a rate of 1.0 mm/day for 12 days in all animals. In a control group of 10 rabbits, a consolidation period of 8 weeks was observed before they were killed. In the experimental group of 10 rabbits, daily alternate compression and distraction of 1 mm (sequential compression and distraction) was performed for 3 weeks followed by a 5-week period of rigid fixation. Each animal received a dose of a fluorescent label at three different time points during the study: at the end of the distraction period, 3 weeks after the completion of the distraction phase, and 3 days before it was killed. All animals were killed 8 weeks after the completion of the distraction phase. Undecalcified histologic analysis and 3-point bending tests to failure were performed on the extracted mandibles. The results of the experimental and control groups were compared. Four animals in the control group and three animals in the experimental group were excluded from the study because of screw loosening resulting in distractor dislodgment or because of infection. On histologic analysis, cortical thickness at the center of the callus was found to be significantly greater in the experimental group compared with the control group when normalized to the

  7. Esthetic and functional rehabilitation of mutilated dentition and loss of vertical dimension due to amelogenesis imperfecta.

    PubMed

    Mittal, Shweta; Tewari, Sanjay; Goel, Rajat

    2014-04-01

    Cases of severe attrition are a common finding. Among the congenital anomalies, amelogenesis imperfecta and dentinogenesis imperfecta are important conditions that may cause accelerated wear of teeth. The following case report describes the complete oral rehabilitation of a patient diagnosed with amelogenesis imperfecta. A detailed treatment plan was chalked out which included proper oral hygiene measures, restoration of carious teeth and endodontic treatment followed by foundation restorations of teeth that were crucial for the final prostheses. Patient was given transitional restorations for about 6 weeks with the aim of regaining the lost vertical dimensions. Final rehabilitation was done by fixed dental prostheses. PMID:25565735

  8. Distal renal tubular acidosis and amelogenesis imperfecta: A rare association.

    PubMed

    Ravi, P; Ekambaranath, T S; Arasi, S Ellil; Fernando, E

    2013-11-01

    Renal tubular acidosis (RTA) is characterized by a normal anion gap with hyperchloremic metabolic acidosis. Primary distal RTA (type I) is the most common RTA in children. Childhood presentation of distal RTA includes vomiting, failure to thrive, metabolic acidosis, and hypokalemia. Amelogenesis imperfecta (AI) represents a condition where the dental enamel and oral tissues are affected in an equal manner resulting in the hypoplastic or hypopigmented teeth. We report a 10-year-old girl, previously asymptomatic presented with the hypokalemic paralysis and on work-up found out to have type I RTA. The discoloration of teeth and enamel was diagnosed as AI. PMID:24339526

  9. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    PubMed

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related. PMID:23958762

  10. Amelogenesis imperfecta and anterior open bite: Etiological, classification, clinical and management interrelationships

    PubMed Central

    Alachioti, Xanthippi Sofia; Dimopoulou, Eleni; Vlasakidou, Anatoli; Athanasiou, Athanasios E

    2014-01-01

    Although amelogenesis imperfecta is not a common dental pathological condition, its etiological, classification, clinical and management aspects have been addressed extensively in the scientific literature. Of special clinical consideration is the frequent co-existence of amelogenesis imperfecta with the anterior open bite. This paper provides an updated review on amelogenesis imperfecta as well as anterior open bite, in general, and documents the association of these two separate entities, in particular. Diagnosis and treatment of amelogenesis imperfecta patients presenting also with anterior open bite require a lengthy, comprehensive and multidisciplinary approach, which should aim to successfully address all dental, occlusal, developmental, skeletal and soft tissue problems associated with these two serious clinical conditions. PMID:24987656

  11. Increased susceptibility to microdamage in Brtl/+ mouse model for osteogenesis imperfecta☆

    PubMed Central

    Davis, Mathieu S.; Kovacic, Bethany L.; Marini, Joan C.; Shih, Albert J.; Kozloff, Kenneth M.

    2012-01-01

    Osteogenesis imperfecta (OI) is a genetic disease of collagen or collagen-related proteins that adversely impacts bone mass and fracture resistance. Little is known regarding the role that microdamage plays in OI and whether or not OI bone is more prone to damage accumulation than bone with unaffected collagen. The Brtl/+ mouse is a heterozygous model for OI which contains a Gly349Cys substitution in one COL1A1 allele, and demonstrates a low ductility phenotype. At 8 weeks of age, Brtl/+ demonstrates an increase in osteoclast number, which mimics the upregulated bone turnover often found in OI patients. We hypothesize that upregulated osteoclast activity in Brtl/+ is due, in part, to increased remodeling associated with microdamage repair. In the present study, we used Brtl/+ to investigate the susceptibility of OI bone to microdamage. The mouse ulnar loading model was used to induce microdamage and to test the hypothesis that Brtl/+ is more susceptible to damage accumulation than age-matched wild type (WT) counterparts. Linear elastic fracture mechanics (LEFM) was used to investigate the fracture toughness properties of both Brtl/+ and WT bones to determine if there is any correlation with toughness and the degree of microdamage. Results show that Brtl/+ ulnae subject to normal cage activity demonstrate an inherently larger amount of microdamage than WT controls. Following axial compressive loading, Brtl/+ ulnae are more prone to damage than WT counterparts despite demonstrating a greater resistance to whole-bone deformation. Fracture toughness results demonstrate that Brtl/+ specimens, despite not exhibiting a significant difference, display a trend toward lower fracture toughness values than their WT counterparts. Correlations show that microdamage levels tend to increase as fracture toughness decreases. Together, these findings may have strong clinical implications for explaining increased fragility and remodeling activity in OI patients. PMID:22207275

  12. Occurrence of epidermolysis bullosa along with Amelogenesis imperfecta in female patient of India

    PubMed Central

    Javed, A. P.; Shenai, Prashanth; Chatra, Laxmikanth; Veena, K. M.; Rao, Prasanna Kumar; Prabhu, Rachana

    2013-01-01

    Epidermolysis bullosa (EB) is an inherited disorder, which is characteristically presented as skin blisters developing in response to minor injury. Junctional variety of EB is also associated with enamel hypoplasia. Amelogenesis imperfecta presents with abnormal formation of the enamel both in deciduous and permanent dentition. This article describes a previously unreported case of Amelogenesis imperfecta with complete loss of enamel in a young female patient with EB. PMID:24379873

  13. Formation of ectopic osteogenesis in weightlessness

    NASA Technical Reports Server (NTRS)

    1977-01-01

    An ectopic osteogenesis experiment aboard the Cosmos-936 biosatellite is described. Decalcified, lyophilized femur and tibia were implanted under the fascia or in the anterior wall of the abdomen in rats. Bone formation before and after the tests is described and illustrated. The extent of formation of ectopic bone in weightlessness did not differ significantly from that in the ground controls, but the bone marrow of the ectopic bone of the flight rats consisted exclusively of fat cells. The deficit of support-muscle loading was considered to cause the disturbance in skeletal bone tissue development.

  14. Angiogenesis and mineralization during distraction osteogenesis.

    PubMed Central

    Choi, In Ho; Chung, Chin Youb; Cho, Tae-Joon; Yoo, Won Joon

    2002-01-01

    Distraction osteogenesis is currently a standard method of bone lengthening. It is a viable method for the treatment of short extremities as well as extensive bone defects, because large amounts of bone can be regenerated in the distraction gap. Mechanical stimulation by distraction induces biological responses of skeletal regeneration that is accomplished by a cascade of biologic processes that may include differentiation of pluripotential tissue, angiogenesis, mineralization, and remodeling. There are complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Regenerate bone forms by three modes of ossification, which include intramembranous, enchondral, and transchondroid ossifications, although intramembraneous bone formation is the predominant mechanism of ossification. In this review we discussed the coupling between angiogenesis and mineralization, the biological and mechanical factors affecting them, the cellular and molecular events occurring during distraction osteogenesis, and the emerging modalities to accelerate regenerate bone healing and remodeling. PMID:12172035

  15. Bilateral nephrocalcinosis and amelogenesis imperfecta: A case report

    PubMed Central

    Patel, Alok; Jagtap, Chetana; Bhat, Chetan; Shah, Rohan

    2015-01-01

    Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. This paper describes the clinicopathological features of a patient who was born of nonconsanguineous parents and who presented with oral alterations, including yellow and misshapen teeth, intrapulpal calcifications, delayed tooth eruption, and gum enlargement. Scanning electron microscopy of the teeth revealed hypoplastic enamel, and a renal ultrasound detected bilateral nephrocalcinosis, leading to a diagnosis of AI and nephrocalcinosis syndrome. Since nephrocalcinosis is often asymptomatic and can be associated with impaired renal function, dentists who see children with a generalized and thin hypoplastic AI should consider a renal ultrasound scan and referral to a Nephrologist. Children with nephrocalcinosis should also be considered for a dental check. PMID:26097369

  16. Amelogenesis Imperfecta, Facial Esthetics and Snap-On Smile.

    PubMed

    Wilson, Lee; Bradshaw, Jonathan P; Marks, Murray K

    2015-01-01

    Amelogenesis imperfecta is a hereditary enamel protein disorder affecting deciduous and secondary crown formation. The prevalence ranges from 1:700 to 1:14,000 depending on the population. These teeth may be hypoplastic, hypomineralized, or hypermineralized and are often discolored, sensitive and caries vulnerable. Patients often present with psychosocial issues due to appearance. Primary teeth are often treated with stainless steel crowns while secondary teeth are treated with full coverage esthetic crowns. The presenting preteen male here was fitted with Snap-On Smile? (www.snaponsmile.com). This treatment option provided cosmetic enhancement of the patient's appearance besides stabilization without altering the primary and secondary dentition during adolescent development. PMID:26433999

  17. Conservative esthetic rehabilitation of a young patient with amelogenesis imperfecta.

    PubMed

    Tunkiwala, Aliasger; Vazifdar, Danesh

    2014-03-01

    Conservative management of young adult patients with amelogenesis imperfecta using contemporary materials and techniques is needed in dentistry. These patients have malformed enamel that tends to wear down at a faster rate than normal and is prone to decay. Conventional management of such patients requires devitalization of all involved teeth, followed by post cores and crown lengthening and preparing them to provide sufficient space to receive full-coverage restorations. This article outlines a minimally invasive method of managing such cases. By increasing the vertical dimension of occlusion and using very minimal or no preparations and fabrication of lithium-disilicate crowns to adhesively bond to the remaining tooth structure, these teeth can be saved from being devitalized, as demonstrated in a case. This allows the structural integrity of the teeth to be maintained, along with their vitality. PMID:24773197

  18. Amelogenesis imperfecta - lifelong management. Restorative management of the adult patient.

    PubMed

    Patel, M; McDonnell, S T; Iram, S; Chan, M F W-Y

    2013-11-01

    The biggest challenge restorative dentists face in rehabilitating patients with amelogenesis imperfecta (AI) is trying to restore aesthetics, function and occlusal stability while keeping the treatment as conservative as possible. The goals of treatment should be to prolong the life of the patient's own teeth and avoid or delay the need for extractions and subsequent replacement with conventional fixed, removable or implant retained prostheses. In order to achieve these goals a stepwise approach to treatment planning is required starting with the most conservative but aesthetically acceptable treatment. This article discusses the management of AI and presents the various treatment options available for restoring the adult patient who presents to the dentist with AI. PMID:24201615

  19. Mild balanoposthitis.

    PubMed Central

    Fornasa, C V; Calabrŏ, A; Miglietta, A; Tarantello, M; Biasinutto, C; Peserico, A

    1994-01-01

    AIM--To identify and study cases of mild balanoposthitis (MBP) with penile pathology among patients observed at a dermatology clinic over an 18-month period. MATERIALS--The study included 321 patients with penile pathology. The term MBP was used to describe balanoposthitis of a localised, inflammatory nature with few, non-specific symptoms and a tendency to become chronic or recur. Two hundred and seventy had diseases clearly identifiable by clinical examination or laboratory tests; 51 cases were diagnosed as MBP and these patients had blood tests (to evaluate immune status) and microbiological examination; when these proved negative, a series of patch tests was also used. RESULTS--Of the 51 patients diagnosed as having MBP, the cause was ascertained in 34 cases (infection, mechanical trauma, contact irritation, contact allergy, etc.), whereas no specific aetiological factor was detected to explain the symptoms in the remaining 17 cases. PMID:8001949

  20. Enamel renal syndrome with associated amelogenesis imperfecta, nephrolithiasis, and hypocitraturia: A case report.

    PubMed

    Bhesania, Dhvani; Arora, Ankit; Kapoor, Sonali

    2015-09-01

    Numerous cases of enamel renal syndrome have been previously reported. Various terms, such as enamel renal syndrome, amelogenesis imperfecta and gingival fibromatosis syndrome, and enamel-renal-gingival syndrome, have been used for patients presenting with the dental phenotype characteristic of this condition, nephrocalcinosis or nephrolithiasis, and gingival findings. This report describes a case of amelogenesis imperfecta of the enamel agenesis variety with nephrolithiasis in a 21-year-old male patient who complained of small teeth. The imaging modalities employed were conventional radiography, cone-beam computed tomography, and renal sonography. Such cases are first encountered by dentists, as other organ or metabolic diseases are generally hidden. Hence, cases of amelogenesis imperfecta should be subjected to advanced diagnostic modalities, incorporating both dental and medical criteria, in order to facilitate comprehensive long-term management. PMID:26389061

  1. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

    PubMed

    Poulter, James A; Murillo, Gina; Brookes, Steven J; Smith, Claire E L; Parry, David A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-10-15

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid. PMID:24858907

  2. Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta

    PubMed Central

    Seymen, F; Lee, K-E; Koruyucu, M; Gencay, K; Bayram, M; Tuna, EB; Lee, ZH; Kim, J-W

    2015-01-01

    Objective Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell–cell and cell–extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. Materials and Methods We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. Results Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the βI-domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. Conclusions In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development. PMID:25431241

  3. Post microtextures accelerate cell proliferation and osteogenesis.

    PubMed

    Kim, Eun Jung; Boehm, Cynthia A; Mata, Alvaro; Fleischman, Aaron J; Muschler, George F; Roy, Shuvo

    2010-01-01

    The influence of surface microtexture on osteogenesis was investigated in vitro by examining the proliferation and differentiation characteristics of a class of adult stem cells and their progeny, collectively known as connective tissue progenitor cells (CTPs). Human bone marrow-derived CTPs were cultured for up to 60 days on smooth polydimethylsiloxane (PDMS) surfaces and on PDMS with post microtextures that were 10 microm in diameter and 6 microm in height, with 10 microm separation. DNA quantification revealed that the numbers of CTPs initially attached to both substrates were similar. However, cells on microtextured PDMS transitioned from lag phase after 4 days of culture, in contrast to 6 days for cells on smooth surfaces. By day 9 cells on the smooth surfaces exhibited arbitrary flattened shapes and migrated without any preferred orientation. In contrast, cells on the microtextured PDMS grew along the array of posts in an orthogonal manner. By days 30 and 60 cells grew and covered all surfaces with extracellular matrix. Western blot analysis revealed that the expression of integrin alpha5 was greater on the microtextured PDMS compared with smooth surfaces. Real time reverse transcription-polymerase chain reaction revealed that gene expression of alkaline phosphatase had decreased by days 30 and 60, compared with that on day 9, for both substrates. Gene expression of collagen I and osteocalcin was consistently greater on post microtextures relative to smooth surfaces at all time points. PMID:19539062

  4. MicroRNAs regulate osteogenesis and chondrogenesis

    SciTech Connect

    Dong, Shiwu; Yang, Bo; Guo, Hongfeng; Kang, Fei

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer To focus on the role of miRNAs in chondrogenesis and osteogenesis. Black-Right-Pointing-Pointer Involved in the regulation of miRNAs in osteoarthritis. Black-Right-Pointing-Pointer To speculate some therapeutic targets for bone diseases. -- Abstract: MicroRNAs (miRNAs) are a class of small molecules and non-coding single strand RNAs that regulate gene expression at the post-transcriptional level by binding to specific sequences within target genes. miRNAs have been recognized as important regulatory factors in organism development and disease expression. Some miRNAs regulate the proliferation and differentiation of osteoblasts, osteoclasts and chondrocytes, eventually influencing metabolism and bone formation. miRNAs are expected to provide potential gene therapy targets for the clinical treatment of metabolic bone diseases and bone injuries. Here, we review the recent research progress on the regulation of miRNAs in bone biology, with a particular focus on the miRNA-mediated control mechanisms of bone and cartilage formation.

  5. Post microtextures accelerate cell proliferation and osteogenesis

    PubMed Central

    Kim, Eun Jung; Boehm, Cynthia A.; Mata, Alvaro; Fleischman, Aaron J.; Muschler, George F.; Roy, Shuvo

    2013-01-01

    The influence of surface microtexture on osteogenesis was investigated in vitro by examining the proliferation and differentiation characteristics of a class of adult stem cells and their progeny, collectively known as connective tissue progenitor cells (CTPs). Human bone marrow-derived CTPs were cultured for up to 60 days on smooth polydimethylsiloxane (PDMS) surfaces and on PDMS with post microtextures that were 10 µm in diameter and 6 µm in height, with 10 µm separation. DNA quantification revealed that the numbers of CTPs initially attached to both substrates were similar. However, cells on microtextured PDMS transitioned from lag phase after 4 days of culture, in contrast to 6 days for cells on smooth surfaces. By day 9 cells on the smooth surfaces exhibited arbitrary flattened shapes and migrated without any preferred orientation. In contrast, cells on the microtextured PDMS grew along the array of posts in an orthogonal manner. By days 30 and 60 cells grew and covered all surfaces with extracellular matrix. Western blot analysis revealed that the expression of integrin α5 was greater on the microtextured PDMS compared with smooth surfaces. Real time reverse transcription-polymerase chain reaction revealed that gene expression of alkaline phosphatase had decreased by days 30 and 60, compared with that on day 9, for both substrates. Gene expression of collagen I and osteocalcin was consistently greater on post microtextures relative to smooth surfaces at all time points. PMID:19539062

  6. Cisplatin inhibits bone healing during distraction osteogenesis.

    PubMed

    Stine, Kimo C; Wahl, Elizabeth C; Liu, Lichu; Skinner, Robert A; Vanderschilden, Jacquelyn; Bunn, Robert C; Montgomery, Corey O; Suva, Larry J; Aronson, James; Becton, David L; Nicholas, Richard W; Swearingen, Christopher J; Lumpkin, Charles K

    2014-03-01

    Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. PMID:24259375

  7. Diffusion model to describe osteogenesis within a porous titanium scaffold.

    PubMed

    Schmitt, M; Allena, R; Schouman, T; Frasca, S; Collombet, J M; Holy, X; Rouch, P

    2016-01-01

    In this study, we develop a two-dimensional finite element model, which is derived from an animal experiment and allows simulating osteogenesis within a porous titanium scaffold implanted in ewe's hemi-mandible during 12 weeks. The cell activity is described through diffusion equations and regulated by the stress state of the structure. We compare our model to (i) histological observations and (ii) experimental data obtained from a mechanical test done on sacrificed animal. We show that our mechano-biological approach provides consistent numerical results and constitutes a useful tool to predict osteogenesis pattern. PMID:25573031

  8. Cordycepin prevents oxidative stress-induced inhibition of osteogenesis

    PubMed Central

    Wang, Feng; Yin, Peipei; Lu, Ye; Zhou, Zubin; Jiang, Chaolai; Liu, Yingjie; Yu, Xiaowei

    2015-01-01

    Oxidative stress is known to be involved in impairment of osteogenesis and age-related osteoporosis. Cordycepin is one of the major bioactive components of Cordyceps militaris that has been shown to exert antioxidant and anti-inflammatory activities. However, there are few reports available regarding the effects of cordycepin on osteogenesis and the underlying mechanism. In this study, we investigated the potential osteoprotective effects of cordycepin and its mechanism systematically using both in vitro model as well as in vivo mouse models. We discovered that hydrogen peroxide (H2O2) induced inhibition of osteogenesis which was rescued by cordycepin treatment in human bone marrow mesenchymal stem cells (BM-MSCs). Cordycepin exerted its protective effects partially by increasing or decreasing expression of osteogenic and osteoclastogenesis marker genes. Treatment with cordycepin increased Wnt-related genes' expression whereas supplementation of Wnt pathway inhibitor reversed its protective effects. In addition, administration of cordycepin promoted osteogenic differentiation of BM-MSCs by reducing oxidative stress in both ovariectomized and aged animal models. Taken together, these results support the protective effects of cordycepin on oxidative stress induced inhibition of osteogenesis by activation of Wnt pathway. PMID:26462178

  9. Cordycepin prevents oxidative stress-induced inhibition of osteogenesis.

    PubMed

    Wang, Feng; Yin, Peipei; Lu, Ye; Zhou, Zubin; Jiang, Chaolai; Liu, Yingjie; Yu, Xiaowei

    2015-11-01

    Oxidative stress is known to be involved in impairment of osteogenesis and age-related osteoporosis. Cordycepin is one of the major bioactive components of Cordyceps militaris that has been shown to exert antioxidant and anti-inflammatory activities. However, there are few reports available regarding the effects of cordycepin on osteogenesis and the underlying mechanism. In this study, we investigated the potential osteoprotective effects of cordycepin and its mechanism systematically using both in vitro model as well as in vivo mouse models. We discovered that hydrogen peroxide (H2O2)-induced inhibition of osteogenesis which was rescued by cordycepin treatment in human bone marrow mesenchymal stem cells (BM-MSCs). Cordycepin exerted its protective effects partially by increasing or decreasing expression of osteogenic and osteoclastogenesis marker genes. Treatment with cordycepin increased Wnt-related genes' expression whereas supplementation of Wnt pathway inhibitor reversed its protective effects. In addition, administration of cordycepin promoted osteogenic differentiation of BM-MSCs by reducing oxidative stress in both ovariectomized and aged animal models. Taken together, these results support the protective effects of cordycepin on oxidative stress induced inhibition of osteogenesis by activation of Wnt pathway. PMID:26462178

  10. Unilateral mandibular ramus elongation by intraoral distraction osteogenesis.

    PubMed

    Kofod, Thomas; Nørholt, Sven Erik; Pedersen, Thomas Klit; Jensen, John

    2005-03-01

    Successful correction of facial asymmetry by mandibular distraction osteogenesis relies on mastering vector control. Lack of necessary vector control continues to compromise the treatment modality. The purpose of this study was to describe a new simplified method for vector transfer and to evaluate this method according to the outcome and the efficacy of distraction osteogenesis in the correction of unilateral mandibular hypoplasia and asymmetry. Twenty-seven patients with unilateral hypoplasia of the mandibular ramus underwent unilateral mandibular distraction osteogenesis with intraoral distraction devices. Posterior-anterior and lateral cephalograms were analyzed by digitalization. Changes in sagittal, vertical, and transversal linear and angular dimensions after the distraction treatment were evaluated by measurements performed on headfilms taken before and after surgery. Means and variances were calculated for selected cephalometric variables for each time point. The differences between the control and the treatment side were calculated, statistically described, and compared with a paired Student t test. Correction of the mandibular asymmetry, chin position, and the canting of the occlusal plane was obtained in all patients clinically, as well as radiographically, by the use of intraoral unidirectional distraction osteogenesis. PMID:15750421

  11. The mineral composition and enamel ultrastructure of hypocalcified amelogenesis imperfecta.

    PubMed

    Wright, J T; Duggal, M S; Robinson, C; Kirkham, J; Shore, R

    1993-01-01

    Hypocalcified amelogenesis imperfecta is characterized clinically by a yellow-brown colored enamel that is prone to severe attrition, often leading to rapid destruction of the crown. While the enamel is thought to be poorly mineralized few studies have evaluated the mineral content, or the histological or microradiographic features of this specific AI type. The purpose of this investigation was to examine teeth affected with autosomal dominant hypocalcified AI histologically using light microscopy (LM), scanning electron microscopy (SEM), and to evaluate the degree of enamel mineralization chemically and with microradiography. Four AI teeth were obtained from an affected individual for comparison with age-matched teeth from normal healthy individuals. Thin sections approximately 100 microns were cut with a diamond disc for examination by LM and microradiography. Using SEM, fractured enamel samples were examined either untreated or after removal of organic material using NaOCl or urea. Normal and AI enamel particles were dissected from thin sections to evaluate the mineral per volume and carbonate content. The enamel was not uniformly affected in all areas of the teeth with the lingual surfaces of the mandibular central incisors appearing clinically and histologically normal. The affected enamel was porous and appeared opaque with LM. Both SEM and LM showed the enamel to be prismatic with relatively normal prism morphology. However, the enamel crystallites were rough and granular compared with those of normal enamel. Extraction to remove organic material did not change the appearance of the crystallites indicating their granular appearance was due to mineral and not residual organic material such as enamel protein. Microradiography showed the enamel was less radiodense and therefore poorly mineralized compared with normal enamel. This was confirmed by chemical determination of the mineral per volume, which showed some areas of the AI enamel had as much as 30% less

  12. Further safety enhancement of a specialized power assisted tricycle for a child with osteogenesis imperfecta type III and design of an adjustble hand power tricycle.

    PubMed

    Geu, Matthew; Madsen, Robert; Weber, Erica; Burnett, Michael; Barrett, Steven

    2006-01-01

    Several tricycles, one a customized power assisted tricycle, and the second a hand powered tricycle were developed, which offered a unique opportunity to serve multiple purposes in several children's development throughout Wyoming. In Both cases these tricycles provide the children with the opportunity to gain muscle mass, strength, coordination, and confidence. The power assisted tricycle was completed as a senior design project in 2002, and over time safety enhancements have been completed to make the tricycle safer for operation. Unfortunately, the safety system enhancements were not acceptable for it to be released for use. For this reason the tricycle was further redesigned to include more redundant safety systems which will allow the tricycle to be safe for the child's use. The second tricycle was designed to allow for a group of children who have limited use of their legs, to be able to use the same tricycle to give them more upper body strength. A gear system using multiple gear sprockets was adapted to a preexisting tricycle to provide hand power rather than foot power. Without these improvements, the children would not have the opportunity to use these tricycles to help with their development. PMID:16817593

  13. The epitheliogenesis imperfecta locus maps to equine chromosome 8 in American Saddlebred horses.

    PubMed

    Lieto, L D; Cothran, E G

    2003-01-01

    Epitheliogenesis imperfecta (EI) is a hereditary junctional mechanobullous disease that occurs in newborn American Saddlebred foals. The pathological signs of epitheliogenesis imperfecta closely match a similar disease in humans known as Herlitz junctional epidermolysis bullosa, which is caused by a mutation in one of the genes (LAMA3, LAMB3 and LAMC2) coding for the subunits of the laminin 5 protein (laminin alpha3, laminin beta3 and laminin gamma2). The LAMA3 gene has been assigned to equine chromosome 8 and LAMB3 and LAMC2 have been mapped to equine chromosome 5. Linkage disequilibrium between microsatellite markers that mapped to equine chromosome 5 and equine chromosome 8 and the EI disease locus was tested in American Saddlebred horses. The allele frequencies of microsatellite alleles at 11 loci were determined for both epitheliogenesis imperfecta affected and unaffected populations of American Saddlebred horses by genotyping and direct counting of alleles. These were used to determine fit to Hardy-Weinberg equilibrium for control and EI populations using Chi square analysis. Two microsatellite loci located on equine chromosome 8q, ASB14 and AHT3, were not in Hardy-Weinberg equilibrium in affected American Saddlebred horses. In comparison, all of the microsatellite markers located on equine chromosome 5 were in Hardy-Weinberg equilibrium in affected American Saddlebred horses. This suggested that the EI disease locus was located on equine chromosome 8q, where LAMA3 is also located. PMID:14970704

  14. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.

    PubMed

    Wu, Xu; Walker, John; Zhang, Jie; Ding, Sheng; Schultz, Peter G

    2004-09-01

    Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease. PMID:15380183

  15. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

    NASA Astrophysics Data System (ADS)

    Ramasamy, Saravana K.; Kusumbe, Anjali P.; Wang, Lin; Adams, Ralf H.

    2014-03-01

    Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

  16. Relationships between tissue dilatation and differentiation in distraction osteogenesis

    PubMed Central

    Morgan, Elise F.; Longaker, Michael T.; Carter, Dennis R.

    2007-01-01

    Mechanical factors modulate the morphogenesis and regeneration of mesenchymally derived tissues via processes mediated by the extracellular matrix (ECM). In distraction osteogenesis, large volumes of new bone are created through discrete applications of tensile displacement across an osteotomy gap. Although many studies have characterized the matrix, cellular and molecular biology of distraction osteogenesis, little is known about relationships between these biological phenomena and the local physical cues generated by distraction. Accordingly, the goal of this study was to characterize the local physical environment created within the osteotomy gap during long bone distraction osteogenesis. Using a computational approach, we quantified spatial and temporal profiles of three previously identified mechanical stimuli for tissue differentiation–pressure, tensile strain and fluid flow–as well as another candidate stimulus–tissue dilatation (volumetric strain). Whereas pressure and fluid velocity throughout the regenerate decayed to less than 31% of initial values within 20 min following distraction, tissue dilatation increased with time, reaching steady state values as high as 43% strain. This dilatation created large reductions and large gradients in cell and ECM densities. When combined with previous findings regarding the effects of strain and of cell and ECM densities on cell migration, proliferation and differentiation, these results indicate two mechanisms by which tissue dilatation may be a key stimulus for bone regeneration: (1) stretching of cells and (2) altering cell and ECM densities. These results are used to suggest experiments that can provide a more mechanistic understanding of the role of tissue dilatation in bone regeneration. PMID:16330195

  17. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

    PubMed Central

    Wang, Lin; Adams, Ralf H.

    2016-01-01

    Blood vessel growth in the skeletal system and osteogenesis appear coupled suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells1,2. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here, we show that vascular growth in bone involves a specialised, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours3,4. Endothelial cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae, and decreased bone mass. Based on a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralisation, chondrocyte maturation, the formation of trabeculae, and osteoprogenitor numbers in endothelial cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications. PMID:24647000

  18. Enhanced Osteogenesis by Reduced Graphene Oxide/Hydroxyapatite Nanocomposites

    PubMed Central

    Lee, Jong Ho; Shin, Yong Cheol; Lee, Sang-Min; Jin, Oh Seong; Kang, Seok Hee; Hong, Suck Won; Jeong, Chang-Mo; Huh, Jung Bo; Han, Dong-Wook

    2015-01-01

    Recently, graphene-based nanomaterials, in the form of two dimensional substrates or three dimensional foams, have attracted considerable attention as bioactive scaffolds to promote the differentiation of various stem cells towards specific lineages. On the other hand, the potential advantages of using graphene-based hybrid composites directly as factors inducing cellular differentiation as well as tissue regeneration are unclear. This study examined whether nanocomposites of reduced graphene oxide (rGO) and hydroxyapatite (HAp) (rGO/HAp NCs) could enhance the osteogenesis of MC3T3-E1 preosteoblasts and promote new bone formation. When combined with HAp, rGO synergistically promoted the spontaneous osteodifferentiation of MC3T3-E1 cells without hindering their proliferation. This enhanced osteogenesis was corroborated from determination of alkaline phosphatase activity as early stage markers of osteodifferentiation and mineralization of calcium and phosphate as late stage markers. Immunoblot analysis showed that rGO/HAp NCs increase the expression levels of osteopontin and osteocalcin significantly. Furthermore, rGO/HAp grafts were found to significantly enhance new bone formation in full-thickness calvarial defects without inflammatory responses. These results suggest that rGO/HAp NCs can be exploited to craft a range of strategies for the development of novel dental and orthopedic bone grafts to accelerate bone regeneration because these graphene-based composite materials have potentials to stimulate osteogenesis. PMID:26685901

  19. Adiponectin Promotes Human Jaw Bone Marrow Stem Cell Osteogenesis.

    PubMed

    Pu, Y; Wu, H; Lu, S; Hu, H; Li, D; Wu, Y; Tang, Z

    2016-07-01

    Human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) are multipotent progenitor cells with osteogenic differentiation potential. The relationship between adiponectin (APN) and the metabolism of h-JBMMSCs has not been fully elucidated, and the underlying mechanism remains unclear. The aim of the study was to investigate the effect and mechanism of APN on h-JBMMSC metabolism. h-JBMMSCs were obtained from the primary culture of human jaw bones and treated with or without APN (1 µg/mL). Osteogenesis-related gene expression was evaluated by real-time polymerase chain reaction (PCR), alkaline phosphatase (ALP) activity assay, and enzyme-linked immunosorbent assay (ELISA). To further investigate the signaling pathway, mechanistic studies were performed using Western blotting, immunofluorescence, lentiviral transduction, and SB202190 (a specific p38 inhibitor). Alizarin Red staining showed that APN promoted h-JBMMSC osteogenesis. Real-time PCR, ALP assay, and ELISA showed that ALP, osteocalcin (OCN), osteopontin, and integrin-binding sialoprotein were up-regulated in APN-treated cells compared to untreated controls. Immunofluorescence revealed that adaptor protein containing a pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL1) translocated from the nucleus to the cytoplasm with APN treatment. Additionally, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased over time with APN treatment. Moreover, knockdown of APPL1 or p38 MAPK inhibition blocked the expression of APN-induced calcification-related genes including ALP, Runt-related transcription factor 2 (RUNX2), and OCN. Furthermore, Alizarin Red staining of calcium nodes was not increased by the knockdown of APPL1 or p38 inhibition. Our data suggest that this regulation is mediated through the APPL1-p38 MAPK signaling pathway. These findings collectively provide evidence that APN induces the osteogenesis of h-JBMMSCs through APPL1-mediated p38 MAPK activation

  20. Stability after Cleft Maxillary Distraction Osteogenesis or Conventional Orthognathic Surgery

    PubMed Central

    Svenstrup, Martin; Pedersen, Thomas Klit; Küseler, Annelise; Jensen, John; Nørholt, Sven Erik

    2015-01-01

    ABSTRACT Objectives To compare stability of maxillary advancements in patients with cleft lip and palate following distraction osteogenesis or orthognathic surgery. Material and Methods Inclusion criteria: 1) cleft lip and palate, 2) advancement > 8 mm. Eleven patients comprised the distraction osteogenesis group (DOG). Seven patients comprised the orthognathic treatment group (CONVG). Skeletal and soft tissue points were traced on lateral cephalograms: T1 (preoperatively), T2 (after surgery), T3 (follow-up). Group differences were analyzed using Students t-test. Results At T1-T2, advancement of 6.98 mm (P = 0.002) was observed in DOG. Horizontal overjet increased 11.62 mm (P = 0.001). A point-nasion-B point (ANB) angle increased 8.82° (P = 0.001). Aesthetic plane to upper lip was reduced 5.44 mm (P = 0.017) and the naso-labial angle increased 16.6° (P = 0.001). Vertical overbite (VOB) increased 2.27 mm (P = 0.021). In T2-T3, no significant changes were observed in DOG. In T1-T2, horizontal overjet increased 8.45 mm (P = 0.02). The ANB angle, 9.33° (P = 0.009) in CONVG. At T2-T3, VOB increased, 2.35 mm (P = 0.046), and the ANB angle reduced, 3.83° (P = 0.003). In T2-T3, no parameters changed in CONVG. At follow-up (T3), VOB increased in CONVG compared with DOG, (P = 0.01). Vertical position of A point differed between the groups (P = 0.04). No significant intergroup differences between soft tissue parameters occurred. Conclusions Distraction osteogenesis resulted in a stable position of the maxilla and movement upwards in vertical plane, however in case of orthognathic treatment sagittal relapse and a continued postoperatively downward movement was registered. PMID:26229581

  1. Mild Cognitive Impairment

    MedlinePlus

    ... Research Portfolio (IADRP) AMP-AD Detecting Cognitive Impairment Database ... Mild cognitive impairment (MCI) is a condition in which people have more memory or other thinking problems than normal for their ...

  2. Mild Cognitive Impairment

    MedlinePlus

    ... other people their age. This condition is called mild cognitive impairment, or MCI. People with MCI can take care of themselves and do their normal activities. MCI memory problems may include Losing things often Forgetting ...

  3. Glycosylation of Dentin Matrix Protein 1 is critical for osteogenesis

    PubMed Central

    Sun, Yao; Weng, Yuteng; Zhang, Chenyang; Liu, Yi; Kang, Chen; Liu, Zhongshuang; Jing, Bo; Zhang, Qi; Wang, Zuolin

    2015-01-01

    Proteoglycans play important roles in regulating osteogenesis. Dentin matrix protein 1 (DMP1) is a highly expressed bone extracellular matrix protein that regulates both bone development and phosphate metabolism. After glycosylation, an N-terminal fragment of DMP1 protein was identified as a new proteoglycan (DMP1-PG) in bone matrix. In vitro investigations showed that Ser89 is the key glycosylation site in mouse DMP1. However, the specific role of DMP1 glycosylation is still not understood. In this study, a mutant DMP1 mouse model was developed in which the glycosylation site S89 was substituted with G89 (S89G-DMP1). The glycosylation level of DMP1 was down-regulated in the bone matrix of S89G-DMP1 mice. Compared with wild type mice, the long bones of S89G-DMP1 mice showed developmental changes, including the speed of bone remodeling and mineralization, the morphology and activities of osteocytes, and activities of both osteoblasts and osteoclasts. These findings indicate that glycosylation of DMP1 is a key posttranslational modification process during development and that DMP1-PG functions as an indispensable proteoglycan in osteogenesis. PMID:26634432

  4. Glycosylation of Dentin Matrix Protein 1 is critical for osteogenesis.

    PubMed

    Sun, Yao; Weng, Yuteng; Zhang, Chenyang; Liu, Yi; Kang, Chen; Liu, Zhongshuang; Jing, Bo; Zhang, Qi; Wang, Zuolin

    2015-01-01

    Proteoglycans play important roles in regulating osteogenesis. Dentin matrix protein 1 (DMP1) is a highly expressed bone extracellular matrix protein that regulates both bone development and phosphate metabolism. After glycosylation, an N-terminal fragment of DMP1 protein was identified as a new proteoglycan (DMP1-PG) in bone matrix. In vitro investigations showed that Ser(89) is the key glycosylation site in mouse DMP1. However, the specific role of DMP1 glycosylation is still not understood. In this study, a mutant DMP1 mouse model was developed in which the glycosylation site S(89) was substituted with G(89) (S89G-DMP1). The glycosylation level of DMP1 was down-regulated in the bone matrix of S89G-DMP1 mice. Compared with wild type mice, the long bones of S89G-DMP1 mice showed developmental changes, including the speed of bone remodeling and mineralization, the morphology and activities of osteocytes, and activities of both osteoblasts and osteoclasts. These findings indicate that glycosylation of DMP1 is a key posttranslational modification process during development and that DMP1-PG functions as an indispensable proteoglycan in osteogenesis. PMID:26634432

  5. Masticatory Mechanics of a Mandibular Distraction Osteogenesis Site: Interfragmentary Micromovement

    PubMed Central

    Sun, Zongyang; Rafferty, Katherine L.; Egbert, Mark A.; Herring, Susan W.

    2007-01-01

    Micromovement at a fracture or distraction osteogenesis (DO) site may play an important role in bone formation and healing. Mastication is an important physiological process that can cause substantial micromovement at a mandibular disjunction. The purpose of this study is to characterize and quantify the micromovement caused by mastication. Eighteen pigs, divided into three groups based on duration of consolidation, received a unilateral (right) mandibular angle distraction osteogenesis protocol. Differential variable reluctance transducers (DVRTs) and ultrasound crystals were used to measure the change of gap width as well as interfragmentary movement during mastication. Synchronized chewing video and interfragmentary movement recordings were used to determine the magnitude and direction of micromovement at different phases of the chewing cycle. The magnitude of micromovement did not increase significantly with distraction up to almost 5 mm, but did decrease gradually with consolidation. The average micromovement magnitude during the distraction phase was 0.2-0.3 mm, equaling 50,000-250,000 microstrain (με) on interfragmentary tissue. The dominant deformation pattern was bending in the sagittal plane. The most common direction of bending at the power stroke of chewing was concave dorsally, i.e. superior shortening and inferior lengthening. These findings elucidate how masticatory mechanics affect a mandibular distraction site, and the measurements may be useful for future simulation studies. PMID:17532283

  6. Miniature osmotic actuators for controlled maxillofacial distraction osteogenesis

    NASA Astrophysics Data System (ADS)

    Li, Yu-Hsien; Su, Yu-Chuan

    2010-06-01

    We have successfully demonstrated miniature actuators that are capable of converting chemical potential directly into steady mechanical movements for maxillofacial distraction osteogenesis. Pistons and diaphragms powered by osmosis are employed to provide the desired linear and volumetric displacements for bone distraction and potentially the release of bone morphogenetic proteins, respectively. The cylindrical-shaped miniature actuators are composed of polymeric materials and fabricated by molding and assembly processes. In the prototype demonstration, vapor-permeable thermoplastic polyurethane was employed as the semi-permeable material. 3 cm long actuators with piston and diaphragm radii of 1 mm and 500 µm, respectively, were fabricated and characterized. The maximum distraction force from the piston-type actuator is found to be 6 N while the piston travels at a constant velocity of 32 µm h-1 (or 0.77 mm/day) for about 1 week. Meanwhile, the release rate from the diaphragm-type actuator is measured to be constant, 0.15 µl h-1 (or 3.6 µl/day), throughout the experiment. Moreover, the sizes and output characteristics of the self-regulating actuators could readily be tailored to realize optimal distraction rate, rhythm and osteogenic activity. As such, the demonstrated miniature osmotic actuators could potentially serve as versatile apparatuses for maxillofacial distraction osteogenesis and fulfill the needs of a variety of implantable and biomedical applications.

  7. Numerical simulation of electrically stimulated osteogenesis in dental implants.

    PubMed

    Vanegas-Acosta, J C; Garzón-Alvarado, D A; Lancellotti, V

    2014-04-01

    Cell behavior and tissue formation are influenced by a static electric field (EF). Several protocols for EF exposure are aimed at increasing the rate of tissue recovery and reducing the healing times in wounds. However, the underlying mechanisms of the EF action on cells and tissues are still a matter of research. In this work we introduce a mathematical model for electrically stimulated osteogenesis at the bone-dental implant interface. The model describes the influence of the EF in the most critical biological processes leading to bone formation at the bone-dental implant interface. The numerical solution is able to reproduce the distribution of spatial-temporal patterns describing the influence of EF during blood clotting, osteogenic cell migration, granulation tissue formation, displacements of the fibrillar matrix, and formation of new bone. In addition, the model describes the EF-mediated cell behavior and tissue formation which lead to an increased osteogenesis in both smooth and rough implant surfaces. Since numerical results compare favorably with experimental evidence, the model can be used to predict the outcome of using electrostimulation in other types of wounds and tissues. PMID:24413341

  8. Potential mechanisms underlying the Runx2 induced osteogenesis of bone marrow mesenchymal stem cells

    PubMed Central

    Xu, Jiahai; Li, Zhanghua; Hou, Yudong; Fang, Weijun

    2015-01-01

    Bone marrow derived mesenchymal stem cells (BM-MSCs) belong a type of pluripotent stem cells and can be induced to differentiate into osteoblasts (OB). Runt-related transcription factor 2 (Runx2) is an osteogenesis specific transcription factor and plays an important role in osteogenesis of BM-MSCs. It can promote the expression of osteogenesis related genes, regulate cell cycle progression, improve bone microenvironment and affect functions of chondrocytes and osteoclasts, which have involvement of a large amount of signal molecules including TGF-β, BMP, Notch, Wnt, Hedgehog, FGF and microRNA. In this paper, we summarize the mechanisms underlying the Runx2 induced osteogenesis of BM-MSCs. PMID:26885254

  9. Compactin enhances osteogenesis in murine embryonic stem cells.

    PubMed

    Phillips, B W; Belmonte, N; Vernochet, C; Ailhaud, G; Dani, C

    2001-06-01

    Embryonic stem (ES) cells have the capacity to differentiate into various cell types in vitro. In this study, we show that retinoic acid is important for the commitment of ES cells into osteoblasts. Culturing retinoic acid treated ES cells in the presence of the osteogenic supplements ascorbic acid and beta-glycerophosphate resulted in the expression of several osteoblast marker genes, osteocalcin, alkaline phosphatase, and osteopontin. However, there was only a slight amount of mineralized matrix secretion. Addition of bone morphogenic protein-2 or compactin, a drug of the statin family of HMG-CoA reductase inhibitors, resulted in a greatly enhanced formation of bone nodules. Compactin did not modify the expression of osteogenic markers, but at the late stage of differentiation promoted an increase in BMP-2 expression. These results establish ES-cell derived osteogenesis as an effective model system to study the molecular mechanisms by which the statin compactin promotes osteoblastic differentiation and bone nodule formation. PMID:11394905

  10. Osteogenesis with hematopoiesis simulating infection in a hydroxyapatite orbital implant.

    PubMed

    Jordan, David R; Belliveau, Michel J; Brownstein, Seymour; Padmore, Ruth F

    2009-01-01

    A 28-year-old woman underwent secondary orbital implant surgery with placement of a hydroxyapatite implant. Over the next 7 years she underwent 3 drilling procedures. She began having copious discharge 1 year after the last drilling procedure. She was seen on numerous occasions with socket discharge, unresponsive to a variety of topical and oral antibiotics. Clinically, with the conjunctiva diffusely inflamed, the implant tender to touch, and the presence of a pyogenic granuloma, implant infection was suspected and the implant subsequently removed. Histopathologic assessment revealed widespread lamellar bone formation, including focal areas of marrow with active extramedullary hematopoiesis. There was no evidence of an inflammatory process or infection. Postoperatively the patient's symptoms and signs resolved. Extramedullary hematopoiesis within hydroxyapatite implants is rare. Porous orbital implant infection is also rare. Osteogenesis with extramedullary hematopoiesis simulating implant infection has not previously been reported. PMID:19273939

  11. [Mandibular advancement: bilateral sagittal split versus -distraction osteogenesis].

    PubMed

    Akkerman, V; Ho, J P; Baas, E M; de Lange, J de

    2015-11-01

    In the 1990s intra-oral distraction osteogenesis (DO) became available as an alternative for bilateral sagittal splitosteotomy (BSSO) for advancement of the mandible. It was thought that DO would lead to more stability in the results and fewer neurosensory disturbances of the inferior alveolar nerve. However, there was no scientific evidence for this assumption. This article describes a number of recently published, prospective studies that demonstrate that BSSO is not inferior to DO with respect to stability and neurosensory disturbances of the inferior alveolar nerve. They also demonstrate that BSSO leads to less pain in patients and to lower total costs. It can be concluded that BSSO should be considered the standard therapy for mandibular advancement up to 10 mm in non-syndromal patients. PMID:26569001

  12. Biomechanical Configurations of Mandibular Transport Distraction Osteogenesis Devices

    PubMed Central

    Zapata, Uriel; Elsalanty, Mohammed E.; Dechow, Paul C.

    2010-01-01

    Mandibular bone transport (MBT) distraction osteogenesis devices are used for achieving reconstruction of mandibular defects in a predictable way, with few complications, less complexity than other alternative surgical procedures, and minimal tissue morbidity. However, selection of appropriate MBT device characteristics is critical for ensuring both their mechanical soundness and their optimal distraction function for each patient's condition. This article assesses six characteristics of currently available MBT devices to characterize their design and function and to classify them in a way that assists the selection of the best device option for each clinical case. In addition, the present work provides a framework for both the biomechanical conception of new devices and the modification of existing ones. PMID:19958167

  13. Complications of distraction osteogenesis in short first metatarsals.

    PubMed

    Oh, Chang Wug; Satish, B R J; Lee, Sung-Tae; Song, Hae-Ryong

    2004-01-01

    The authors analyzed the results and complications of metatarsal lengthening in short first metatarsals by distraction osteogenesis. There were 13 first metatarsal lengthenings in eight patients. Mean age was 18.8 years and the average percentage of lengthening was 49.2%. The average healing index was 72.4 days/cm. The major complication was cavus foot, which was noticed in four feet. All great toes showed some loss of motion at metatarsophalangeal (MP) joint. Other complications were hallux valgus, angulation of the metatarsals, and pin tract infection each in two feet. The functional score according to the American Orthopedic Foot and Ankle Society (AOFAS) hallux MP joint, interphalangeal joint scale was excellent in 11 and good in 2. All patients were satisfied with the procedure. To avoid potential complications such as MP joint subluxation, cavus foot, and hallux valgus, the first metatarsal lengthening should not exceed 50% of the original length. PMID:15502575

  14. Ethanol exposure represses osteogenesis in the developing chick embryo.

    PubMed

    Li, Zhong-Yang; Ma, Zheng-Lai; Lu, Wen-Hui; Cheng, Xin; Chen, Jian-Long; Song, Xiao-Yu; Chuai, Manli; Lee, Kenneth Ka Ho; Yang, Xuesong

    2016-07-01

    It is known that excess alcohol consumption during pregnancy can increase the risk of fetal alcohol spectrum disorder (FASD). However, the effect of ethanol exposure on bone morphogenesis in fetus is largely unknown. In this study, we demonstrated that ethanol treatment of gastrulating chick embryos could inhibit long bone (humerus, radius and ulna) development. Histological examination revealed that ethanol exposure reduced the width of the proliferation and hypertrophic zones. In addition, cell proliferation and alkaline phosphatase activities were repressed. We also investigated the effect on chondrogenesis and chondrogenesis was inhibited. Ethanol exposure also induced excess reactive oxygen species (ROS) production and altered the expression of osteogenesis-related genes. The inhibiting effect on flat bone (sclerotic ossicle) and the generation of cranial neural crest cells (progenitors of craniofacial bones) was also presented. In conclusion, ethanol exposure during the embryonic period retards bone development through excess ROS production and altered bone-associated gene expression. PMID:27112526

  15. Stem Cells Rejuvenate Radiation-Impaired Vasculogenesis in Murine Distraction Osteogenesis

    PubMed Central

    Deshpande, Sagar S.; Gallagher, Kathleen K.; Donneys, Alexis; Nelson, Noah S.; Guys, Nicholas P.; Felice, Peter A.; Page, Erin E.; Sun, Hongli; Krebsbach, Paul H.; Buchman, Steven R.

    2015-01-01

    Background Radiotherapy is known to be detrimental to bone and soft-tissue repair. Bone marrow stromal cells have been shown to enhance bone regeneration during distraction osteogenesis following radiation therapy. The authors posit that transplanted bone marrow stromal cells will significantly augment the mandibular vascularity devastated by radiation therapy. Methods Nineteen male Lewis rats were split randomly into three groups: distraction osteogenesis only (n = 5), radiation therapy plus distraction osteogenesis (n = 7), and radiation therapy plus distraction osteogenesis with intraoperative placement of 2 million bone marrow stromal cells (n = 7). A mandibular osteotomy was performed, and an external fixator device was installed. From postoperative days 4 through 12, rats underwent a gradual 5.1-mm distraction followed by a 28-day consolidation period. On postoperative day 40, Microfil was perfused into the vasculature and imaging commenced. Vascular radiomorphometric values were calculated for regions of interest. An analysis of variance with post hoc Tukey or Games-Howell tests was used, dependent on data homogeneity. Results Stereologic analysis indicated significant remediation in vasculature in the bone marrow stromal cell group compared with the radiation therapy/distraction osteogenesis group. Each of five metrics idicated significant improvements from radiation therapy/distraction osteogenesis to the bone marrow stromal cell group, with no difference between the bone marrow stromal cell group and the distraction osteogenesis group. Conclusions Bone marrow stromal cells used together with distraction osteogenesis can rejuvenate radiation-impaired vasculogenesis in the mandible, reversing radiation therapy–induced isotropy and creating a robust vascular network. Bone marrow stromal cells may offer clinicians an alternative reconstructive modality that could improve the lifestyle of patients with hypovascular bone. PMID:25415276

  16. Parathyroid Hormone Therapy Mollifies Radiation-Induced Biomechanical Degradation in Murine Distraction Osteogenesis

    PubMed Central

    Deshpande, Sagar S.; Gallagher, Katherine K.; Donneys, Alexis; Tchanque-Fossuo, Catherine N.; Sarhaddi, Deniz; Nelson, Noah S.; Chepeha, Douglas B.; Buchman, Steven R.

    2015-01-01

    Objective Descriptions of mandibular distraction osteogenesis for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis have been limited. Previous work demonstrated radiation decreases union formation, cellularity and mineral density in mandibular distraction osteogenesis. The authors posit that intermittent systemic administration of parathyroid hormone will serve as a stimulant to cellular function, reversing radiation-induced damage and enhancing bone regeneration. Methods Twenty male Lewis rats were randomly assigned to three groups: group 1 (radiation and distraction osteogenesis, n = 7) and group 2 (radiation, distraction osteogenesis, and parathyroid hormone, n = 5) received a human-equivalent dose of 35 Gy of radiation (human bioequivalent, 70 Gy) fractionated over 5 days. All groups, including group 3 (distraction osteogenesis, n = 8), underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Distraction osteogenesis was performed at a rate of 0.3 mm every 12 hours to reach a gap of 5.1 mm. Group 2 was injected with parathyroid hormone (60 μg/kg) subcutaneously daily for 3 weeks after the start of distraction osteogenesis. On postoperative day 40, all left hemimandibles were harvested. Biomechanical response parameters were generated. Statistical significance was considered at p ≤ 0.05. Results Parathyroid hormone–treated mandibles had significantly higher failure load and higher yield than did untreated mandibles. However, these values were still significantly lower than those of nonirradiated mandibles. Conclusions The authors have successfully demonstrated the therapeutic efficacy of parathyroid hormone to stimulate and enhance bone regeneration in their irradiated murine mandibular model of distraction osteogenesis. Anabolic regimens of parathyroid hormone, a U.S. Food and Drug Administration–approved drug on formulary, significantly improve outcomes in a model of

  17. Letrozole inhibits the osteogenesis of medullary bone in prelay pullets.

    PubMed

    Deng, Y-F; Chen, X-X; Zhou, Z-L; Hou, J-F

    2010-05-01

    This study was performed to investigate the effect of letrozole, an aromatase inhibitor, on osteogenesis of medullary bone in prelay pullets. Three hundred fifteen 95-d-old ISA prelay pullets were used. After 10 d of adaptation in the cages, 15 pullets were selected randomly to collect the serum and bone samples and the rest were randomly assigned to 2 groups with 3 replicates each. One group was control and the other was letrozole-treated, fed 0.5 mg of letrozole per prelay pullet per day for 18 d. The serum and bone samples from these birds were collected during the experiment. Estradiol and testosterone in serum were assayed using commercial RIA kits. The serum alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), Ca, and inorganic P were measured by an automatic biochemistry analyzer with commercial kits. The periosteum perimeter, endosteum perimeter, cortical bone index, cortical width, cortical bone area, and cortical area ratios of tibia were measured by transmitted scanner and a computer-assisted image analyzer. Our results showed that relative to the control-fed pullet, letrozole-fed pullets had reduced serum estrogen (57.5%), Ca (33.2%), ALP (33.6%), and TRAP (24.2%) and that values of serum estrogen, Ca, estrogen receptor expression, tibia radiographic density, serum ALP, and TRAP were all reduced (P < 0.05) and the serum P had a degressive trend in letrozole-treated groups. By contrast, the serum androgen and the tibia cortical bone index values were higher in the letrozole-treated group (P < 0.05). No differences were observed in the periosteum perimeter, endosteum perimeter, cortical width, and cortical area ratios of tibia between the 2 groups. The results showed that letrozole can inhibit the development of bone and medullary osteogenesis by inhibiting the synthesis of estrogen and its receptor in prelay pullets. PMID:20371843

  18. Effects of Electromagnetic Fields on Osteogenesis of Human Alveolar Bone-Derived Mesenchymal Stem Cells

    PubMed Central

    Lim, KiTaek; Hexiu, Jin; Kim, Jangho; Seonwoo, Hoon; Cho, Woo Jae; Choung, Pill-Hoon; Chung, Jong Hoon

    2013-01-01

    This study was performed to investigate the effects of extremely low frequency pulsed electromagnetic fields (ELF-PEMFs) on the proliferation and differentiation of human alveolar bone-derived mesenchymal stem cells (hABMSCs). Osteogenesis is a complex series of events involving the differentiation of mesenchymal stem cells to generate new bone. In this study, we examined not merely the effect of ELF-PEMFs on cell proliferation, alkaline phosphatase (ALP) activity, and mineralization of the extracellular matrix but vinculin, vimentin, and calmodulin (CaM) expressions in hABMSCs during osteogenic differentiation. Exposure of hABMSCs to ELF-PEMFs increased proliferation by 15% compared to untreated cells at day 5. In addition, exposure to ELF-PEMFs significantly increased ALP expression during the early stages of osteogenesis and substantially enhanced mineralization near the midpoint of osteogenesis within 2 weeks. ELF-PEMFs also increased vinculin, vimentin, and CaM expressions, compared to control. In particular, CaM indicated that ELF-PEMFs significantly altered the expression of osteogenesis-related genes. The results indicated that ELF-PEMFs could enhance early cell proliferation in hABMSCs-mediated osteogenesis and accelerate the osteogenesis. PMID:23862141

  19. A historical case of amelogenesis imperfecta: Giovanna of Austria, Grand Duchess of Tuscany (1547-1578).

    PubMed

    Giuffra, Valentina; Panetta, Daniele; Salvadori, Piero A; Fornaciari, Gino

    2014-02-01

    The skeletal remains of Giovanna of Austria (1547-1578), daughter of the Emperor Ferdinand I of Habsburg (1503-1564) and first wife of the Grand Duke of Tuscany, Francesco I (1541-1587), exhumed from the Basilica of San Lorenzo in Florence, were submitted to paleopathological study. Examination of the dentition, which was in a good state of preservation, showed maxillary retrognathism, together with a caries lesion, moderate periodontal disease, malposition of the upper second premolars and tooth wear. Furthermore, several horizontal grooves were observed in both the buccal and the lingual crown surfaces of almost all teeth, especially the anterior ones. The orthopantomogram showed hypomineralized enamel and alveolar bone loss. Two third-molar teeth were investigated using micro-computed tomography (micro-CT) analysis, revealing highly irregular enamel caps with reduced average thickness. The observed features suggest a diagnosis of hypoplastic amelogenesis imperfecta, a developmental condition affecting enamel formation. PMID:24405030

  20. Novel ENAM and LAMB3 Mutations in Chinese Families with Hypoplastic Amelogenesis Imperfecta

    PubMed Central

    Wang, Xin; Zhao, Yuming; Yang, Yuan; Qin, Man

    2015-01-01

    Amelogenesis imperfecta is a group of inherited diseases affecting the quality and quantity of dental enamel. To date, mutations in more than ten genes have been associated with non-syndromic amelogenesis imperfecta (AI). Among these, ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. When both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB), while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. We enrolled three Chinese families with hypoplastic autosomal-dominant AI. Despite the diagnosis falling into the same type, the characteristics of their enamel hypoplasia were different. Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. Disease-causing mutations were identified and perfectly segregated with the enamel defects in three families: a 19-bp insertion mutation in the exon 7 of ENAM (c.406_407insTCAAAAAAGCCGACCACAA, p.K136Ifs*16) in Family 1, a single-base deletion mutation in the exon 5 of ENAM (c. 139delA, p. M47Cfs*11) in Family 2, and a LAMB3 nonsense mutation in the last exon (c.3466C>T, p.Q1156X) in Family 3. Our results suggest that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients. And these findings extend the mutation spectrum of both genes and can be used for mutation screening of AI in the Chinese population. PMID:25769099

  1. Rehabilitation of a patient with amelogenesis imperfecta using porcelain veneers and CAD/CAM polymer restorations: A clinical report.

    PubMed

    Saeidi Pour, Reza; Edelhoff, Daniel; Prandtner, Otto; Liebermann, Anja

    2015-01-01

    The complete dental rehabilitation of patients with a vertical dimension loss (VDL) caused by structural enamel deficits associated with amelogenesis imperfecta (AI) represents a difficult challenge for restorative teams. Accurate analysis and treatment planning that includes esthetic and functional evaluations and adequate material selection are important prerequisites for successful results. Long-term provisional restorations play an important role in exploring and elucidating the patients' esthetic demands and functional needs. Restorative treatment options can vary from requiring only oral hygiene instructions to extensive dental restorations that include composite fillings, ceramic veneers, metal-ceramic, or all-ceramic crowns. This case report describes a full-mouth rehabilitation of a patient with amelogenesis imperfecta including the case planning, bite replacement, preparation, and restoration setting steps with an experimental CAD/CAM polymer and porcelain veneers. PMID:26345104

  2. Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow.

    PubMed

    Yue, Rui; Zhou, Bo O; Shimada, Issei S; Zhao, Zhiyu; Morrison, Sean J

    2016-06-01

    Skeletal stem cells (SSCs) that are the major source of osteoblasts and adipocytes in adult bone marrow express leptin receptor (LepR). To test whether LepR regulates SSC function, we conditionally deleted Lepr from limb bone marrow stromal cells, but not from the axial skeleton or hypothalamic neurons, using Prx1-Cre. Prx1-Cre;Lepr(fl/fl) mice exhibited normal body mass and normal hematopoiesis. However, limb bones from Prx1-Cre;Lepr(fl/fl) mice exhibited increased osteogenesis, decreased adipogenesis, and accelerated fracture healing. Leptin increased adipogenesis and reduced osteogenesis by activating Jak2/Stat3 signaling in bone marrow stromal cells. A high-fat diet increased adipogenesis and reduced osteogenesis in limb bones from wild-type mice, but not from Prx1-Cre;Lepr(fl/fl) mice. This reflected local effects of LepR on osteogenesis and adipogenesis by bone marrow stromal cells and systemic effects on bone resorption. Leptin/LepR signaling regulates adipogenesis and osteogenesis by mesenchymal stromal cells in the bone marrow in response to diet and adiposity. PMID:27053299

  3. Effects of ethanol on the osteogenesis around porous hydroxyapatite implants.

    PubMed

    Lima, C C; Silva, T D; Santos, L; Nakagaki, W R; Loyola, Y C S; Resck, M C C; Camilli, J A; Soares, E A; Garcia, J A D

    2011-02-01

    Alcohol consumption compromises bone tissue, and thus may either impair or stop the fixation and maintenance of osseointegrated implants. To evaluate the effects of 5% and 15% ethanol on bone neoformation around porous hydroxiapatite implants. Fifteen rats were separated into 3 groups of 5 animals each: control (CT); 5% alcohol (A); and 15% alcohol (AA). After four weeks of ethanol consumption, the rats received porous hydroxiapatite implants into surgically made cavities in the femur. After surgery, the animals continued to consume ethanol until day 90 of the experiment, when they were euthanised and their femurs removed for histological processing. Bone tissue was found around the ceramic specimens of all the animals. The largest volume of neoformed bone around ceramic specimens occurred in the CT group, and the smallest in the AA group, followed by the A group. It was concluded that ethanol consumption produced a negative effect on osteogenesis around hydroxyapatite implants. Even small doses, such as the 5% ethanol dilution can interfere with bone repair. PMID:21437407

  4. Versatility of Distraction Osteogenesis for the Craniofacial Skeleton.

    PubMed

    Klement, Kristen A; Black, Jonathan S; Denny, Arlen D

    2016-05-01

    Malformations of the craniofacial skeleton are common. Restoration of anatomic shape, size, and position has been traditionally accomplished using autologous bone grafting to fill gaps created by surgery and segmental movement. The authors present their practice using distraction in many different ages and settings over 20 years. A retrospective review was performed of all craniofacial patients treated using distraction osteogenesis for mandible, midface, and calvarium. The authors identified 205 patient. Mandible: 112 patients were treated at an average age of 3.4 years. 18.8% of patients required repeat distraction. There was no difference in the neonatal versus older group (P = 0.71). There were significantly higher reoperation rates in syndromic children (P < 0.01). Midface: 58 patients underwent Lefort III distraction at an average age of 13.6 years. One (1.7%) required repeat distraction (Miller syndrome). Five (8.6%) patients underwent subsequent Lefort I advancement for occlusal changes. Calvarium: 33 patients were treated at an average age of 4.7 years. No repeat distractions were performed. One patient required an additional advancement procedure. Distraction demonstrates successful long-term correction of defects in the craniofacial skeleton with the versatility and control needed to treat the wide spectrum of deformity. PMID:26999694

  5. A unique stylopod patterning mechanism by Shox2-controlled osteogenesis.

    PubMed

    Ye, Wenduo; Song, Yingnan; Huang, Zhen; Osterwalder, Marco; Ljubojevic, Anja; Xu, Jue; Bobick, Brent; Abassah-Oppong, Samuel; Ruan, Ningsheng; Shamby, Ross; Yu, Diankun; Zhang, Lu; Cai, Chen-Leng; Visel, Axel; Zhang, Yanding; Cobb, John; Chen, YiPing

    2016-07-15

    Vertebrate appendage patterning is programmed by Hox-TALE factor-bound regulatory elements. However, it remains unclear which cell lineages are commissioned by Hox-TALE factors to generate regional specific patterns and whether other Hox-TALE co-factors exist. In this study, we investigated the transcriptional mechanisms controlled by the Shox2 transcriptional regulator in limb patterning. Harnessing an osteogenic lineage-specific Shox2 inactivation approach we show that despite widespread Shox2 expression in multiple cell lineages, lack of the stylopod observed upon Shox2 deficiency is a specific result of Shox2 loss of function in the osteogenic lineage. ChIP-Seq revealed robust interaction of Shox2 with cis-regulatory enhancers clustering around skeletogenic genes that are also bound by Hox-TALE factors, supporting a lineage autonomous function of Shox2 in osteogenic lineage fate determination and skeleton patterning. Pbx ChIP-Seq further allowed the genome-wide identification of cis-regulatory modules exhibiting co-occupancy of Pbx, Meis and Shox2 transcriptional regulators. Integrative analysis of ChIP-Seq and RNA-Seq data and transgenic enhancer assays indicate that Shox2 patterns the stylopod as a repressor via interaction with enhancers active in the proximal limb mesenchyme and antagonizes the repressive function of TALE factors in osteogenesis. PMID:27287812

  6. Inhibin A enhances bone formation during distraction osteogenesis.

    PubMed

    Perrien, Daniel S; Nicks, Kristy M; Liu, Lichu; Akel, Nisreen S; Bacon, Anthony W; Skinner, Robert A; Swain, Frances L; Aronson, James; Suva, Larry J; Gaddy, Dana

    2012-02-01

    Given the aging population and the increased incidence of fracture in the elderly population, the need exists for agents that can enhance bone healing, particularly in situations of delayed fracture healing and/or non-union. Our previous studies demonstrated that overexpression of the gonadal peptide, human inhibin A (hInhA), in transgenic mice enhances bone formation and strength via increased osteoblast activity. We tested the hypothesis that hInhA can also exert anabolic effects in a murine model of distraction osteogenesis (DO), using both transgenic hInhA overexpression and administration of normal physiological levels of hInhA in adult male Swiss-Webster mice. Tibial osteotomies and external ring fixation were performed, followed by a 3-day latency period, 14-day distraction, and sacrifice on day 18. Supraphysiological levels of hInhA in transgenic mice, but not normal physiological levels of hInhA, significantly increased endosteal bone formation and mineralized bone area in the distraction gap, as determined by radiographic and µCT analysis. Significantly, increased PCNA and osteocalcin expression in the primary matrix front suggested that hInhA increased osteoblast proliferation. This mechanism is consistent with the effects of other agents and pathologies that modulate bone formation during DO, and demonstrates the potential of hInhA to enhance bone repair and regeneration. PMID:21809377

  7. Inhibin A enhances bone formation during distraction osteogenesis

    PubMed Central

    Perrien, Daniel S.; Nicks, Kristy M.; Liu, Lichu; Akel, Nisreen S.; Bacon, Anthony W.; Skinner, Robert A.; Swain, Frances L.; Aronson, James; Suva, Larry J; Gaddy, Dana

    2013-01-01

    Given the aging population and the increased incidence of fracture in the elderly population, the need exists for agents that can enhance bone healing, particularly in situations of delayed fracture healing and/or non-union. Our previous studies demonstrated that over-expression of the gonadal peptide, human Inhibin A (hInhA), in transgenic mice enhances bone formation and strength via increased osteoblast activity. We tested the hypothesis that hInhA can also exert anabolic effects in a murine model of distraction osteogenesis (DO), using both transgenic hInhA overexpression and administration of normal physiological levels of hInhA in adult male Swiss-Webster mice. Tibial osteotomies and external ring fixation were performed, followed by a 3 day latency period, 14 day distraction, and sacrifice on day 18. Supraphysiological levels of hInhA in transgenic mice, but not normal physiological levels of hInhA, significantly increased endosteal bone formation and mineralized bone area in the distraction gap, as determined by radiographic and µCT analysis. Significantly, increased PCNA and osteocalcin expression in the primary matrix front suggested that hInhA increased osteoblast proliferation. This mechanism is consistent with the effects of other agents and pathologies that modulate bone formation during DO, and demonstrates the potential of hInhA to enhance bone repair and regeneration. PMID:21809377

  8. Hepcidin inhibition on the effect of osteogenesis in zebrafish.

    PubMed

    Jiang, Yu; Yan, Yilin; Wang, Xiao; Zhu, Guoxing; Xu, You-Jia

    2016-07-15

    Iron overload, as a risk factor for osteoporosis, can result in the up-regulation of Hepcidin, and Hepcidin knockout mice display defects in their bone microarchitecture. However, the molecular and genetic mechanisms underlying Hepcidin deficiency-derived bone loss remain unclear. Here, we show that hepcidin knockdown in zebrafish using morpholinos leads to iron overload. Furthermore, a mineralization delay is observed in osteoblast cells in hepcidin morphants, and these defects could be partially restored with microinjection of hepcidin mRNA. Quantitative real-time PCR analyses revealed the osteoblast-specific genes alp, runx2a, runx2b, and sp7 in morphants are down-regulated. Furthermore, we confirmed qRT-PCR results by in situ hybridization and found down-regulated genes related to osteoblast function in hepcidin morphants. Most importantly, we revealed that hepcidin was capable of removing whole-body iron which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload. PMID:27233600

  9. Nano-Fibrous Biopolymer Hydrogels via Biological Conjugation for Osteogenesis.

    PubMed

    Chen, Huinan; Xing, Xiaodong; Jia, Yang; Mao, Jiahui; Zhang, Ziwei; Tan, Huaping

    2016-06-01

    Nanostructured biopolymer hydrogels have great potential in the field of drug delivery and regenerative medicine. In this work, a nano-fibrous (NF) biopolymer hydrogel was developed for cell growth factors (GFs) delivery and in vitro osteogenesis. The nano-fibrous hydrogel was produced via biological conjugation of streptavidin functionalized hyaluronic acid (HA-Streptavidin) and biotin terminated star-shaped poly(ethylene glycol) (PEG-Biotin). In the present work, in vitro gelation, mechanical properties, degradation and equilibrium swelling of the NF hydrogel were examined. The potential application of this NF gel scaffold in bone tissue engineering was confirmed by encapsulation behavior of osteoblasts. Osteoblasts seeded directly in NF gel scaffold containing cell growth factor, e.g. bone morphogenetic protein 2 (BMP-2), was to mimic the in vivo microenvironment in which cells interface biomaterials and interact with BMP-2. In combination with BMP-2, the NF hydrogel exhibited beneficial effects on osteoblast activity and differentiation, which suggested a promising future for local treatment of pathologies involving bone loss. PMID:27427597

  10. Potential Role of Activating Transcription Factor 5 during Osteogenesis.

    PubMed

    Vicari, Luisa; Calabrese, Giovanna; Forte, Stefano; Giuffrida, Raffaella; Colarossi, Cristina; Parrinello, Nunziatina Laura; Memeo, Lorenzo

    2016-01-01

    Human adipose-derived stem cells are an abundant population of stem cells readily isolated from human adipose tissue that can differentiate into connective tissue lineages including bone, cartilage, fat, and muscle. Activating transcription factor 5 is a transcription factor of the ATF/cAMP response element-binding protein (CREB) family. It is transcribed in two types of mRNAs (activating transcription factor 5 isoform 1 and activating transcription factor 5 isoform 2), encoding the same single 30-kDa protein. Although it is well demonstrated that it regulates the proliferation, differentiation, and apoptosis, little is known about its potential role in osteogenic differentiation. The aim of this study was to evaluate the expression levels of the two isoforms and protein during osteogenic differentiation of human adipose-derived stem cells. Our data indicate that activating transcription factor 5 is differentially expressed reaching a peak of expression at the stage of bone mineralization. These findings suggest that activating transcription factor 5 could play an interesting regulatory role during osteogenesis, which would provide a powerful tool to study bone physiology. PMID:26770207

  11. Amelogenesis imperfecta

    MedlinePlus

    ... is low in sugar and practicing very good oral hygiene can reduce the chance of developing cavities. Outlook (Prognosis) Treatment is often successful in protecting the teeth. ... by: Ilona Fotek, DMD, MS, Palm Beach Prosthodontics Dental Associates, West Palm Beach, FL. Review provided by ...

  12. Overexpression of the Circadian Clock Gene Rev-erbα Affects Murine Bone Mesenchymal Stem Cell Proliferation and Osteogenesis

    PubMed Central

    He, Yao; Lin, Fuwei; Chen, Yaqun; Tan, Zhen; Bai, Ding

    2015-01-01

    Bone mesenchymal stem cell (BMSC) age-related changes include decreased osteogenesis and increased adipogenesis. Rev-erbα and the Wnt/β-catenin signaling pathway were known to play important roles in BMSC aging. In this study, we have aimed to elucidate whether Rev-erbα and Wnt/β-catenin signaling interact during BMSC proliferation and osteogenesis. Our results showed that Rev-erbα expression gradually dropped during BMSC osteogenesis, and overexpression of Rev-erbα in BMSCs inhibited cell proliferation and osteogenesis. The inhibition of cell proliferation induced by Rev-erbα overexpression was partially reversed when Wnt/β-catenin signaling was activated. These results suggested that Rev-erbα could promote BMSC aging and may be the negative regulator during the late stage of osteogenesis. The clock gene Rev-erbα and Wnt/β-catenin signaling interact in the regulation of cell proliferation. PMID:25539035

  13. Posterior Cranial Vault Distraction Osteogenesis with Barrel Stave Osteotomy in the Treatment of Craniosynostosis

    PubMed Central

    KOMURO, Yuzo; SHIMIZU, Azusa; SHIMOJI, Kazuaki; MIYAJIMA, Masakazu; ARAI, Hajime

    2015-01-01

    Twenty years have passed since distraction osteogenesis was introduced into the field of craniomaxillofacial surgery, with distraction osteogenesis gradually consolidating its position for midface advancement in syndromic craniosynostosis. On the other hand, no consensus has been reached regarding its adaptation to calvarial bone. We reported that distraction osteogenesis was useful in posterior cranial vault expansion, and subsequently, similar reports have been successively observed worldwide. In posterior cranial vault distraction, intracranial capacity could be greatly expanded due to its simultaneous expansion with the scalp, with little risk of relapse because new bone is regenerated in the distraction gap. The possibility was suggested that the standard of first carrying out fronto-orbital advancement (FOA) for brachycephaly observed in syndromic craniosynostosis will greatly change posterior cranial vault distraction. PMID:26226978

  14. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone

    PubMed Central

    Adams, Ralf H.

    2016-01-01

    Summary The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms leading to loss of bone mass and increased fracture incidence. There is evidence indicating that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors, and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, which was pharmacologically reversible to restore bone mass. PMID:24646994

  15. A scaffold-free multicellular three-dimensional in vitro model of osteogenesis.

    PubMed

    Gurkan, Umut A; Kishore, Vipuil; Condon, Keith W; Bellido, Teresita M; Akkus, Ozan

    2011-05-01

    In vitro models of osteogenesis are essential for investigating bone biology and the effects of pharmaceutical, chemical, and physical cues on bone formation. Osteogenesis takes place in a complex three-dimensional (3D) environment with cells from both mesenchymal and hematopoietic origins. Existing in vitro models of osteogenesis include two-dimensional (2D) single type cell monolayers and 3D cultures. However, an in vitro scaffold-free multicellular 3D model of osteogenesis is missing. We hypothesized that the self-inductive ossification capacity of bone marrow tissue can be harnessed in vitro and employed as a scaffold-free multicellular 3D model of osteogenesis. Therefore, rat bone marrow tissue was cultured for 28 days in three settings: 2D monolayer, 3D homogenized pellet, and 3D organotypic explant. The ossification potential of marrow in each condition was quantified by micro-computed tomography. The 3D organotypic marrow explant culture resulted in the greatest level of ossification with plate-like bone formations (up to 5 mm in diameter and 0.24 mm in thickness). To evaluate the mimicry of the organotypic marrow explants to newly forming native bone tissue, detailed compositional and morphological analyses were performed, including characterization of the ossified matrix by histochemistry, immunohistochemistry, Raman microspectroscopy, energy dispersive X-ray spectroscopy, backscattered electron microscopy, and micromechanical tests. The results indicated that the 3D organotypic marrow explant culture model mimics newly forming native bone tissue in terms of the characteristics studied. Therefore, this platform holds significant potential to be used as a model of osteogenesis, offering an alternative to in vitro monolayer cultures and in vivo animal models. PMID:21318400

  16. Regenerate Healing Outcomes in Unilateral Mandibular Distraction Osteogenesis Using Quantitative Histomorphometry

    PubMed Central

    Schwarz, Daniel A.; Arman, Krikor G.; Kakwan, Mehreen S.; Jamali, Ameen M.; Elmeligy, Ayman A.; Buchman, Steven R.

    2015-01-01

    Background The authors’ goal was to ascertain regenerate bone-healing metrics using quantitative histomorphometry at a single consolidation period. Methods Rats underwent either mandibular distraction osteogenesis (n=7) or partially reduced fractures (n=7); their contralateral mandibles were used as controls (n=11). External fixators were secured and unilateral osteotomies performed, followed by either mandibular distraction osteogenesis (4 days’ latency, then 0.3 mm every 12 hours for 8 days; 5.1 mm) or partially reduced fractures (fixed immediately postoperatively; 2.1 mm); both groups underwent 4 weeks of consolidation. After tissue processing, bone volume/tissue volume ratio, osteoid volume/tissue volume ratio, and osteocyte count per high-power field were analyzed by means of quantitative histomorphometry. Results Contralateral mandibles had statistically greater bone volume/tissue volume ratio and osteocyte count per high-power field compared with both mandibular distraction osteogenesis and partially reduced fractures by almost 50 percent, whereas osteoid volume/tissue volume ratio was statistically greater in both mandibular distraction osteogenesis specimens and partially reduced fractures compared with contralateral mandibles. No statistical difference in bone volume/tissue volume ratio, osteoid volume/tissue volume ratio, or osteocyte count per high-power field was found between mandibular distraction osteogenesis specimens and partially reduced fractures. Conclusions The authors’ findings demonstrate significantly decreased bone quantity and maturity in mandibular distraction osteogenesis specimens and partially reduced fractures compared with contralateral mandibles using the clinically analogous protocols. If these results are extrapolated clinically, treatment strategies may require modification to ensure reliable, predictable, and improved outcomes. PMID:20463629

  17. AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfi1-OPN axis.

    PubMed

    Wang, Yu-Gang; Qu, Xin-Hua; Yang, Ying; Han, Xiu-Guo; Wang, Lei; Qiao, Han; Fan, Qi-Ming; Tang, Ting-Ting; Dai, Ke-Rong

    2016-09-01

    Several metabolic, genetic and oncogenic bone diseases share the common pathological phenotype of defective bone marrow stromal cell (BMSC) differentiation. Many reports in bone science in the past several years have suggested that the skeleton also has an endocrine role. The role of AMP-activated protein kinase (AMPK) as an energy metabolism sensor and how it regulates BMSC differentiation is largely unknown. In the current study, we used AMPK agonists to activate AMPK in MC3T3-E1 cells to investigate the functional roles of AMPK in osteogenesis. However, metformin and AICAR failed to activate AMPK consistently. Therefore, we established MC3T3-E1 and 3T3-L1 cell models of AMPK α subunit overexpression through lentivirus vector, in which AMPK was overactivated. AMPK hyperactivation stimulated MC3T3-E1 cell osteogenesis and inhibited 3T3-L1 cell adipogenesis. Osteopontin (OPN) mediated AMPK regulation of osteogenesis and adipogenesis. Furthermore, we provided evidence that the transcriptional repressor growth factor independence-1 (Gfi1) was downregulated and disassociated from the OPN promoter in response to AMPK activation, resulting in the upregulation of OPN. Overexpression of wild-type and dominant-negative Gfi1 modulated MC3T3-E1 osteogenesis and 3T3-L1 adipogenesis. Further evidence suggested that AMPK enhanced ectopic bone formation of MC3T3-E1 cells through the AMPK-Gfi1-OPN axis. In conclusion, AMPK was sufficient to stimulate osteogenesis of MC3T3-E1 cells and inhibit adipogenesis of 3T3-L1 cells through the AMPK-Gfi1-OPN axis. These findings helped elucidate the molecular mechanisms underlying AMPK regulation of osteogenesis and adipogenesis. PMID:27283242

  18. Macrophage-mediated osteogenesis activation in co-culture with osteoblast on calcium silicate cement.

    PubMed

    Tu, Ming-Gene; Chen, Yi-Wen; Shie, Ming-You

    2015-12-01

    The use of calcium silicate (CS) cement holds great promise for bone substitute biomaterials. However, the effects of CS on osteoblast and macrophage cells are not fully understood. This study examines cell proliferation and differentiation of mono- or co-cultured MC3T3-E1 and Raw 264.7 cells on CS cement. Very few studies to date have looked at the effects of osteoblast and macrophages on biomaterial-regulated osteogenesis. In this study the proliferation and differentiation of MC3T3-E1, Raw 264.7 and co-cultured MC3T3-E1/Raw 264.7 on CS cements have been analyzed using a PrestoBlue kit and ELISA. In addition, the effect of macrophages on CS-coordinated osteogenesis of MC3T3-E1 has been investigated. Results show that MC3T3-E1, Raw 264.7 and co-cultured MC3T3-E1/Raw 264.7 adhere to and proliferate well on the CS cement. In a co-culture, the CS cements inhibit receptor activator of nuclear factor kappa B ligand expression of both genes and proteins in Raw 264.7 cells when compared to those grown in mono-cultured system. Ca deposition of MC3T3-E1 in the co-culture is higher than that of cells in a mono-culture. Bone morphogenetic protein 2 (BMP2) is also significantly up-regulated by the CS cement stimulation, indicating that macrophages may participate in the CS stimulated osteogenesis. Interestingly, when macrophage are cultured with BMP2 receptor-blocking MC3T3-E1 on the CS cements, the osteogenesis differentiation of the cells is significantly inhibited, indicating the important role of macrophages in biomaterial-induced osteogenesis via BMP2 receptors. It is assumed that it is an increase in the secretion of the BMP2 from the Raw 264.7 cell that is primarily involved in the promotion of the osteogenesis of the MC3T3-E1. These results provide valuable insights into both the mechanism of CS-stimulated osteogenesis, and strategies to optimize the evaluation system for the in vitro osteogenesis capacity of bone substitute biomaterials. PMID:26543022

  19. Experience with Mandibular Reconstruction Using Transport-Disc-Distraction Osteogenesis

    PubMed Central

    Pingarrón-Martín, Lorena; Otero, T. González; Gallo, L.J. Arias

    2014-01-01

    The goal of transport-disc-distraction osteogenesis (TDDO) is to restore bone continuity by using in-situ bone. It may be useful following trauma, gunshot injuries, or tumor ablation, especially when there may be contraindications at the donor site or for prolonged surgery. To the best of the authors' knowledge, this is the first time TDDO has been used for mandibular reconstruction reporting additional procedures, which include osseointegrated dental implants rehabilitation and orthognathic surgery. A retrospective study is performed analyzing all mandibular reconstruction cases that may be suitable for distraction from January 2006 to December 2011. A thorough description of the documented cases includes details about sex, gender, complications, duration of hospitalization, etiology, size, and location of the defect. Eight cases of mandibular reconstruction were included. Six cases correspond to mandibular ameloblastoma. The remaining two cases were mandibular gunshot comminuted fractures. Range of the defects was from 45 to 60 mm. Length of the transport disc was 15 to 20 mm. Protocolized technique consisted of 5 days of latency period, 19 to 45 days of activation term (average 30 days), and 8 to 12 weeks for consolidation. Mean distraction length achieved was 40.45 mm. We can conclude that TDDO is an alternative to conventional and more invasive procedures, when we face severe segmental mandibular defects reconstruction. It shows the potential to restore a better anatomical bone regeneration, also providing soft tissues and reducing donor-site morbidity. Patients' education and awareness about the proper use of the transport-disc-distraction device is important to optimize functional outcomes. PMID:26000082

  20. Amelogenesis Imperfecta: Rehabilitation and Brainstorming on the Treatment Outcome after the First Year.

    PubMed

    İzgi, Ayça Deniz; Kale, Ediz; Niğiz, Remzi

    2015-01-01

    Amelogenesis imperfecta (AI) affects enamel on primary and permanent dentition. This hereditary disorder is characterized by loss of enamel, poor esthetics, and hypersensitivity. Functional and cosmetic rehabilitation is challenging with variety of treatment options. This report presents the treatment of an AI patient using conventional fixed dentures and discusses issues related to posttreatment complications and prosthetic treatment outcome after 1 year of follow-up. A 19-year-old male AI patient with impaired self-esteem presented with hypersensitive, discolored, and mutilated teeth. Clinical examination revealed compromised occlusion and anterior open-bite. After hygiene maintenance full-coverage porcelain-fused-to-metal fixed restorations were indicated and applied. At the end of the treatment acceptable functional and esthetic results could be achieved. However, nearly a year after treatment a gingival inflammation in the esthetic zone complicated the outcome. Insufficient oral hygiene was to be blamed. Tooth sensitivity present from early childhood in these patients may prevent oral hygiene from becoming a habit. The relaxation due to relieve of hypersensitivity after treatment makes oral hygiene learning difficult. Continuous oral hygiene maintenance motivation may be crucial for the success of the treatment of AI patients. Treatment of AI patients should be carefully planned and an acceptable risk-benefit balance should be established. PMID:26783475

  1. Multidisciplinary Approach for Restoring Function and Esthetics in a Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Kamble, Vaibhav D; Parkhedkar, Rambhau D

    2013-01-01

    Amelogenesis Imperfecta (AI) is a genetically determined and enamel mineralization defect reported, depicted as “Hereditary brown teeth.” AI is characterized as a clinical entity and its clinical manifestations, histological appearance, and genetic pattern are characterized by their heterogeneity. The need for prosthodontic management of this group of patients varies. Some patients need oral hygiene instructions only, whereas others need extensive dental treatment that includes composite restorations, metal ceramic crowns, all ceramic crowns, porcelain veneers. A 20-year-old male patient presented with sensitive, discoloured, and mutilated teeth, with a decreased vertical dimension of occlusion. The 4-year recall examination revealed no pathology associated with the full mouth rehabilitation, and the patient’s aesthetic and functional expectations were satisfied. The rehabilitation included all-ceramic crowns on anterior teeth and metal-ceramic crowns on posterior teeth following endodontic treatment and a crown-lengthening procedure for eliminating tooth sensitivity, improving the aesthetics and occlusion, and for restoring function. PMID:24551735

  2. Amelogenesis Imperfecta: Rehabilitation and Brainstorming on the Treatment Outcome after the First Year

    PubMed Central

    İzgi, Ayça Deniz; Kale, Ediz; Niğiz, Remzi

    2015-01-01

    Amelogenesis imperfecta (AI) affects enamel on primary and permanent dentition. This hereditary disorder is characterized by loss of enamel, poor esthetics, and hypersensitivity. Functional and cosmetic rehabilitation is challenging with variety of treatment options. This report presents the treatment of an AI patient using conventional fixed dentures and discusses issues related to posttreatment complications and prosthetic treatment outcome after 1 year of follow-up. A 19-year-old male AI patient with impaired self-esteem presented with hypersensitive, discolored, and mutilated teeth. Clinical examination revealed compromised occlusion and anterior open-bite. After hygiene maintenance full-coverage porcelain-fused-to-metal fixed restorations were indicated and applied. At the end of the treatment acceptable functional and esthetic results could be achieved. However, nearly a year after treatment a gingival inflammation in the esthetic zone complicated the outcome. Insufficient oral hygiene was to be blamed. Tooth sensitivity present from early childhood in these patients may prevent oral hygiene from becoming a habit. The relaxation due to relieve of hypersensitivity after treatment makes oral hygiene learning difficult. Continuous oral hygiene maintenance motivation may be crucial for the success of the treatment of AI patients. Treatment of AI patients should be carefully planned and an acceptable risk-benefit balance should be established. PMID:26783475

  3. Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds.

    PubMed

    Gandolfi, Barbara; Liu, Hongwei; Griffioen, Layle; Pedersen, Niels C

    2013-08-01

    We report a familial enamel hypoplasia in Italian Greyhounds resembling non-syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait. PMID:23638899

  4. Aesthetic and functional rehabilitation of the primary dentition affected by amelogenesis imperfecta.

    PubMed

    Marquezin, Maria Carolina Salomé; Zancopé, Bruna Raquel; Pacheco, Larissa Ferreira; Gavião, Maria Beatriz Duarte; Pascon, Fernanda Miori

    2015-01-01

    The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID:25705526

  5. Aesthetic and Functional Rehabilitation of the Primary Dentition Affected by Amelogenesis Imperfecta

    PubMed Central

    Marquezin, Maria Carolina Salomé; Zancopé, Bruna Raquel; Pacheco, Larissa Ferreira; Gavião, Maria Beatriz Duarte; Pascon, Fernanda Miori

    2015-01-01

    The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID:25705526

  6. Dentin phosphoprotein gene locus is not associated with dentinogenesis imperfecta types II and III

    SciTech Connect

    MacDougall, M.; Zeichner-David, M.; Davis, A.; Slavkin, H. ); Murray, J. ); Crall, M. )

    1992-01-01

    Dentinogenesis imperfecta (DGI) is an autosomal dominant inherited dental disease which affects dentin production and mineralization. Genetic linkage studies have been performed on several multigeneration informative kindreds. These studies determined linkage between DGI types II and III and group-specific component (vitamin D-binding protein). This gene locus has been localized to the long arm of human chromosome 4 in the region 4q11-q21. Although this disease has been mapped to chromosome 4, the defective gene product is yet to be determined. Biochemical studies have suggested abnormal levels of dentin phosphoprotein (DPP) associated with DGI type II. This highly acidic protein is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal derived odontoblast cells of the tooth. The purpose of the present study was to establish whether DPP is associated with DGI types II and III, by using molecular biology techniques. The results indicated that DPP is not localized to any region of human chromosome 4, thus suggesting that the DPP gene is not directly associated with DGI type II or DGI type III. The data do not exclude the possibility that other proteins associated with DPP posttranslational modifications might be responsible for this genetic disease.

  7. Cognitive Processing in Mild Disabilities.

    ERIC Educational Resources Information Center

    Al-Hilawani, Yasser A.; Poteet, James A.

    Research regarding the cognitive processing of students with learning disabilities, mild mental handicap, and emotional handicap is reviewed. In considering cognitive processing for students with mild mental handicap, research attention has been directed to the issues of memory and learning, acquisition and retrieval deficits, inefficient…

  8. Osteogenesis differentiation of human periodontal ligament cells by CO2 laser-treatment stimulating macrophages via BMP2 signalling pathway

    NASA Astrophysics Data System (ADS)

    Hsieh, Wen-Hui; Chen, Yi-Jyun; Hung, Chi-Jr; Huang, Tsui-Hsien; Kao, Chia-Tze; Shie, Ming-You

    2014-11-01

    Immune reactions play an important role in determining the biostimulation of bone formation, either in new bone formation or inflammatory fibrous tissue encapsulation. Macrophage cell, the important effector cells in the immune reaction, which are indispensable for osteogenesis and their heterogeneity and plasticity, render macrophages a primer target for immune system modulation. However, there are very few studies about the effects of macrophage cells on laser treatment-regulated osteogenesis. In this study, we used CO2 laser as a model biostimulation to investigate the role of macrophage cells on the CO2 laser stimulated osteogenesis. Bone morphogenetic protein 2 (BMP2) was also significantly up regulated by the CO2 laser stimulation, indicating that macrophage may participate in the CO2 laser stimulated osteogenesis. Interestingly, when laser treatment macrophage-conditioned medium were applied to human periodontal ligament cells (hPDLs), the osteogenesis differentiation of hPDLs was significantly enhanced, indicating the important role of macrophages in CO2 laser-induced osteogenesis. These findings provided valuable insights into the mechanism of CO2 laser-stimulated osteogenic differentiation, and a strategy to optimize the evaluation system for the in vitro osteogenesis capacity of laser treatment.

  9. Plate-guided distraction osteogenesis to recreate two-thirds of the mandible including symphysis.

    PubMed

    Mohammed-Ali, Ricardo I; Henry, Alastair M; Khurram, Syed A; Yousefpour, Afshin

    2012-12-01

    We report a case of plate-guided distraction osteogenesis to reconstruct a large mandibular defect caused by recurrence of an ameloblastoma in a 17-year-old male patient who had previously had reconstruction using a fibula bone graft. PMID:22726522

  10. Biodegradable Mg-Cu alloys with enhanced osteogenesis, angiogenesis, and long-lasting antibacterial effects

    PubMed Central

    Liu, Chen; Fu, Xuekun; Pan, Haobo; Wan, Peng; Wang, Lei; Tan, Lili; Wang, Kehong; Zhao, Ying; Yang, Ke; Chu, Paul K.

    2016-01-01

    A series of biodegradable Mg-Cu alloys is designed to induce osteogenesis, stimulate angiogenesis, and provide long-lasting antibacterial performance at the same time. The Mg-Cu alloys with precipitated Mg2Cu intermetallic phases exhibit accelerated degradation in the physiological environment due to galvanic corrosion and the alkaline environment combined with Cu release endows the Mg-Cu alloys with prolonged antibacterial effects. In addition to no cytotoxicity towards HUVECs and MC3T3-E1 cells, the Mg-Cu alloys, particularly Mg-0.03Cu, enhance the cell viability, alkaline phosphatase activity, matrix mineralization, collagen secretion, osteogenesis-related gene and protein expressions of MC3T3-E1 cells, cell proliferation, migration, endothelial tubule forming, angiogenesis-related gene, and protein expressions of HUVECs compared to pure Mg. The favorable osteogenesis and angiogenesis are believed to arise from the release of bioactive Mg and Cu ions into the biological environment and the biodegradable Mg-Cu alloys with osteogenesis, angiogenesis, and long-term antibacterial ability are very promising in orthopedic applications. PMID:27271057

  11. DEVELOPMENT OF TENSILE STRENGTH DURING DISTRACTION OSTEOGENESIS IN A RAT MODEL

    Technology Transfer Automated Retrieval System (TEKTRAN)

    These studies were designed to determine the reliability of in vitro tensile testing to measure the temporal development of regenerate bone strength in rats during limb lengthening (distraction osteogenesis, DO). External fixators were placed on the right tibiae of 36 virus-free, 400-450 g male Spr...

  12. Rheological, biocompatibility and osteogenesis assessment of fish collagen scaffold for bone tissue engineering.

    PubMed

    Elango, Jeevithan; Zhang, Jingyi; Bao, Bin; Palaniyandi, Krishnamoorthy; Wang, Shujun; Wenhui, Wu; Robinson, Jeya Shakila

    2016-10-01

    In the present investigation, an attempt was made to find an alternative to mammalian collagen with better osteogenesis ability. Three types of collagen scaffolds - collagen, collagen-chitosan (CCH), and collagen-hydroxyapatite (CHA) - were prepared from the cartilage of Blue shark and investigated for their physico-functional and mechanical properties in relation to biocompatibility and osteogenesis. CCH scaffold was superior with pH 4.5-4.9 and viscosity 9.7-10.9cP. Notably, addition of chitosan and HA (hydroxyapatite) improved the stiffness (11-23MPa) and degradation rate but lowered the water binding capacity and porosity of the scaffold. Interestingly, CCH scaffolds remained for 3days before complete in-vitro biodegradation. The decreased amount of viable T-cells and higher level of FAS/APO-1 were substantiated the biocompatibility properties of prepared collagen scaffolds. Osteogenesis study revealed that the addition of CH and HA in both fish and mammalian collagen scaffolds could efficiently promote osteoblast cell formation. The ALP activity was significantly high in CHA scaffold-treated osteoblast cells, which suggests an enhanced bone-healing process. Therefore, the present study concludes that the composite scaffolds prepared from fish collagen with higher stiffness, lower biodegradation rate, better biocompatible, and osteogenesis properties were suitable biomaterial for a bone tissue engineering application as an alternative to mammalian collagen scaffolds. PMID:27211297

  13. Alveolar vertical distraction osteogenesis: historical and biologic review and case presentation.

    PubMed

    Emtiaz, Shahram; Noroozi, Sohrab; Caramês, João; Fonseca, Luís

    2006-12-01

    Dental rehabilitation of partially or totally edentulous patients with dental implants has become common practice in the last few decades, with reliable long-term results. However, local conditions of edentulous alveolar ridges may be unfavorable for implant placement. Vertically deficient alveolar ridges, in particular, may have insufficient bone volume to hold implants of adequate dimensions, making implant placement difficult or impossible. To correct this situation, a variety of surgical procedures have been proposed, including onlay bone grafts, vertical guided bone regeneration, and alveolar distraction osteogenesis. Distraction osteogenesis is a biologic process of new bone formation between the surfaces of bone segments that are gradually separated by incremental traction. This process is initiated when a traction force is applied to the bone segments and continues as long as the callus tissues are stretched. This traction force, in turn, generates tension within the tissues that connect the bone segments, which stimulates new bone formation parallel to the vector of distraction. The aim of this article is to provide clinicians with the historical background of and biologic basis for the concept of distraction osteogenesis, which can be traced back to the 1800s. Finally, a clinical case is presented to demonstrate a step-by-step application of alveolar distraction osteogenesis as a treatment protocol in a partially edentulous ridge for improvement of esthetics. PMID:17243326

  14. Biodegradable Mg-Cu alloys with enhanced osteogenesis, angiogenesis, and long-lasting antibacterial effects.

    PubMed

    Liu, Chen; Fu, Xuekun; Pan, Haobo; Wan, Peng; Wang, Lei; Tan, Lili; Wang, Kehong; Zhao, Ying; Yang, Ke; Chu, Paul K

    2016-01-01

    A series of biodegradable Mg-Cu alloys is designed to induce osteogenesis, stimulate angiogenesis, and provide long-lasting antibacterial performance at the same time. The Mg-Cu alloys with precipitated Mg2Cu intermetallic phases exhibit accelerated degradation in the physiological environment due to galvanic corrosion and the alkaline environment combined with Cu release endows the Mg-Cu alloys with prolonged antibacterial effects. In addition to no cytotoxicity towards HUVECs and MC3T3-E1 cells, the Mg-Cu alloys, particularly Mg-0.03Cu, enhance the cell viability, alkaline phosphatase activity, matrix mineralization, collagen secretion, osteogenesis-related gene and protein expressions of MC3T3-E1 cells, cell proliferation, migration, endothelial tubule forming, angiogenesis-related gene, and protein expressions of HUVECs compared to pure Mg. The favorable osteogenesis and angiogenesis are believed to arise from the release of bioactive Mg and Cu ions into the biological environment and the biodegradable Mg-Cu alloys with osteogenesis, angiogenesis, and long-term antibacterial ability are very promising in orthopedic applications. PMID:27271057

  15. Fontanelles - excessively large

    MedlinePlus

    ... Hydrocephalus Intrauterine growth retardation (IUGR) Premature birth Rarer causes: Achondroplasia Apert syndrome Cleidocranial dysostosis Congenital rubella Neonatal hypothyroidism Osteogenesis imperfecta Rickets When to Contact a Medical ...

  16. The effect of aging on distraction osteogenesis in the rat.

    PubMed

    Aronson, J; Gao, G G; Shen, X C; McLaren, S G; Skinner, R A; Badger, T M; Lumpkin, C K

    2001-05-01

    The effect of age on bone formation in the limb lengthening model of distraction osteogenesis (DO) was investigated in two studies using Sprague-Dawley (SD) rats from two colonies at various ages (CAMM: 9 vs 24 months, Harlan: 4 vs 24 months). External fixators were placed on the right tibiae of 30 male SD rats (20 CAMM, 10 Harlan) and mid-diaphyseal osteotomies were performed. Distraction was performed at 0.2 mm bid for 20 days (CAMM) or 14 days (Harlan). The experimental (DO) and control (contra-lateral) tibiae were removed for high-resolution radiography and decalcified histology. Videomicroscopy was used to quantitate radiodensity, histology (matrix type) and relative areas of cell proliferation, which was identified by proliferating cell nuclear antigen (PCNA) immunochemistry. Both studies demonstrated an age-related decrease in the percent mineralized bone (radiodensity) in the distraction gap (CAMM 9 vs 24 months: 68% vs 51%, P < 0.003; Harlan 4 vs 24 months: 95% vs 36%, P < 0.001) and no significant colony or distraction time-specific difference was seen between the two colonies of 24-month-old rats. Histology was performed on the Harlan rats. The DO gaps in the 24-month-old rats demonstrated less endosteal new bone compared to the 4-month-old rats (P < 0.01), but equivalent periosteal new bone. In 4-month-old rats, PCNA-immunostained cells were organized along the primary matrix front (where the first deposition of osteoid occurs) extending across both periosteal and endosteal surfaces. In 24-month-old rats, PCNA+ cells were organized in zones along the periosteal new bone fronts only and irregularly scattered throughout the endosteal gap within a fibrovascular non-ossifying matrix. These results indicate that 24-month-old rats have a relative deficit in endosteal bone formation which may not be related to cell proliferation but rather to cell organization. This model reflects the clinical situation where radiographic findings in older patients demonstrate

  17. Dento-Alveolar Distraction Osteogenesis for rapid Orthodontic Canine Retraction

    PubMed Central

    Kumar, Naveen; Prashantha, GS; Raikar, Sudhir; Ranganath, Krishnappa; Mathew, Silju; Nambiar, Sandeep

    2013-01-01

    technique reduces orthodontic treatment duration by 6 to 9 months in patients who need extraction, with no need for any sort of anchorage reinforcement. How to cite this article: Kumar N, Prashantha GS, Raikar S, Ranganath K, Mathew S, Nambiar S. Dento-Alveolar Distraction Osteogenesis for rapid Orthodontic Canine Retraction. J Int Oral Health 2013; 5(6):31-41 . PMID:24453442

  18. Clinical findings and long-term managements of patients with amelogenesis imperfecta

    PubMed Central

    Koruyucu, Mine; Bayram, Merve; Tuna, Elif Bahar; Gencay, Koray; Seymen, Figen

    2014-01-01

    The aim of this clinical case series is to present a diagnosis and different treatment methods of patients in different ages with amelogenesis imperfecta (AI) as well as further treatments during a 3-6 years follow-up period. A number of 31 patients (16 female, 15 male with a mean age of 10.77 ± 2.65 years) with AI have been examined for the study group between 2007 and 2010 years. A detailed anamnesis was recorded, followed by a clinical and radiological assessment of oral health. The types of AI classified for each patient according to clinical and radiographic evaluation. The main complaints of patients, presence of dental caries and dental anomalies were noted. Necessary treatments had been planned for the individual cases of AI. A number of 19 patients had hypoplastic (HP) form, and 10 patients showed hypomaturation (HM) form of AI, while one patient showed hypocalcified form of AI and one patient had HM-HP form with taurodontism. Main complaints were chiefly related to dissatisfactory esthetics and dental sensitivity. Caries prevalence index was 93.5%. Mean decayed, missing, filling permanent teeth (DMF) and DMF surface (DMFS) were found as 2.74 ± 1.71 and 6.23 ± 3.99; df (decayed, filling primary teeth) and dfs (decayed, filling primary teeth surface) were found as 3.12 ± 2.85 and 5.24 ± 4.97, respectively. All patients received individual clinical care, including preventive, restorative, and prosthetic treatments. Patients have scheduled for regular follow-up in every 3 months. Composite restorations were used as the most common treatment (25 patients, 80.6%). The treatment plan should be based on patient's age, type of defects and individual needs of the patients. Necessary treatment plan is essential, not only due to functional and aesthetic reasons, but also for the positive psychological impact on young patients. PMID:25512739

  19. Phenotype-Genotype Correlations in Mouse Models of Amelogenesis Imperfecta Caused by Amelx and Enam Mutations

    PubMed Central

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of AmelxWT, AmelxX/Y64H, AmelxY/Y64H, AmelxY64H/Y64H, and EnamWT, EnamRgsc395 heterozygous and EnamRgsc395 homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The AmelxWT mice had the largest mandibles and incisors, followed in descending order of size by the AmelxX/Y64H, AmelxY/Y64H and AmelxY64H/Y64H mice. Within the Enam groups the EnamWT incisors were largest and the EnamRgsc395 heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization. PMID:22759786

  20. Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta

    PubMed Central

    El-Sayed, Walid; Parry, David A.; Shore, Roger C.; Ahmed, Mushtaq; Jafri, Hussain; Rashid, Yasmin; Al-Bahlani, Suhaila; Al Harasi, Sharifa; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

    2009-01-01

    Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative β propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation. PMID:19853237

  1. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression.

    PubMed

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-01-01

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2(f/f);Bmp4(f/f)ameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

  2. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression

    PubMed Central

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H.; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-01-01

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2f/f;Bmp4f/fameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

  3. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    PubMed Central

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-01-01

    In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates. PMID:23055792

  4. The temporal expression of estrogen receptor alpha-36 and runx2 in human bone marrow derived stromal cells during osteogenesis

    SciTech Connect

    Francis, W.R.; Owens, S.E.; Wilde, C.; Pallister, I.; Kanamarlapudi, V.; Zou, W.; Xia, Z.

    2014-10-24

    Highlights: • ERα36 is the predominant ERα isoform involved in bone regulation in human BMSC. • ERα36 mRNA is significantly upregulated during the process of osteogenesis. • The pattern of ERα36 and runx2 mRNA expression is similar during osteogenesis. • ERα36 appears to be co-localised with runx2 during osteogenesis. - Abstract: During bone maintenance in vivo, estrogen signals through estrogen receptor (ER)-α. The objectives of this study were to investigate the temporal expression of ERα36 and ascertain its functional relevance during osteogenesis in human bone marrow derived stromal cells (BMSC). This was assessed in relation to runt-related transcription factor-2 (runx2), a main modulatory protein involved in bone formation. ERα36 and runx2 subcellular localisation was assessed using immunocytochemistry, and their mRNA expression levels by real time PCR throughout the process of osteogenesis. The osteogenically induced BMSCs demonstrated a rise in ERα36 mRNA during proliferation followed by a decline in expression at day 10, which represents a change in dynamics within the culture between the proliferative stage and the differentiative stage. The mRNA expression profile of runx2 mirrored that of ERα36 and showed a degree subcellular co-localisation with ERα36. This study suggests that ERα36 is involved in the process of osteogenesis in BMSCs, which has implications in estrogen deficient environments.

  5. Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3.

    PubMed

    Du, Zhaojie; Wang, Lei; Zhao, Yinghua; Cao, Jian; Wang, Tao; Liu, Peng; Zhang, Yabo; Yang, Xinjie; Cheng, Xiaobing; Liu, Baolin; Lei, Delin

    2014-01-01

    The sympathetic nervous system regulates bone formation and resorption under physiological conditions. However, it is still unclear how the sympathetic nerves affect stem cell migration and differentiation in bone regeneration. Distraction osteogenesis is an ideal model of bone regeneration due to its special nature as a self-engineering tissue. In this study, a rat model of mandibular distraction osteogenesis with transection of cervical sympathetic trunk was used to demonstrate that sympathetic denervation can deplete norepinephrine (NE) in distraction-induced bone callus, down-regulate β3-adrenergic receptor (adrb3) in bone marrow mesenchymal stem cells (MSCs), and promote MSC migration from perivascular regions to bone-forming units. An in vitro Transwell assay was here used to demonstrate that NE can inhibit stroma-derived factor-1 (SDF-1)-induced MSC migration and expression of the migration-related gene matrix metalloproteinase-2 (MMP-2) and downregulate that of the anti-migration gene tissue inhibitor of metalloproteinase-3 (TIMP-3). Knockdown of adrb3 using siRNA abolishes inhibition of MSC migration. An in vitro osteogenic assay was used to show that NE can inhibit the formation of MSC bone nodules and expression of the osteogenic marker genes alkaline phosphatase (ALP), osteocalcin (OCN), and runt-related transcription factor-2 (RUNX2), but knockdown of adrb3 by siRNA can abolish such inhibition of the osteogenic differentiation of MSCs. It is here concluded that sympathetic denervation-induced MSC mobilization in rat mandibular distraction osteogenesis is associated with inhibition of MSC migration and osteogenic differentiation by NE/adrb3 in vitro. These findings may facilitate understanding of the relationship of MSC mobilization and sympathetic nervous system across a wide spectrum of tissue regeneration processes. PMID:25144690

  6. Decreased heterotopic osteogenesis in vitamin-D-deficient, but normocalcemic guinea pigs

    NASA Technical Reports Server (NTRS)

    Dziedzic-Goclawska, A.; Toverud, S. U.; Kaminski, A.; Boass, A.; Yamauchi, M.

    1992-01-01

    The effect of vitamin D deficiency unhampered by hypocalcemia on de novo bone formation was studied in guinea pigs. Heterotopic induction of osteogenesis was evaluated 4 weeks after intramuscular transplantation of allogenic urinary bladder transitional epithelium from vitamin-D-repleted (+D) donors into +D and -D recipients. In -D recipients the frequency of osteogenesis and the amount of induced bone were significantly diminished; induced bone was less mature, scantly cellular woven bone poorly repopulated with bone marrow. No effect of vitamin D deficiency on orthotopic bone growth and on mineralization of orthotopic and heterotopically induced bone was observed. It is proposed that in addition to inducing factors (BMPs, growth factors) which may be responsible for transformation of mesenchymal cells to osteoprogenitor cells, normal concentrations of 1,25-(OH)2D3 may be required for proliferation and further differentiation of these cells into osteoblasts and for expression of genes engaged in extracellular matrix formation and maturation.

  7. LEUCINE-RICH AMELOGENIN PEPTIDE INDUCES OSTEOGENESIS IN MOUSE EMBRYONIC STEM CELLS

    PubMed Central

    Warotayanont, Rungnapa; Zhu, Danhong; Snead, Malcolm L.; Zhou, Yan

    2008-01-01

    Leucine-rich amelogenin peptide (LRAP), an alternatively spliced amelogenin protein, possesses a signaling property shown to induce osteogenic differentiation. In the current study, we detected LRAP expression during osteogenesis of wild-type (WT) embryonic stem (ES) cells and observed the absence of LRAP expression in amelogenin-null (KO) ES cells. We explored the signaling effect of LRAP on wild-type ES cells, and the ability of LRAP to rescue the impaired osteogenesis phenotype observed in KO ES cells. Our data indicate that LRAP treatment of WT and KO ES cells induces a significant increase in mineral matrix formation, and significant increases in bone sialoprotein and osterix gene expression. In addition, the amelogenin KO phenotype is partially rescued by the addition of exogenous LRAP. These data suggest a unique function of LRAP during ES cell differentiation along osteogenic lineage. PMID:18086559

  8. Bilateral Distraction Osteogenesis of Vascularized Iliac Crest Free Flaps Used in Mandibular Reconstruction

    PubMed Central

    Subramaniam, Shiva S.; Vujcich, Nathan J.; Nastri, Alf L.

    2016-01-01

    Summary: Vascularized free flaps have become the gold standard in reconstructing large segmental mandibular defects; however, even when bony union and soft-tissue coverage is achieved, insufficient bone stock and altered facial contour can create functional and cosmetic problems for the patient. There have been limited case reports on the use of secondary distraction osteogenesis to address these issues. The authors report a case of bilateral mandibular distraction of deep circumflex iliac artery free flaps, used for mandibular reconstruction after total mandibulectomy for treatment of osteosarcoma. Performed for reasons of retrognathia and facilitation of dental prosthetic rehabilitation, this is the first case of bilateral horizontal distraction osteogenesis of deep circumflex iliac artery free flaps reported in the literature.

  9. Study on osteogenesis promoted by low sound pressure level infrasound in vivo and some underlying mechanisms.

    PubMed

    Long, Hua; Zheng, Liheng; Gomes, Fernando Cardoso; Zhang, Jinhui; Mou, Xiang; Yuan, Hua

    2013-09-01

    To clarify the effects of low sound pressure level (LSPL) infrasound on local bone turnover and explore its underlying mechanisms, femoral defected rats were stabilized with a single-side external fixator. After exposure to LSPL infrasound for 30min twice everyday for 6 weeks, the pertinent features of bone healing were assessed by radiography, peripheral quantitative computerized tomography (pQCT), histology and immunofluorescence assay. Infrasound group showed a more consecutive and smoother process of fracture healing and modeling in radiographs and histomorphology. It also showed significantly higher average bone mineral content (BMC) and bone mineral density (BMD). Immunofluorescence showed increased expression of calcitonin gene related peptide (CGRP) and decreased Neuropeptide Y (NPY) innervation in microenvironment. The results suggested the osteogenesis promotion effects of LSPL infrasound in vivo. Neuro-osteogenic network in local microenvironment was probably one target mediating infrasonic osteogenesis, which might provide new strategy to accelerate bone healing and remodeling. PMID:23770453

  10. Exosome: A Novel Approach to Stimulate Bone Regeneration through Regulation of Osteogenesis and Angiogenesis.

    PubMed

    Qin, Yunhao; Sun, Ruixin; Wu, Chuanlong; Wang, Lian; Zhang, Changqing

    2016-01-01

    The clinical need for effective bone regeneration therapy remains in huge demands. However, the current "gold standard" treatments of autologous and allogeneic bone grafts may result in various complications. Furthermore, safety considerations of biomaterials and cell-based treatment require further clarification. Therefore, developing new therapies with stronger osteogenic potential and a lower incidence of complications is worthwhile. Recently, exosomes, small vesicles of endocytic origin, have attracted attention in bone regeneration field. The vesicles travel between cells and deliver functional cargoes, such as proteins and RNAs, thereby regulating targeted cells differentiation, commitment, function, and proliferation. Much evidence has demonstrated the important roles of exosomes in osteogenesis both in vitro and in vivo. In this review, we summarize the properties, origins and biogenesis of exosomes, and the recent reports using exosomes to regulate osteogenesis and promote bone regeneration. PMID:27213355

  11. Trace element doping in calcium phosphate ceramics to Understand osteogenesis and angiogenesis

    PubMed Central

    Bose, Susmita; Fielding, Gary; Tarafder, Solaiman; Bandyopadhyay, Amit

    2013-01-01

    The general trends in synthetic bone grafting materials are shifting towards approaches that can illicit osteoinductive properties. Pharmacologics and biologics have been used in combination with calcium phosphate (CaP) ceramics, however, recently have become the target of scrutiny over the safety. The importance of trace elements in natural bone health is well documented. Ions, e.g. lithium, zinc, magnesium, manganese, silicon, strontium etc. have shown to increase osteogenesis and neovascularization. Incorporation of dopants into CaPs can provide a platform for safe and efficient delivery in clinical applications where increased bone healing is favorable. This review highlights use of trace elements in CaP biomaterials, and offers an insight into the mechanisms of how metal ions can enhance both osteogenesis and angiogenesis. PMID:24012308

  12. Exosome: A Novel Approach to Stimulate Bone Regeneration through Regulation of Osteogenesis and Angiogenesis

    PubMed Central

    Qin, Yunhao; Sun, Ruixin; Wu, Chuanlong; Wang, Lian; Zhang, Changqing

    2016-01-01

    The clinical need for effective bone regeneration therapy remains in huge demands. However, the current “gold standard” treatments of autologous and allogeneic bone grafts may result in various complications. Furthermore, safety considerations of biomaterials and cell-based treatment require further clarification. Therefore, developing new therapies with stronger osteogenic potential and a lower incidence of complications is worthwhile. Recently, exosomes, small vesicles of endocytic origin, have attracted attention in bone regeneration field. The vesicles travel between cells and deliver functional cargoes, such as proteins and RNAs, thereby regulating targeted cells differentiation, commitment, function, and proliferation. Much evidence has demonstrated the important roles of exosomes in osteogenesis both in vitro and in vivo. In this review, we summarize the properties, origins and biogenesis of exosomes, and the recent reports using exosomes to regulate osteogenesis and promote bone regeneration. PMID:27213355

  13. Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients

    PubMed Central

    Herranz, Eva; Rodríguez-Rodríguez, Luis; Mucientes, Arkaitz; Abásolo, Lydia; Marco, Fernando; Fernández-Gutiérrez, Benjamín; Lamas, José Ramón

    2015-01-01

    Introduction Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis. Methods MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases. Results Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs. Conclusion Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential. PMID:26352263

  14. Spatiotemporal Analyses of Osteogenesis and Angiogenesis via Intravital Imaging in Cranial Bone Defect Repair

    PubMed Central

    Huang, Chunlan; Ness, Vincent P.; Yang, Xiaochuan; Chen, Hongli; Luo, Jiebo; Brown, Edward B; Zhang, Xinping

    2015-01-01

    Osteogenesis and angiogenesis are two integrated components in bone repair and regeneration. A deeper understanding of osteogenesis and angiogenesis has been hampered by technical difficulties of analyzing bone and neovasculature simultaneously in spatiotemporal scales and in three-dimensional formats. To overcome these barriers, a cranial defect window chamber model was established that enabled high-resolution, longitudinal, and real-time tracking of angiogenesis and bone defect healing via Multiphoton Laser Scanning Microscopy (MPLSM). By simultaneously probing new bone matrix via second harmonic generation (SHG), neovascular networks via intravenous perfusion of fluorophore, and osteoblast differentiation via 2.3kb collagen type I promoter driven GFP (Col2.3GFP), we examined the morphogenetic sequence of cranial bone defect healing and further established the spatiotemporal analyses of osteogenesis and angiogenesis coupling in repair and regeneration. We demonstrated that bone defect closure was initiated in the residual bone around the edge of the defect. The expansion and migration of osteoprogenitors into the bone defect occurred during the first 3 weeks of healing, coupled with vigorous microvessel angiogenesis at the leading edge of the defect. Subsequent bone repair was marked by matrix deposition and active vascular network remodeling within new bone. Implantation of bone marrow stromal cells (BMSCs) isolated from Col2.3GFP mice further showed that donor-dependent bone formation occurred rapidly within the first 3 weeks of implantation, in concert with early angiogenesis. The subsequent bone wound closure was largely host-dependent, associated with localized modest induction of angiogenesis. The establishment of a live imaging platform via cranial window provides a unique tool to understand osteogenesis and angiogenesis in repair and regeneration, enabling further elucidation of the spatiotemporal regulatory mechanisms of osteoprogenitor cell interactions

  15. Foxc2 regulates osteogenesis and angiogenesis of bone marrow mesenchymal stem cells

    PubMed Central

    2013-01-01

    Background The Forkhead/Fox transcription factor Foxc2 is a critical regulator of osteogenesis and angiogenesis of cells. Bone marrow mesenchymal stem cells (BMSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes and fibroblasts. The present study investigates the role of Foxc2 overexpression in osteogenesis and angiogenesis of BMSCs in vitro. Methods BMSCs were isolated from SD rat femurs and tibias, and characterized by cell surface antigen identification and osteoblasts and adipocytes differentiation. The cells were transfected with lentiviral Foxc2 (Lv-Foxc2) or green fluorescent protein (Lv-GFP). Seventy hours later, Foxc2 expression was observed using real time-PCR and Western blot. The transfected cells were stained with Alizarin red S or alkaline phosphatase (ALP) after osteogenic induction. Meanwhile, the expression levels of osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor-β (PDGF-β) were measured by real time-PCR, Western blot and immunostaining. Results Results of cell characterization showed that the cells were positive to CD44 (99.56%) and negative to CD34 (0.44%), and could differentiate into osteoblasts and adipocytes. Foxc2 overexpression not only increased the numbers of mineralized nodes and ALP activity, but also enhanced the expressions of Runx2, OCN, VEGF and PDGF-β in transfected BMSCs after osteogenic induction. The effects of Foxc2 on osteogenesis and angiogenesis were significantly different between Lv-Foxc2 transfected BMSCs and Lv-GFP transfected BMSCs (P<0.05). In addition, the MAPK-specific inhibitors, PD98059 and LY294002, blocked the Foxc2-induced regulation of BMSC differentiation. Conclusions Foxc2 gene is successfully transfected into BMSCs with stable and high expression. The overexpression of Foxc2 acts on BMSCs to stimulate osteogenesis and angiogenesis. The effect of Foxc2 on angiogenesis of

  16. Spatiotemporal Analyses of Osteogenesis and Angiogenesis via Intravital Imaging in Cranial Bone Defect Repair.

    PubMed

    Huang, Chunlan; Ness, Vincent P; Yang, Xiaochuan; Chen, Hongli; Luo, Jiebo; Brown, Edward B; Zhang, Xinping

    2015-07-01

    Osteogenesis and angiogenesis are two integrated components in bone repair and regeneration. A deeper understanding of osteogenesis and angiogenesis has been hampered by technical difficulties of analyzing bone and neovasculature simultaneously in spatiotemporal scales and in 3D formats. To overcome these barriers, a cranial defect window chamber model was established that enabled high-resolution, longitudinal, and real-time tracking of angiogenesis and bone defect healing via multiphoton laser scanning microscopy (MPLSM). By simultaneously probing new bone matrix via second harmonic generation (SHG), neovascular networks via intravenous perfusion of fluorophore, and osteoblast differentiation via 2.3-kb collagen type I promoter-driven GFP (Col2.3GFP), we examined the morphogenetic sequence of cranial bone defect healing and further established the spatiotemporal analyses of osteogenesis and angiogenesis coupling in repair and regeneration. We showed that bone defect closure was initiated in the residual bone around the edge of the defect. The expansion and migration of osteoprogenitors into the bone defect occurred during the first 3 weeks of healing, coupled with vigorous microvessel angiogenesis at the leading edge of the defect. Subsequent bone repair was marked by matrix deposition and active vascular network remodeling within new bone. Implantation of bone marrow stromal cells (BMSCs) isolated from Col2.3GFP mice further showed that donor-dependent bone formation occurred rapidly within the first 3 weeks of implantation, in concert with early angiogenesis. The subsequent bone wound closure was largely host-dependent, associated with localized modest induction of angiogenesis. The establishment of a live imaging platform via cranial window provides a unique tool to understand osteogenesis and angiogenesis in repair and regeneration, enabling further elucidation of the spatiotemporal regulatory mechanisms of osteoprogenitor cell interactions with host bone

  17. Vascular Development during Distraction Osteogenesis Proceeds by Sequential Intramuscular Arteriogenesis Followed by Intraosteal Angiogenesis

    PubMed Central

    Morgan, Elise F.; Hussein, Amira I.; Al-Awadhi, Bader A.; Hogan, Daniel E.; Matsubara, Hidenori; Al-Alq, Zainab; Fitch, Jennifer; Andre, Billy; Hosur, Krutika; Gerstenfeld, Louis C.

    2012-01-01

    Vascular formation is intimately associated with bone formation during distraction osteogenesis (DO). While prior studies on this association have focused on vascular formation locally within the regenerate, we hypothesized that this vascular formation, as well as the resulting osteogenesis, rely heavily on the response of the vascular network in surrounding muscular compartments. To test this hypothesis, the spatiotemporal sequence of vascular formation was assessed in both muscular and osseous compartments in a murine model of DO and was compared to the progression of osteogenesis. Micro-computed tomography (μCT) scans were performed sequentially, before and after demineralization, on specimens containing contrast-enhanced vascular casts. Image registration and subtraction procedures were developed to examine the co-related, spatiotemporal patterns of vascular and osseous tissue formation. Immunohistochemistry was used to assess the contributory roles of arteriogenesis (formation of large vessels) and angiogenesis (formation of small vessels) to overall vessel formation. Mean vessel thickness showed an increasing trend during the period of active distraction (p=0.068), whereas vessel volume showed maximal increases during the consolidation period (p=0.009). The volume of mineralized tissue in the regenerate increased over time (p<0.039), was correlated with vessel volume (r=0.59; p=0.025), and occurred primarily during consolidation. Immunohistological data suggested that: 1) the period of active distraction was characterized primarily by arteriogenesis in the surrounding muscle; 2) during consolidation, angiogenesis predominated in the intraosteal region; 3) vessel formation proceeded from the surrounding muscle into the regenerate. These data show that formation of vascular tissue occurs in both muscular and osseous compartments during DO and that periods of intense osteogenesis are concurrent with those of angiogenesis. The results further suggest the

  18. Akermanite bioceramics promote osteogenesis, angiogenesis and suppress osteoclastogenesis for osteoporotic bone regeneration

    PubMed Central

    Xia, Lunguo; Yin, Zhilan; Mao, Lixia; Wang, Xiuhui; Liu, Jiaqiang; Jiang, Xinquan; Zhang, Zhiyuan; Lin, Kaili; Chang, Jiang; Fang, Bing

    2016-01-01

    It is a big challenge for bone healing under osteoporotic pathological condition with impaired angiogenesis, osteogenesis and remodeling. In the present study, the effect of Ca, Mg, Si containing akermanite bioceramics (Ca2MgSi2O7) extract on cell proliferation, osteogenic differentiation and angiogenic factor expression of BMSCs derived from ovariectomized rats (BMSCs-OVX) as well as the expression of osteoclastogenic factors was evaluated. The results showed that akermanite could enhance cell proliferation, ALP activity, expression of Runx2, BMP-2, BSP, OPN, OCN, OPG and angiogenic factors including VEGF and ANG-1. Meanwhile, akermanite could repress expression of osteoclastogenic factors including RANKL and TNF-α. Moreover, akermanite could activate ERK, P38, AKT and STAT3 signaling pathways, while crosstalk among these signaling pathways was evident. More importantly, the effect of akermanite extract on RANKL-induced osteoclastogenesis was evaluated by TRAP staining and real-time PCR assay. The results showed that akermanite could suppress osteoclast formation and expression of TRAP, cathepsin K and NFATc1. The in vivo experiments revealed that akermanite bioceramics dramatically stimulated osteogenesis and angiogenesis in an OVX rat critical-sized calvarial defect model. All these results suggest that akermanite bioceramics with the effects of Mg and Si ions on osteogenesis, angiogenesis and osteoclastogenesis are promising biomaterials for osteoporotic bone regeneration. PMID:26911441

  19. Comprehensive Review of Adipose Stem Cells and Their Implication in Distraction Osteogenesis and Bone Regeneration

    PubMed Central

    Morcos, Mina W.; Al-Jallad, Hadil; Hamdy, Reggie

    2015-01-01

    Bone is one of the most dynamic tissues in the human body that can heal following injury without leaving a scar. However, in instances of extensive bone loss, this intrinsic capacity of bone to heal may not be sufficient and external intervention becomes necessary. Several techniques are available to address this problem, including autogenous bone grafts and allografts. However, all these techniques have their own limitations. An alternative method is the technique of distraction osteogenesis, where gradual and controlled distraction of two bony segments after osteotomy leads to induction of new bone formation. Although distraction osteogenesis usually gives satisfactory results, its major limitation is the prolonged duration of time required before the external fixator is removed, which may lead to numerous complications. Numerous methods to accelerate bone formation in the context of distraction osteogenesis have been reported. A viable alternative to autogenous bone grafts for a source of osteogenic cells is mesenchymal stem cells from bone marrow. However, there are certain problems with bone marrow aspirate. Hence, scientists have investigated other sources for mesenchymal stem cells, specifically adipose tissue, which has been shown to be an excellent source of mesenchymal stem cells. In this paper, the potential use of adipose stem cells to stimulate bone formation is discussed. PMID:26448947

  20. Akermanite bioceramics promote osteogenesis, angiogenesis and suppress osteoclastogenesis for osteoporotic bone regeneration.

    PubMed

    Xia, Lunguo; Yin, Zhilan; Mao, Lixia; Wang, Xiuhui; Liu, Jiaqiang; Jiang, Xinquan; Zhang, Zhiyuan; Lin, Kaili; Chang, Jiang; Fang, Bing

    2016-01-01

    It is a big challenge for bone healing under osteoporotic pathological condition with impaired angiogenesis, osteogenesis and remodeling. In the present study, the effect of Ca, Mg, Si containing akermanite bioceramics (Ca2MgSi2O7) extract on cell proliferation, osteogenic differentiation and angiogenic factor expression of BMSCs derived from ovariectomized rats (BMSCs-OVX) as well as the expression of osteoclastogenic factors was evaluated. The results showed that akermanite could enhance cell proliferation, ALP activity, expression of Runx2, BMP-2, BSP, OPN, OCN, OPG and angiogenic factors including VEGF and ANG-1. Meanwhile, akermanite could repress expression of osteoclastogenic factors including RANKL and TNF-α. Moreover, akermanite could activate ERK, P38, AKT and STAT3 signaling pathways, while crosstalk among these signaling pathways was evident. More importantly, the effect of akermanite extract on RANKL-induced osteoclastogenesis was evaluated by TRAP staining and real-time PCR assay. The results showed that akermanite could suppress osteoclast formation and expression of TRAP, cathepsin K and NFATc1. The in vivo experiments revealed that akermanite bioceramics dramatically stimulated osteogenesis and angiogenesis in an OVX rat critical-sized calvarial defect model. All these results suggest that akermanite bioceramics with the effects of Mg and Si ions on osteogenesis, angiogenesis and osteoclastogenesis are promising biomaterials for osteoporotic bone regeneration. PMID:26911441

  1. Lnk-dependent axis of SCF–cKit signal for osteogenesis in bone fracture healing

    PubMed Central

    Matsumoto, Tomoyuki; Ii, Masaaki; Nishimura, Hiromi; Shoji, Taro; Mifune, Yutaka; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Fukui, Tomoaki; Kawakami, Yohei; Kuroda, Tomoya; Kwon, Sang Mo; Iwasaki, Hiroto; Horii, Miki; Yokoyama, Ayumi; Oyamada, Akira; Lee, Sang Yang; Hayashi, Shinya; Kurosaka, Masahiro; Takaki, Satoshi

    2010-01-01

    The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)–cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF–cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF–cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing. PMID:20855498

  2. Craniofacial reconstruction by transport distraction osteogenesis: corticotomy versus osteotomy--an experimental study.

    PubMed

    Kramer, Franz-Josef; Mueller, Michal; Rahmstorf, Meike; Swennen, Gwen; Dempf, Rupert; Schierle, Hannes

    2004-07-01

    Transport osteogenesis is a modified technique of callus distraction appropriate for the reconstruction of extended osseous defects of long or flat bones. The aim of this study was to determine the regenerative potential of this technique related to the degree of mobilization of the transport segment. In 10 adult sheep, critically sized defects of the calvaria were treated by gradual movement of a transport segment consisting of calvarial bone. The transport segments were either corticotomized (n = 5) or osteotomized (n = 5). The latency period was 5 days; the rate of distraction was 1 mm/d, extended for approximately 40 days. The consolidation period was 28 days. Specimens were investigated by conventional radiography, computed tomography scans, immunofluorescence, and histological examination. In both groups, transport osteogenesis resulted in a complete closure of the defect. The volume and thickness of newly formed bone at the defect site did not differ significantly between the groups, nor did the extent of vascularization. Bone formation and remodeling occurred during the entire period of distraction and consolidation. Osteotomized transport segments became smaller during distraction, whereas the volume of corticotomized segments remained relatively constant. In conclusion, transport osteogenesis resulted in reliable closure of extended skull defects in adult organisms; corticotomy and osteotomy of the transport segment led to a similar extent of bone formation. PMID:15213530

  3. The biology of distraction osteogenesis for correction of mandibular and craniomaxillofacial defects: A review

    PubMed Central

    Natu, Subodh Shankar; Ali, Iqbal; Alam, Sarwar; Giri, Kolli Yada; Agarwal, Anshita; Kulkarni, Vrishali Ajit

    2014-01-01

    Limb lengthening by distraction osteogenesis was first described in 1905. The technique did not gain wide acceptance until Gavril Ilizarov identified the physiologic and mechanical factors governing successful regeneration of bone formation. Distraction osteogenesis is a new variation of more traditional orthognathic surgical procedure for the correction of dentofacial deformities. It is most commonly used for the correction of more severe deformities and syndromes of both the maxilla and the mandible and can also be used in children at ages previously untreatable. The basic technique includes surgical fracture of deformed bone, insertion of device, 5-7 days rest, and gradual separation of bony segments by subsequent activation at the rate of 1 mm per day, followed by an 8-12 weeks consolidation phase. This allows surgeons, the lengthening and reshaping of deformed bone. The aim of this paper is to review the principle, technical considerations, applications and limitations of distraction osteogenesis. The application of osteodistraction offers novel solutions for surgical-orthodontic management of developmental anomalies of the craniofacial skeleton as bone may be molded into different shapes along with the soft tissue component gradually thereby resulting in less relapse. PMID:24688555

  4. Effect of Dietary Ascorbic Acid on Osteogenesis of Expanding Midpalatal Suture in Rats

    PubMed Central

    Farhadian, Nasrin; Miresmaeili, Amirfarhang; Azar, Ramin; Zargaran, Massoumeh; Moghimbeigi, Abbas; Soheilifar, Sanaz

    2015-01-01

    Objectives: After maxillary expansion, a long period of retention is necessary to prevent early relapse. Therefore, it is beneficial to accelerate bone formation in the expanding midpalatal suture to reduce relapse. This study was designed to evaluate the effect of dietary vitamin C on osteogenesis of rat midpalatal suture during expansion. Materials and Methods: Fifty-four male Wistar rats were randomly divided into three groups, each with a control and an experimental subgroup. An open-loop spring was bonded to maxillary incisors of each animal to expand the premaxillary suture. Experimental groups received dietary vitamin C in their water. The rats in the three groups were sacrificed at three, nine or 17-day intervals after bonding the spring. Then, the premaxilla was dissected and sections were made and stained with hematoxylin and eosin and osteopontin marker. Osteoblasts and osteoclasts were counted in the suture. Two-way ANOVA and the Mann-Whitney-U test were used for analyzing the data. Results: After three days, the number of osteoblasts was significantly higher in the vitamin C group but after nine days it was significantly higher in the control group and after seventeen days there were no significant differences between the groups. Osteoclast counts were not significantly different between vitamin C and control groups. Conclusion: Vitamin C had a positive effect on osteogenesis at the beginning of bone formation in the expanding suture, but after nine days it had a negative effect on suture osteogenesis in rats. PMID:26005453

  5. Maxillary distraction osteogenesis using Le Fort I osteotomy without intraoperative down-fracture.

    PubMed

    Yamauchi, K; Mitsugi, M; Takahashi, T

    2006-06-01

    The aim of this study is to present a technique for maxillary distraction osteogenesis using Le Fort I osteotomy without down-fracture. Six cleft-related patients suffering from severe midfacial deficiency were treated with maxillary distraction osteogenesis. The RED II system was chosen as the extraoral device and the Leipzig retention plate system to anchor the maxillary segment. Maxillary distraction osteogenesis was successful in all cases. Cephalometric and clinical evaluation after an average follow-up period of 1 year showed stable results with respect to skeletal and dental relationships. The SNA angle increased from 72.3 degrees to 81.4 degrees and the ANB angle increased by 11.0 degrees immediately after removing the distraction device. After 1 year, the sagittal bone gain remained and the SNA angle had decreased by 0.8 degrees . This technique seems to minimize the risk of the surgical procedure and shorten the operation time. It may become an alternative method for the treatment of patients with severe midfacial hypoplasia. PMID:16513321

  6. A highly polymorphic (ACT)n VNTR (variable nucleotide of tandem repeats) locus inside intron 12 of COL1A2, one of the two genes involved in dominant osteogenesis imperfecta.

    PubMed

    Pepe, G

    1993-01-01

    A new, highly polymorphic, region consisting of variable number of tandem repeats (VNTR) is described that occurs within intron 12 of the COL1A2 gene. This VNTR consists of the trinucleotide ACT repeated from 6 to 12 times. Of the six alleles so far detected four are common in the three major races. The two rare alleles, (ACT)11 and (ACT)12, have been found only in Africans. In addition, a rapid technique has been developed that can be used successfully with very small amounts of even partially degraded DNA, thus allowing the use of this VNTR for forensic applications. Since dominant OI can be due to mutations at either of two loci (COL1A1 and COL1A2) prenatal diagnosis becomes feasible in the majority of the affected families only if a very informative marker is available for both of these genes. This VNTR provides a very powerful marker for COL1A2. In fact the heterozygosity for it ranges from 0.634 to 0.741 with PIC values from 0.562 to 0.696, respectively. Since trinucleotide repeats can be "unstable," and sometimes pathogenic, the unexplained collagenopathies (or suspected collagenopathies) should be analyzed from this point of view. PMID:8104634

  7. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta.

    PubMed

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-06-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder. PMID:25669657

  8. Interdisciplinary Full Mouth Rehabilitation of a Patient with Amelogenesis Imperfecta: A Case Report with 8 Years Follow-up.

    PubMed

    Sreedevi, S; Sanjeev, R; Ephraim, Rena; Joseph, Mathai

    2014-01-01

    This case report deals with the interdisciplinary approach of a 28-year-old lady with Amelogenesis imperfecta of the hypoplastic kind. The patient came with a chief illness of worn out teeth, unsatisfactory esthetics and severe sensitivity of teeth. Her family history revealed a related situation in her father's brother and her sister. On clinical assessment, the crowns of all teeth were worn out. The plan of the treatment was to protect as much tooth structure, restore the vertical dimension, and improve esthetics and masticatory function. The treatment procedures involved prosthodontic, endodontic, and periodontic interventions. After recording the vertical height, endodontic treatment and crown lengthening were performed with respect to the lower anteriors. The lost vertical height was regained in stages by insertion of full coverage crowns for all the teeth. The patient's esthetic and functional needs were met with systematic and sequential interdisciplinary treatment approach. PMID:25628493

  9. Restoring Function and Aesthetics in a Class II Division 1 Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Doruk, Cenk; Ozturk, Firat; Sari, Fatih; Turgut, Mehmet

    2011-01-01

    Amelogenesis imperfecta (AI) encompasses a complicated group of hereditary conditions that cause developmental alterations in the structure of the enamel in the absence of a systemic disorder. AI primarily affects the quality and/or quantity of dental enamel, and it may affect all or only some of the teeth in the primary and/or permanent dentition. This clinical report describes the oral rehabilitation of a 21-year-old man diagnosed with hypomaturation-type AI. He presented with discolored and mutilated teeth. Cephalometrically, the patient has skeletal class II malocclusion due to mandibular deficiency considered as a result of maxillary constriction. The interdisciplinary approach was followed because of the complex needs of the patient. The aim of treatment was to restore aesthetics, improve malocclusion and masticatory function. Aesthetic and functional expectations were met with metal ceramic restorations. In this report, the interdisciplinary approach for a patient with AI and a malocclusion is described. PMID:21494393

  10. Amelogenin signal peptide mutation: Correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta

    SciTech Connect

    Lagerstroem-Fermer, M.; Nilsson, M.; Pettersson, U.

    1995-03-01

    Formation of tooth enamel is a poorly understood biological process. In this study the authors describe a 9-bp deletion in exon 2 of the amelogenin gene (AMGX) causing X-linked hypoplastic amelogenesis imperfecta, a disease characterized by defective enamel. The mutation results in the loss of 3 amino acids and exchange of 1 in the signal peptide of the amelogenin protein. This deletion in the signal peptide probably interferes with translocation of the amelogenin protein during synthesis, resulting in the thin enamel observed in affected members of the family. The authors compare this mutation to a previously reported mutation in the amelogenin gene that causes a different disease phenotype. The study illustrates that molecular analysis can help explain the various manifestations of a tooth disorder and thereby provide insights into the mechanisms of tooth enamel formation. 16 refs., 2 figs., 1 tab.

  11. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

    PubMed Central

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K.; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B.; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-01-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder. PMID:25669657

  12. Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells

    PubMed Central

    Watt, James; Schlezinger, Jennifer J.

    2015-01-01

    Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

  13. Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells.

    PubMed

    Watt, James; Schlezinger, Jennifer J

    2015-05-01

    Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

  14. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth

    PubMed Central

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-01-01

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20Aflox/flox mice, we created K14-Cre;Fam20Aflox/flox (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues. PMID:27281036

  15. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth.

    PubMed

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-01-01

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20A(flox/flox) mice, we created K14-Cre;Fam20A(flox/flox) (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues. PMID:27281036

  16. Mechanical and Vascular Cues Synergistically Enhance Osteogenesis in Human Mesenchymal Stem Cells.

    PubMed

    Steward, Andrew J; Cole, Jacqueline H; Ligler, Frances S; Loboa, Elizabeth G

    2016-08-01

    Development and maintenance of a vascular network are critical for bone growth and homeostasis; strategies that promote vascular function are critical for clinical success of tissue-engineered bone constructs. Co-culture of endothelial cells (ECs) with mesenchymal stem cells (MSCs) and exposure to 10% cyclic tensile strain have both been shown to regulate osteogenesis in isolation, but potential synergistic effects have yet to be explored. The objective of this study was to expose an MSC-EC co-culture to 10% cyclic tensile strain to examine the role of this mechanical stimulus on MSC-EC behavior. We hypothesized that paracrine signaling from ECs would stimulate osteogenesis of MSCs, and exposure to 10% cyclic tensile strain would enhance this anabolic signal. Human umbilical vein ECs and human bone marrow-derived MSCs were either monocultured or co-cultured at a 1:1 ratio in a mixed osteo/angiogenic medium, exposed to 10% cyclic tensile strain at 1 Hz for 4 h/day for 2 weeks, and biochemically and histologically analyzed for endothelial and osteogenic markers. While neither 10% cyclic tensile strain nor co-culture alone had a significant effect on osteogenesis, the concurrent application of strain to an MSC-EC co-culture resulted in a significant increase in calcium accretion and mineral deposition, suggesting that co-culture and strain synergistically enhance osteogenesis. Neither co-culture, 10% cyclic tensile strain, nor a combination of these stimuli affected endothelial markers, indicating that the endothelial phenotype remained stable, but unresponsive to the stimuli evaluated in this study. This study is the first to investigate the role of cyclic tensile strain on the complex interplay between ECs and MSCs in co-culture. The results of this study provide key insights into the synergistic effects of 10% cyclic tensile strain and co-culture on osteogenesis. Understanding mechanobiological factors affecting MSC-EC crosstalk will help enhance strategies for

  17. Educating Students with Mild Disabilities.

    ERIC Educational Resources Information Center

    Meyen, Edward L., Ed.; And Others

    The book contains 19 papers from the journal, "Focus on Exceptional Children," that discuss new perspectives and practices in educating students with mild disabilities. The first half of the book is titled "New Perspectives" and includes the following articles: "Beyond the Regular Education Initiative/Inclusion and the Resource Room Controversy"…

  18. "White Privilege": A Mild Critique

    ERIC Educational Resources Information Center

    Blum, Lawrence

    2008-01-01

    White privilege analysis has been influential in philosophy of education. I offer some mild criticisms of this largely salutary direction--its inadequate exploration of its own normative foundations, and failure to distinguish between "spared injustice", "unjust enrichment" and "non-injustice-related" privileges; its inadequate exploration of the…

  19. Bone marrow ablation demonstrates that estrogen plays an important role in osteogenesis and bone turnover via an antioxidative mechanism.

    PubMed

    Shi, Chunmin; Wu, Jun; Yan, Quanquan; Wang, Rong; Miao, Dengshun

    2015-10-01

    To assess the effect of estrogen deficiency on osteogenesis and bone turnover in vivo, 8-week-old mice were sham-operated or bilaterally ovariectomized (OVX), and after 8 weeks, mechanical bone marrow ablation (BMX) was performed and newly formed bone tissue was analyzed from 6 days to 2 weeks after BMX. Our results demonstrated that OVX mice following BMX displayed 2 reversed phase changes, one phase observed at 6 and 8 days after BMX delayed osteogenesis accompanied by a delay in osteoclastogenesis, and the other phase observed at 12 and 14 days after BMX increased osteoblastic activity and osteoclastic activity. Furthermore, we asked whether impaired osteogenesis caused by estrogen deficiency was associated with increased oxidative stress, and oxidative stress parameters were examined in bone tissue from sham-operated and OVX mice and OVX mice were administrated with antioxidant N-acetyl-l-cysteine (NAC) or vehicle after BMX. Results demonstrated that estrogen deficiency induced oxidative stress in mouse bone tissue with reduced antioxidase levels and activity, whereas NAC administration almost rescued the abnormalities in osteogenesis and bone turnover caused by OVX. Results from this study indicate that estrogen deficiency resulted in primarily impaired osteogenesis and subsequently accelerated bone turnover by increasing oxidative stress and oxidative stress promises to be an effective target in the process of treatment of postmenopausal osteoporosis. PMID:26036172

  20. Development of mild gasification process

    SciTech Connect

    Chu, C.I.C.; Derting, T.M.

    1988-07-01

    Under a previous contract with Morgantown Energy Technology Center (METC), Department of Energy (DOE) Contract No. AC21-84MC21108, UCC Research Corporation (UCCRC) built and tested a 1500 lb/day Mild Gasification Process Development Unit (MGU). The MGU, as tested under the previous contract, is shown in Figure 1. Testing completed under the previous contract showed that good quality hydrocarbon liquids and good quality char can be produced in the MGU. However, the MGU is not optimized. The primary objectives of the current project are to optimize the MGU and determine the suitability of char for several commercial applications. The program consists of four tasks; Task 1 -- Test Plan; Task 2 -- Optimization of Mild Gasification Process; Task 3 -- Evaluation of Char and Char/Coal Blends as a Boiler/Blast Furnace Fuel; and Task 4 -- Analysis of Data and Preparation of Final Report. Task 1 has been completed while work continued on Task 2.

  1. Development of mild gasification process

    SciTech Connect

    Chu, C.I.C.; Gillespie, B.L.

    1988-02-01

    Under a previous contract with Morgantown Energy Technology Center (METC), Department of Energy (DOE) Contract No. DE-AC21-84MC21108, UCC Research Corporation (UCCRC) built and tested a 1500 lb/day Mild Gasification Process Development Unit (MGU). The MGU, as tested under the previous contract, is shown in Figure 1. Testing completed under the previous contract showed that good quality hydrocarbon liquids and good quality char can be produced in the MGU. However, the MGU is not optimized. The primary objectives of the current project are to optimize the MGU and determine the suitability of char for several commercial applications. The program consists of four tasks; Task 1-Test Plan; Task 2-Optimization of Mild Gasification Process; Task 3-Evaluation of Char and Char/Coal Blends as a Boiler/Blast Furnace Fuel; and Task 4-Analysis of Data and Preparation of Final Report. Task 1 has been completed while work continued on Task 2.

  2. Development of mild gasification process

    SciTech Connect

    Chu, C.I.C.; Williams, S.W.

    1989-01-01

    Under a previous contract with Morgantown Energy Technology Center (METC), Department of Energy (DOE) Contract No. AC21-84MC21108, UCC Research Corporation (UCCRC) built and tested a 1500 lb/day Mild Gasification Process Development Unit (MGU). The MGU, as tested under the previous contract, is shown in Figure 1. Testing completed under the previous contract showed that good quality hydrocarbon liquids and good quality char can be produced in the MGU. However, the MGU is not optimized. The primary objectives of the current project are to optimize the MGU and determine the suitability of char for several commercial applications. The program consists of four tasks; Task 1 -- Test Plan; Task 2 -- Optimization of Mild Gasification Process; Task 3 -- Evaluation of Char and Char/Coal Blends as a Boiler/Blast Furnace Fuel; and Task 4 -- Analysis of Data and Preparation of Final Report. Task 1 has been completed while work continued on Task 2.

  3. Development of mild gasification process

    SciTech Connect

    Chu, C.I.C.; Gillespie, B.L.

    1987-11-01

    Under a previous contract with Morgantown Energy Technology Center (METC), Department of Energy (DOE) Contract No. AC21-84MC21108, UCC Research Corporation (UCCRC) built and tested a 1500 lb/day Mild Gasification Process Development Unit (MGU). The MGU, as tested under the previous contract, is shown in Figure 1. Testing completed under the previous contract showed that good quality hydrocarbon liquids and good quality char can be produced in the MGU. However, the MGU is not optimized. The primary objectives of the current project are to optimize the MGU and determine the suitability of char for several commercial applications. The program consists of four tasks; Task 1 -- Test Plan; Task 2 -- Optimization of Mild Gasification Process; Task 3 -- Evaluation of Char and Char/Coal Blends as a Boiler/Blast Furnace Fuel; and Task 4 -- Analysis of Data and Preparation of Final Report. Task 1 has been completed while work continued on Task 2.

  4. Mild coal gasification: Product separation

    SciTech Connect

    Wallman, P.H.; Singleton, M.F.

    1992-08-04

    Our general objective is to further the development of efficient continuous mild coal gasification processes. The research this year has been focused on product separation problems and particularly the problem of separating entrained ultra-fine particles from the chemically reactive environment of the product gas stream. Specifically, the objective of the present work has been to study candidate barrier filters for application to mild coal gasification processes. Our approach has been to select the most promising existing designs, to develop a design of our own and to test the designs in our bench-scale gasification apparatus. As a first step towards selection of the most promising barrier filter we have determined coking rates on several candidate filter media.

  5. Memory dysfunction in mild aphasics.

    PubMed

    Rönnberg, J; Larsson, C; Fogelsjöö, A; Nilsson, L G; Lindberg, M; Angquist, K A

    1996-03-01

    The effect of mild aphasia (n = 9), as a result of subarachnoid haemorrhage (SAH), was evaluated against one matched (sex, age, and education) control group suffering from SAH of unknown origin without aphasia, and against one matched healthy control group. According to aphasia testing (Reinvang & Engvik, 1980), criteria for a classical diagnosis were not met. Therefore, the patients were characterized as mild aphasics: They generally displayed intact audo-verbal comprehension and repetition abilities, and they demonstrated a fluent, spontaneous speech. However, they showed phonemic and semantic paraphasias, with self-corrections; a few patients displayed alexia and agraphia. Memory performance of these three groups was evaluated by a neuropsychological test battery, designed to tap various components of verbal memory function. From the results it was concluded that: (a) Short-term memory is impaired, as regards the phonological loop and the central executive in working memory, whereas maintenance rehearsal is unaffected, given that the demands on phonological coding is minimized, (b) long-term memory is also generally impaired, whereas long-term learning and forgetting by means of subject-performed tasks proceeds within a normal range. Impairments were hypothesized to reflect less efficient central executive functions of working memory, involving generation of less appropriate semantic codes and phonological representations, (c) mildly aphasic patients are not subjectively aware of their own memory deficits, and (d) aphasia classification by means of standard procedures do not sufficiently characterize the nature of a mildy aphasic patient's memory problems. PMID:8900819

  6. Mild Hypertransaminasemia in Primary Care

    PubMed Central

    Al-Busafi, Said A.; Hilzenrat, Nir

    2013-01-01

    The liver enzymes, alanine transaminase (ALT) or aspartate transaminase (AST), are commonly used in clinical practice as screening as well as diagnostic tests for liver diseases. ALT is more specific for liver injury than AST and has been shown to be a good predictor of liver related and all-cause mortality. Asymptomatic mild hypertransaminasemia (i.e., less than five times normal) is a common finding in primary care and this could be attributed to serious underlying condition or has transient and benign cause. Unfortunately, there are no good literatures available on the cost-effectiveness of evaluating patients with asymptomatic mild hypertransaminasemia. However, if the history and physical examination do not suggest a clear cause, a stepwise approach should be initiated based on pretest probability of the underlying liver disease. Nonalcoholic fatty liver disease is becoming the most common cause of mild hypertransaminasemia worldwide. Other causes include alcohol abuse, medications, and hepatitis B and C. Less common causes include hemochromatosis, α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson's disease. Nonhepatic causes such as celiac disease, thyroid, and muscle disorders should be considered in the differential diagnosis. Referral to a specialist and a possible liver biopsy should be considered if persistent hypertransaminasemia for six months or more of unclear etiology.

  7. Synthesis and characterization of cationic polymeric nanoparticles as simvastatin carriers for enhancing the osteogenesis of bone marrow mesenchymal stem cells.

    PubMed

    Wang, Chau-Zen; Fu, Yin-Chih; Jian, Shih-Ciang; Wang, Yan-Hsiung; Liu, Po-Len; Ho, Mei-Ling; Wang, Chih-Kuang

    2014-10-15

    Simvastatin (SIM) can increase osteoblast activity and enhance osteogenesis. However, some limitations of SIM have been noted, such as statin-associated rhabdomyolysis and its poor solubility in water. In this study, we fabricated new cationic nanoparticles (NPs) designed for the controlled release of hydrophobic SIM and endocytosis by cells with the aim of reducing the total required amount of SIM administered and enhancing the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). New copolymers of bis(poly(lactic-co-glycolic acid)-phenylalanine-polyethylene glycol)-quaternary ammonium grafted diethyltriamine (bis(PLGA-phe-PEG)-qDETA; BPPD) were created using a diethyltriamine-quaternary ammonium (qDETA) moiety, hetero-bifunctional polyethylene glycol (COOH-PEG-NH2), phenylalanine (phe) and poly(lactic-co-glycolic acid) (PLGA). SIM encapsulated in BPPD NPs (SIM/BPPD) was fabricated using a water-miscible solvent. The size distributions of BPPD NPs and SIM/BPPD NPs, the encapsulation efficacy and the in vitro release profile of SIM in SIM/BPPD NPs over 6days were investigated. Based on the results of Alizarin Red S staining, alkaline phosphatase (ALP) activity assays and quantitative polymerase chain reaction (Q-PCR) results, we propose that SIM/BPPD NPs may induce osteogenesis in BMSCs by enhancing the expression of an osteogenic gene, which subsequently elevates ALP activity and mineralization, resulting in enhanced BMSC osteogenesis. These results suggest that the SIM/BPPD NPs may be used as hydrophobic drug carriers to reduce the total required amount of SIM administered and to provide an effective SIM release mechanism for enhancing BMSC osteogenesis. Surprisingly, BPPD NPs were also shown to have the ability to promote osteogenesis in BMSCs by enhancing the expression of osteogenic genes, especially osteocalcin (OC), and subsequently elevating ALP activity and mineralization. PMID:25086394

  8. Effects of Thyroxine Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts

    PubMed Central

    Cray, James J.; Khaksarfard, Kameron; Weinberg, Seth M.; Elsalanty, Mohammed; Yu, Jack C.

    2013-01-01

    The incidence of craniosynostosis is one in every 1,800–2500 births. The gene-environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene-environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. PMID:23935926

  9. Osteogenesis induced by frizzled-related protein (FRZB) is linked to the netrin-like domain.

    PubMed

    Thysen, Sarah; Cailotto, Frederic; Lories, Rik

    2016-05-01

    Abnormal Wnt signaling is associated with bone mass disorders. Frizzled-related protein (FRZB, also known as secreted frizzled-related protein-3 (SFRP3)) is a Wnt modulator that contains an amino-terminal cysteine-rich domain (CRD) and a carboxy-terminal Netrin-like (NTN) motif. Frzb(-/-) mice show increased cortical thickness. However, the direct effect of FRZB on osteogenic differentiation and the involvement of the structural domains herein are not fully understood. In this study, we observed that stable overexpression of Frzb in MC3T3-E1 cells increased calcium deposition and osteoblast markers compared with control. Western blot analysis showed that the increased osteogenesis was associated with reduced canonical, but increased non-canonical Wnt signaling. On the contrary, loss of Frzb induced the opposite effects on osteogenesis and Wnt signaling. To translationally validate the positive effects of FRZB on primary human cells, we treated human periosteal and human bone marrow stromal cells with conditioned medium from MC3T3-E1 cells overexpressing Frzb and observed an increase in Alizarin red staining. We further studied the effect of the domains. FrzbNTN overexpression induced similar effects on osteogenesis as full-length Frzb, whereas FrzbCRD overexpressing cells mimicked loss of Frzb experiments. The CRD is considered as the Wnt binding domain, but the NTN domain also has important effects on bone biology. FRZB and other SFRPs or their specific domains may hold surprising potential as therapeutics for bone and joint disorders considering that excess of SFRPs has effects that are not expected under physiological, endogenous expression conditions. PMID:26927515

  10. A new approach to repairing cleft palate and acquired palatal defects with distraction osteogenesis.

    PubMed

    Wang, D-Z; Chen, G; Liao, Y-M; Liu, S-G; Gao, Z-W; Hu, J; Li, J-H; Liao, C-H

    2006-08-01

    Cleft palate (CP) is one of the most common human congenital deformities, and acquired palate defects after trauma or tumour resection are also common. In this study, distraction osteogenesis (DO) for CP and other palatal bone defects was evaluated. Twenty cats were assigned randomly to 3 groups of (1) 15, (2) 3 and (3) 2 cats. In groups 1 and 2, a rectangular ostectomy, in the posterior of the palatal bone shelf, was performed in the sagittal axis to establish the CP defect model. At the same time, a pure titanium intraoral distractor was fixed to molar teeth with brackets and to the palatal bone shelf across the defect with titanium miniscrews bilaterally. Four weeks later, a secondary transport disc (TD) osteotomy was performed, and gradual DO treatment started at 0.4mm twice a day, after 6 days of latency. DO was performed until the TD reached the opposite margin over the gap in 5-6 days. Three cats each of group 1 were killed at 2, 4, 6, 8 and 12 weeks after completion of DO. In group 2, the bone and soft-tissue defects were untreated until death 6 weeks later. Group 3 cats (control) were killed after 6 weeks. The TD successfully recombined with the opposite palatal bone stump, and proportional expansion of the overlay mucoperiosteal flap was achieved. Intramembranous bone formation was revealed: parallel collagen bundles gradually deposited on new bone trabeculae while the proliferative osteoblasts produced bone matrix. The bone defect was finally reconstructed by de novo osteogenesis. The control group was observed to have no spontaneous repairing. These results suggest that the CP defect was reconstructed by osteogenesis in situ, and the soft tissues expanded simultaneously to achieve functional correction. The intraoral distractor provided both effective distraction and stability. PMID:16690250

  11. Combined micro computed tomography and histology study of bone augmentation and distraction osteogenesis

    NASA Astrophysics Data System (ADS)

    Ilgenstein, Bernd; Deyhle, Hans; Jaquiery, Claude; Kunz, Christoph; Stalder, Anja; Stübinger, Stefan; Jundt, Gernot; Beckmann, Felix; Müller, Bert; Hieber, Simone E.

    2012-10-01

    Bone augmentation is a vital part of surgical interventions of the oral and maxillofacial area including dental implantology. Prior to implant placement, sufficient bone volume is needed to reduce the risk of peri-implantitis. While augmentation using harvested autologous bone is still considered as gold standard, many surgeons prefer bone substitutes to reduce operation time and to avoid donor site morbidity. To assess the osteogenic efficacy of commercially available augmentation materials we analyzed drill cores extracted before implant insertion. In younger patients, distraction osteogenesis is successfully applied to correct craniofacial deformities through targeted bone formation. To study the influence of mesenchymal stem cells on bone regeneration during distraction osteogenesis, human mesenchymal stem cells were injected into the distraction gap of nude rat mandibles immediately after osteotomy. The distraction was performed over eleven days to reach a distraction gap of 6 mm. Both the rat mandibles and the drill cores were scanned using synchrotron radiation-based micro computed tomography. The three-dimensional data were manually registered and compared with corresponding two-dimensional histological sections to assess bone regeneration and its morphology. The analysis of the rat mandibles indicates that bone formation is enhanced by mesenchymal stem cells injected before distraction. The bone substitutes yielded a wide range of bone volume and degree of resorption. The volume fraction of the newly formed bone was determined to 34.4% in the computed tomography dataset for the augmentation material Geistlich Bio-Oss®. The combination of computed tomography and histology allowed a complementary assessment for both bone augmentation and distraction osteogenesis.

  12. Combinatorial incorporation of fluoride and cobalt ions into calcium phosphates to stimulate osteogenesis and angiogenesis.

    PubMed

    Birgani, Zeinab Tahmasebi; Gharraee, Nazli; Malhotra, Angad; van Blitterswijk, Clemens A; Habibovic, Pamela

    2016-02-01

    Bone healing requires two critical mechanisms, angiogenesis and osteogenesis. In order to improve bone graft substitutes, both mechanisms should be addressed simultaneously. While the individual effects of various bioinorganics have been studied, an understanding of the combinatorial effects is lacking. Cobalt and fluoride ions, in appropriate concentrations, are known to individually favor the vascularization and mineralization processes, respectively. This study investigated the potential of using a combination of fluoride and cobalt ions to simultaneously promote osteogenesis and angiogenesis in human mesenchymal stromal cells (hMSCs). Using a two-step biomimetic method, wells of tissue culture plates were coated with a calcium phosphate (CaP) layer without or with the incorporation of cobalt, fluoride, or both. In parallel, hMSCs were cultured on uncoated well plates, and cultured with cobalt and/or fluoride ions within the media. The results revealed that cobalt ions increased the expression of angiogenic markers, with the effects being stronger when the ions were added as a dissolved salt in cell medium as compared to incorporation into CaP. Cobalt ions generally suppressed the ALP activity, the expression of osteogenic genes, and the level of mineralization, regardless of delivery method. Fluoride ions, individually or in combination with cobalt, significantly increased the expression of many of the selected osteogenic markers, as well as mineral deposition. This study demonstrates an approach to simultaneously target the two essential mechanisms in bone healing: angiogenesis and osteogenesis. The incorporation of cobalt and fluoride into CaPs is a promising method to improve the biological performance of fully synthetic bone graft substitutes. PMID:26929187

  13. Tributyltin engages multiple nuclear receptor pathways and suppresses osteogenesis in bone marrow multipotent stromal cells.

    PubMed

    Baker, Amelia H; Watt, James; Huang, Cassie K; Gerstenfeld, Louis C; Schlezinger, Jennifer J

    2015-06-15

    Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor γ (PPARγ), the essential regulator of adipogenesis. Exposure to thiazolidinediones (PPARγ ligands used to treat type 2 diabetes) is associated with increased fractures. Diminished bone quality likely results from PPARγ's role in promoting adipogenesis while suppressing osteogenesis of bone marrow multipotent mesenchymal stromal cells (BM-MSC). We hypothesized that tributyltin (TBT) would be a potent modifier of BM-MSC differentiation and a negative regulator of bone formation. Organotins interact with both PPARγ and retinoid X receptors (RXR), suggesting that they activate multiple nuclear receptor pathways. To investigate the role of RXR in the actions of TBT, the effects of PPARγ (rosiglitazone) and RXR (bexarotene, LG100268) agonists were compared to the effects of TBT in BMS2 cells and primary mouse BM-MSC cultures. In BMS2 cells, TBT induced the expression of Fabp4, Abca1, and Tgm2 in an RXR-dependent manner. All agonists suppressed osteogenesis in primary mouse BM-MSC cultures, based on decreased alkaline phosphatase activity, mineralization, and expression of osteoblast-related genes. While rosiglitazone and TBT strongly activated adipogenesis, based on lipid accumulation and expression of adipocyte-related genes, the RXR agonists did not. Extending these analyses to other RXR heterodimers showed that TBT and the RXR agonists activated the liver X receptor pathway, whereas rosiglitazone did not. Application of either a PPARγ antagonist (T0070907) or an RXR antagonist (HX531) significantly reduced rosiglitazone-induced suppression of bone nodule formation. Only the RXR antagonist significantly reduced LG100268- and TBT-induced bone suppression. The RXR antagonist also inhibited LG100268- and TBT-induced expression of Abca1, an LXR target gene, in primary BM-MSC cultures. These results provide novel evidence that

  14. Corticotomy and compression osteogenesis in the posterior maxilla for treating severe anterior open bite.

    PubMed

    Kanno, T; Mitsugi, M; Furuki, Y; Kozato, S; Ayasaka, N; Mori, H

    2007-04-01

    A new technique is described for outpatient treatment of anterior open bite. The compression osteogenesis method with a two-stage corticotomy was used in the posterior maxilla to treat a woman with severe anterior open bite. Three-week post-surgical compression using anchor plates and elastics repositioned the posterior maxillary bone/teeth segments by 7 mm to the ideal superior position. The patient had a stable skeletal position of the maxilla at 14-month follow-up with satisfactory results and no complications after orthodontic treatment. This technique appears to be an efficient option for treating patients with anterior open bite. PMID:17110086

  15. Mouse Models in Orthopaedic Research: An Overview of Fracture, Marrow Ablation, and Distraction Osteogenesis

    PubMed Central

    Lybrand, Kyle; Bragdon, Beth; Gerstenfeld, Louis

    2015-01-01

    Three commonly used murine surgical models of bone healing (closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming) are presented. Detailed surgical protocols for each model are outlined. The nature of the regenerative processes and the types of research questions that may be addressed with these models are briefly outlined. The relative strengths and weaknesses of these models are compared to a number of other surgical models that are used to address similar research questions. Refer to our companion article for more detailed overview of the underlying biology of each model. PMID:25727199

  16. Myocardial protection with mild hypothermia.

    PubMed

    Tissier, Renaud; Ghaleh, Bijan; Cohen, Michael V; Downey, James M; Berdeaux, Alain

    2012-05-01

    Mild hypothermia, 32-35° C, is very potent at reducing myocardial infarct size in rabbits, dogs, sheep, pigs, and rats. The benefit is directly related to reduction in normothermic ischaemic time, supporting the relevance of early and rapid cooling. The cardioprotective effect of mild hypothermia is not limited to its recognized reduction of infarct size, but also results in conservation of post-ischaemic contractile function, prevention of no-reflow or microvascular obstruction, and ultimately attenuation of left ventricular remodelling. The mechanism of the anti-infarct effect does not appear to be related to diminished energy utilization and metabolic preservation, but rather to survival signalling that involves either the extracellular signal-regulated kinases and/or the Akt/phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Initial clinical trials of hypothermia in patients with ST-segment elevation myocardial infarction were disappointing, probably because cooling was too slow to shorten normothermic ischaemic time appreciably. New approaches to more rapid cooling have recently been described and may soon be available for clinical use. Alternatively, it may be possible to pharmacologically mimic the protection provided by cooling soon after the onset of ischaemia with an activator of mild hypothermia signalling, e.g. extracellular signal-regulated kinase activator, that could be given by emergency medical personnel. Finally, the protection afforded by cooling can be added to that of pre- and post-conditioning because their mechanisms differ. Thus, myocardial salvage might be greatly increased by rapidly cooling patients as soon as possible and then giving a pharmacological post-conditioning agent immediately prior to reperfusion. PMID:22131353

  17. LNGFR induction during osteogenesis of human jaw periosteum-derived cells.

    PubMed

    Alexander, Dorothea; Schäfer, Fabian; Munz, Adelheid; Friedrich, Björn; Klein, Christian; Hoffmann, Jürgen; Bühring, Hans-Jörg; Reinert, Siegmar

    2009-01-01

    Isolated jaw periosteum-derived cells (JPCs) comprise a morphologically heterogeneous population. There are no known specific surface markers that are able to distinguish between progenitors and cells of other tissue types. The aim of our study was to identify differentiation markers as predictors of JPC mineralization capacity. JPCs underwent osteogenic differentiation after cultivation in osteogenic medium containing known activators. By FACS analysis, we found the low affinity nerve growth factor receptor (LNGFR-CD271) to be induced during the first five days of osteogenesis and that it was expressed at higher levels in mineralizing JPCs (mJPCs) in comparison to non-mineralizing JPCs (nmJPCs). Similar results were obtained by semi-quantitative immunohistochemical stainings and western blot analyses. Quantitative real-time PCR results showed significantly higher LNGFR and alkaline phosphatase transcript levels in mJPCs compared to nmJPCs. LNGFR is a differentiation marker that distinguishes between mineralizing JPCs and non-mineralizing JPCs during the first phase of osteogenesis and can therefore be considered an early surface marker of osteogenic capacity in vitro. PMID:19710543

  18. Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish

    PubMed Central

    Asharani, P.V.; Keupp, Katharina; Semler, Oliver; Wang, Wenshen; Li, Yun; Thiele, Holger; Yigit, Gökhan; Pohl, Esther; Becker, Jutta; Frommolt, Peter; Sonntag, Carmen; Altmüller, Janine; Zimmermann, Katharina; Greenspan, Daniel S.; Akarsu, Nurten A.; Netzer, Christian; Schönau, Eckhard; Wirth, Radu; Hammerschmidt, Matthias; Nürnberg, Peter; Wollnik, Bernd; Carney, Thomas J.

    2012-01-01

    Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability. PMID:22482805

  19. Modulation of Osteogenesis in MC3T3-E1 Cells by Different Frequency Electrical Stimulation

    PubMed Central

    Wang, Yu; Cui, Haitao; Wu, Zhenxu; Wu, Naipeng; Wang, Zongliang; Chen, Xuesi; Wei, Yen; Zhang, Peibiao

    2016-01-01

    Electrical stimulation (ES) is therapeutic to many bone diseases, from promoting fracture regeneration to orthopedic intervention. The application of ES offers substantial therapeutic potential, while optimal ES parameters and the underlying mechanisms responsible for the positive clinical impact are poorly understood. In this study, we assembled an ES cell culture and monitoring device. Mc-3T3-E1 cells were subjected to different frequency to investigate the effect of osteogenesis. Cell proliferation, DNA synthesis, the mRNA levels of osteosis-related genes, the activity of alkaline phosphatase (ALP), and intracellular concentration of Ca2+ were thoroughly evaluated. We found that 100 Hz could up-regulate the mRNA levels of collagen I, collagen II and Runx2. On the contrary, ES could down-regulate the mRNA levels of osteopontin (OPN). ALP activity assay and Fast Blue RR salt stain showed that 100 Hz could accelerate cells differentiation. Compared to the control group, 100 Hz could promote cell proliferation. Furthermore, 1 Hz to 10 Hz could improve calcium deposition in the intracellular matrix. Overall, these results indicate that 100Hz ES exhibits superior potentialities in osteogenesis, which should be beneficial for the clinical applications of ES for the treatment of bone diseases. PMID:27149625

  20. Bimaxillary distraction osteogenesis used for treatment of crowding in non-growing individuals. Case report.

    PubMed

    Corega, C; Vaida, L; Festila, D G; Rigoni, G; Albanese, M; D'Agostino, A; Chiarini, G; Nocini, P F; Bertossi, D

    2014-01-14

    Dental crowding is frequently associated with transverse jaw discrepancies, resulting in a less-than-ideal position of the teeth in the basal bone. The classic aproach for correcting bimaxillary crowding are extractions or arch expansion. Rapid maxilla-mandibular expansion was used to treat transverse discrepancies in growing patients, but with aging, the upper and lower jaw bones become increasingly resistant to expansion. The surgically assisted rapid maxillary expansion (SARME) and the mandibular midsymphyseal distraction osteogenesis procedure overcome this age limitation and are of great importance for the treatment of transverse discrepancies in adults. The aim of this paper is to report a case with a severe transverse deficiency treated with SARME, mandibular midsymphyseal distraction together with orthodontic treatment in an adult patient. The case highlights the esthetic advantages of increasing the transversal dimension of both jaws in patients with severe crowding associated with constricted dental arches and recommends the maxillo-mandibular transverse distraction osteogenesis as an and effective form of surgical treatment for patients with malocclusions or dentofacial deformities featuring severe transverse discrepancies, combined with a carefully monitored orthodontic treatment. PMID:24423741

  1. Perpendicular serial maxillary distraction osteogenesis in cleft lip and palate patients

    PubMed Central

    Ylikontiola, Leena P.; Sándor, George K.; Harila, Virpi

    2015-01-01

    Background: Cleft lip and palate patients often have a retruded maxilla with a severely narrowed deficient maxillary arch. This report aims to describe the management of severe maxillary retrusion and constriction in cleft lip and palate patients using distraction osteogenesis applied in serial sequence in two directions perpendicular to each other. Materials and Methods: Two adult male cleft lip and palate patients were treated with maxillary distraction osteogenesis in two stages. In the first stage, surgically assisted rapid palatal expansion with a tooth-borne device was performed to significantly expand the maxillary arch in the transverse dimension. After the teeth were orthodontically aligned, the horizontal distraction of the maxilla was made by two internal maxillary distraction devices. Results: In the first patient, the maxilla was initially widened by 11 mm and then distracted forward by 20 mm. Despite the breakage of the shaft of one of the two distractors at the end of distraction, a satisfactory occlusion was found at the time of distractor device removal. The maxillary position has remained stable through 8 years of follow-up. In the second patient, the palate was widened by 14 mm and the maxilla was distracted forward by 22 mm. The maxillary position has remained stable through 3 years of follow-up. Conclusion: Sequential serial distraction of maxilla in two planes perpendicular to each other is a safe and stable approach for the treatment of cleft lip and palate patients with severe transverse and anteroposterior discrepancies. PMID:26981462

  2. The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis

    PubMed Central

    Yang, Shuying; Wang, Changdong

    2012-01-01

    Intraflagellar transport (IFT) proteins are essential for the assembly and maintenance of cilia, which play important roles in development and homeostasis. IFT80 is a newly defined IFT protein. Partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III with abnormal skeletal development. However, the role and mechanism of IFT80 in osteogenesis is unknown. Here, we first detected IFT80 expression pattern and found that IFT80 was highly expressed in mouse long bone, skull, and during osteoblast differentiation. By using lentivirus-mediated RNA interference (RNAi) technology to silence IFT80 in murine mesenchymal progenitor cell line-C3H10T1/2 and bone marrow derived stromal cells, we found that silencing IFT80 led to either shortening or loss of cilia and the decrease of Arl13b expression - a small GTPase that is localized in cilia. Additionally, silencing IFT80 blocked the expression of osteoblast markers and significantly inhibited ALP activity and cell mineralization. We further found that IFT80 silencing inhibited the expression of Gli2, a critical transcriptional factor in the hedgehog signaling pathway. Overexpression of Gli2 rescued the deficiency of osteoblast differentiation from IFT80-silenced cells, and dramatically promoted osteoblast differentiation. Moreover, introduction of Smo agonist (SAG) promotes osteoblast differentiation, which was partially inhibited by IFT80 silencing. Thus, these results suggested that IFT80 plays an important role in osteogenesis through regulating Hedgehog/Gli signal pathways. PMID:22771375

  3. Temporo-spatial analysis of Osterix, HNK1 and Sox10 during odontogenesis and maxillaries osteogenesis.

    PubMed

    Tomazelli, Karin Berria; Modolo, Filipe; Trentin, Andrea Gonçalves; Garcez, Ricardo Castilho; Biz, Michelle Tillmann

    2015-10-01

    Cell differentiation is essential for maxillaries and tooth development. Facial mesenchymal tissue is formed by neural crest cells (NC). These cells are highly migratory, giving rise to various cell types, considered with a high level of plasticity, indicating that they contain progenitor cells with a great power of differentiation. In this study, it was analyzed the presence of NC cell progenitors and mesenchymal stem cells (MSC) during maxillaries osteogenesis and odontogenesis in rats. Histological slides were collected in two phases: embryonic age of 15 and 17 days; 2, 4 and 7 days after birth. Immunohistochemistry for MSC markers (Osterix) and NC cells (Sox10, HNK1) was performed. The results showed positive expression for Osterix and HNK1 in undifferentiated ectomesenchymal cells in early and late stages; Sox10 was present only in early stages in undifferentiated cells. All markers were present in differentiated cells. Although the experiments performed do not allow us to explain a possible role for Osx, HNK1 and Sox10 in both differentiated and undifferentiated cells during osteogenesis and odontogenesis, it had shown important results not yet described: the presence of HNK1 and Sox10 in osteoblasts and odontoblasts in late development stages and in the tooth germ epithelial cells and ameloblasts. PMID:26253417

  4. Three-dimensional computed tomographic evaluation of Le Fort III distraction osteogenesis with an external device in syndromic craniosynostosis.

    PubMed

    Wery, M F; Nada, R M; van der Meulen, J J; Wolvius, E B; Ongkosuwito, E M

    2015-03-01

    There is little anteroposterior growth of the midface in patients with syndromic craniosynostosis who are followed up over time without intervention. A Le Fort III with distraction osteogenesis can be done to correct this. This is a controlled way in which to achieve appreciable stable advancement of the midface without the need for bone grafting, but the vector of the movement is not always predictable. The purpose of this study was to evaluate the 3-dimensional effect of Le Fort III distraction osteogenesis with an external frame. Ten patients (aged 7-19 years) who had the procedure were included in the study. The le Fort III procedure and the placement of the external frame were followed by an activation period and then a 3-month retention period. Computed tomographic (CT) images taken before and after operation were converted and loaded into 3-dimensional image rendering software and compared with the aid of a paired sample t test and a colour-coded qualitative analysis. Comparison of the CT data before and after distraction indicated that the amount of midface advancement was significant. Le Fort III distraction osteogenesis is an effective way to advance the midface. However, the movement during osteogenesis is not always exactly in the intended direction, and a secondary operation is often necessary. Three-dimensional evaluation over a longer period of time is necessary. PMID:25605236

  5. Upregulation of BMSCs Osteogenesis by Positively-Charged Tertiary Amines on Polymeric Implants via Charge/iNOS Signaling Pathway

    NASA Astrophysics Data System (ADS)

    Zhang, Wei; Liu, Na; Shi, Haigang; Liu, Jun; Shi, Lianxin; Zhang, Bo; Wang, Huaiyu; Ji, Junhui; Chu, Paul K.

    2015-03-01

    Positively-charged surfaces on implants have a similar potential to upregulate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) as electromagnetic therapy approved for bone regeneration. Generally, their osteogenesis functions are generally considered to stem from the charge-induced adhesion of extracellular matrix (ECM) proteins without exploring the underlying surface charge/cell signaling molecule pathways. Herein, a positively-charged surface with controllable tertiary amines is produced on a polymer implant by plasma surface modification. In addition to inhibiting the TNF-α expression, the positively-charged surface with tertiary amines exhibits excellent cytocompatibility as well as remarkably upregulated osteogenesis-related gene/protein expressions and calcification of the contacted BMSCs. Stimulated by the charged surface, these BMSCs display high iNOS expressions among the three NOS isoforms. Meanwhile, downregulation of the iNOS by L-Can or siRNA inhibit osteogenic differentiation in the BMSCs. These findings suggest that a positively-charged surface with tertiary amines induces osteogenesis of BMSCs via the surface charge/iNOS signaling pathway in addition to elevated ECM protein adhesion. Therefore, creating a positively-charged surface with tertiary amines is a promising approach to promote osseointegration with bone tissues.

  6. Distraction osteogenesis of the sternum for thoracic expansion in a severe case of jeune syndrome: a preliminary report.

    PubMed

    Imai, Yoshimichi; Kitanishi, Ryuta; Saiki, Yoshikatsu; Takeda, Atsushi; Tachi, Masahiro

    2016-06-01

    Severe asphyxiating thoracic dystrophy (Jeune syndrome) is usually fatal. The authors used distraction osteogenesis in a severe case and achieved 45 mm distraction of the sternum and improvement in tidal volume, lung compliance, and mean airway pressure. PMID:27009488

  7. Upregulation of BMSCs Osteogenesis by Positively-Charged Tertiary Amines on Polymeric Implants via Charge/iNOS Signaling Pathway

    PubMed Central

    Zhang, Wei; Liu, Na; Shi, Haigang; Liu, Jun; Shi, Lianxin; Zhang, Bo; Wang, Huaiyu; Ji, Junhui; Chu, Paul K.

    2015-01-01

    Positively-charged surfaces on implants have a similar potential to upregulate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) as electromagnetic therapy approved for bone regeneration. Generally, their osteogenesis functions are generally considered to stem from the charge-induced adhesion of extracellular matrix (ECM) proteins without exploring the underlying surface charge/cell signaling molecule pathways. Herein, a positively-charged surface with controllable tertiary amines is produced on a polymer implant by plasma surface modification. In addition to inhibiting the TNF-α expression, the positively-charged surface with tertiary amines exhibits excellent cytocompatibility as well as remarkably upregulated osteogenesis-related gene/protein expressions and calcification of the contacted BMSCs. Stimulated by the charged surface, these BMSCs display high iNOS expressions among the three NOS isoforms. Meanwhile, downregulation of the iNOS by L-Can or siRNA inhibit osteogenic differentiation in the BMSCs. These findings suggest that a positively-charged surface with tertiary amines induces osteogenesis of BMSCs via the surface charge/iNOS signaling pathway in addition to elevated ECM protein adhesion. Therefore, creating a positively-charged surface with tertiary amines is a promising approach to promote osseointegration with bone tissues. PMID:25791957

  8. Full-mouth adhesive rehabilitation in a case of amelogenesis imperfecta: a 5-year follow-up case report.

    PubMed

    Gerdolle, David; Mortier, Eric; Richard, Adeline; Vailati, Francesca

    2015-01-01

    Amelogenesis imperfecta (AI) is a hereditary disorder caused by mutations of genes primarily involved in the enamel formation. Several different types of AI have been identified, based on the phenotype and on the mode of inheritance. Regardless of the type, the dental treatment tends to be the same, favoring the complete removal of the compromised enamel late in the patient's life. With the new dentistry guidelines that orient clinicians towards minimal invasiveness, it should be mandatory to intercept patients affected by AI earlier, not only to protect the dentition from further degradation but also to help patients improve their self-esteem. This article examines the restorative dentistry performed on a 24-year-old Caucasian female suffering from the hypoplastic type of AI, using only adhesive procedures. Due to the complex needs of the patient, an interdisciplinary approach was followed, involving orthodontics, periodontics, and restorative dentistry. A full-mouth adhesive rehabilitation was achieved by means of direct composite restorations, veneer/onlays and facial/palatal veneers. No elective endodontic therapy was necessary for restorative purposes. The esthetics, mechanics, and biological success were achieved and maintained. The bond to the enamel did not show signs of degradation (eg, discoloration or infiltration) even after 5 years of function. This is encouraging as it shows that adhesive techniques may be a reliable approach even in the presence of a compromised enamel layer. PMID:25625125

  9. Noninvasive and Multidisciplinary Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta: A Pediatric Case Report

    PubMed Central

    de Souza, Juliana Feltrin; Fragelli, Camila Maria Bullio; Paschoal, Marco Aurélio Benini; Campos, Edson Alves; Cunha, Leonardo Fernandes; Losso, Estela Maris; Cordeiro, Rita de Cássia Loiola

    2014-01-01

    Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth. Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed . Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed. PMID:25061528

  10. Noninvasive and multidisciplinary approach to the functional and esthetic rehabilitation of amelogenesis imperfecta: a pediatric case report.

    PubMed

    de Souza, Juliana Feltrin; Fragelli, Camila Maria Bullio; Paschoal, Marco Aurélio Benini; Campos, Edson Alves; Cunha, Leonardo Fernandes; Losso, Estela Maris; Cordeiro, Rita de Cássia Loiola

    2014-01-01

    Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth. Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed . Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed. PMID:25061528

  11. Amelogenesis Imperfecta and Early Restorative Crown Therapy: An Interview Study with Adolescents and Young Adults on Their Experiences.

    PubMed

    Pousette Lundgren, Gunilla; Wickström, Anette; Hasselblad, Tove; Dahllöf, Göran

    2016-01-01

    Patients with Amelogenesis imperfecta (AI) can present with rapid tooth loss or fractures of enamel as well as alterations in enamel thickness, color, and shape; factors that may compromise aesthetic appearance and masticatory function. The aim was to explore the experiences and perceptions of adolescents and young adults living with AI and receiving early prosthetic therapy. Seven patients with severe AI aged 16 to 23 years who underwent porcelain crown therapy participated in one-to-one individual interviews. The interviews followed a topic guide consisting of open-ended questions related to experiences of having AI. Transcripts from the interviews were analyzed using thematic analysis. The analysis process identified three main themes: Disturbances in daily life, Managing disturbances, and Normalization of daily life. These themes explain the experiences of patients living with enamel disturbances caused by AI and receiving early crown therapy. Experiences include severe pain and sensitivity problems, feelings of embarrassment, and dealing with dental staff that lack knowledge and understanding of their condition. The patients described ways to manage their disturbances and to reduce pain when eating or drinking, and strategies for meeting other people. After definitive treatment with porcelain crown therapy, they described feeling like a normal patient. In conclusion the results showed that adolescents and young adults describe a profound effect of AI on several aspects of their daily life. PMID:27359125

  12. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

    PubMed Central

    Parry, David A.; Mighell, Alan J.; El-Sayed, Walid; Shore, Roger C.; Jalili, Ismail K.; Dollfus, Hélène; Bloch-Zupan, Agnes; Carlos, Roman; Carr, Ian M.; Downey, Louise M.; Blain, Katharine M.; Mansfield, David C.; Shahrabi, Mehdi; Heidari, Mansour; Aref, Parissa; Abbasi, Mohsen; Michaelides, Michel; Moore, Anthony T.; Kirkham, Jennifer; Inglehearn, Chris F.

    2009-01-01

    The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization. PMID:19200525

  13. Amelogenesis Imperfecta and Early Restorative Crown Therapy: An Interview Study with Adolescents and Young Adults on Their Experiences

    PubMed Central

    Wickström, Anette; Hasselblad, Tove; Dahllöf, Göran

    2016-01-01

    Patients with Amelogenesis imperfecta (AI) can present with rapid tooth loss or fractures of enamel as well as alterations in enamel thickness, color, and shape; factors that may compromise aesthetic appearance and masticatory function. The aim was to explore the experiences and perceptions of adolescents and young adults living with AI and receiving early prosthetic therapy. Seven patients with severe AI aged 16 to 23 years who underwent porcelain crown therapy participated in one-to-one individual interviews. The interviews followed a topic guide consisting of open-ended questions related to experiences of having AI. Transcripts from the interviews were analyzed using thematic analysis. The analysis process identified three main themes: Disturbances in daily life, Managing disturbances, and Normalization of daily life. These themes explain the experiences of patients living with enamel disturbances caused by AI and receiving early crown therapy. Experiences include severe pain and sensitivity problems, feelings of embarrassment, and dealing with dental staff that lack knowledge and understanding of their condition. The patients described ways to manage their disturbances and to reduce pain when eating or drinking, and strategies for meeting other people. After definitive treatment with porcelain crown therapy, they described feeling like a normal patient. In conclusion the results showed that adolescents and young adults describe a profound effect of AI on several aspects of their daily life. PMID:27359125

  14. Cyclic stretch promotes osteogenesis-related gene expression in osteoblast-like cells through a cofilin-associated mechanism

    PubMed Central

    GAO, JIE; FU, SHANMIN; ZENG, ZHAOBIN; LI, FEIFEI; NIU, QIANNAN; JING, DA; FENG, XUE

    2016-01-01

    Osteoblasts have the capacity to perceive and transduce mechanical signals, and thus, regulate the mRNA and protein expression of a variety of genes associated with osteogenesis. Cytoskeletal reconstruction, as one of the earliest perception events for external mechanical stimulation, has previously been demonstrated to be essential for mechanotransduction in bone cells. However, the mechanism by which mechanical signals induce cytoskeletal deformation remains poorly understood. The actin-binding protein, cofilin, promotes the depolymerization of actin and is understood to be important in the regulation of activities in various cell types, including endothelial, neuronal and muscle cells. However, to the best of our knowledge, the importance of cofilin in osteoblastic mechanotransduction has not been previously investigated. In the present study, osteoblast-like MG-63 cells were subjected to physiological cyclic stretch stimulation (12% elongation) for 1, 4, 8, 12 and 24 h, and the expression levels of cofilin and osteogenesis-associated genes were quantified with reverse transcription-quantitative polymerase chain reaction, immunofluorescence staining and western blotting analyses. Additionally, knockdown of cofilin using RNA interference was conducted, and the mRNA levels of osteogenesis-associated genes were compared between osteoblast-like cells in the presence and absence of cofilin gene knockdown. The results of the present study demonstrated that cyclic stretch stimulates the expression of genes associated with osteoblastic activities in MG-63 cells, including alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (Runx2) and collagen-1 (COL-1). Cyclic stretch also regulates the mRNA and protein expression of cofilin in MG-63 cells. Furthermore, stretch-induced increases in the levels of osteogenesis-associated genes, including ALP, OCN, Runx2 and COL-1, were reduced following cofilin gene knockdown. Together, these results

  15. Mild traumatic brain injury in a gymnast.

    PubMed

    Knight, Debra; Dewitt, Rachel; Moser, Sharon

    2016-07-01

    Primary care providers often are responsible for the initial evaluation and management plan of young patients with mild traumatic brain injury (mild TBI, also called concussion), and need to be familiar with new protocols and how to incorporate them into a patient's treatment plan. This article describes a patient who suffered a mild TBI and returned to sports too early, and discusses the appropriate protocols for managing concussion in children. PMID:27351644

  16. Combined exposure to big endothelin-1 and mechanical loading in bovine sternal cores promotes osteogenesis.

    PubMed

    Meyer, Luisa A; Johnson, Michael G; Cullen, Diane M; Vivanco, Juan F; Blank, Robert D; Ploeg, Heidi-Lynn; Smith, Everett L

    2016-04-01

    Increased bone formation resulting from mechanical loading is well documented; however, the interactions of the mechanotransduction pathways are less well understood. Endothelin-1, a ubiquitous autocrine/paracrine signaling molecule promotes osteogenesis in metastatic disease. In the present study, it was hypothesized that exposure to big endothelin-1 (big ET1) and/or mechanical loading would promote osteogenesis in ex vivo trabecular bone cores. In a 2×2 factorial trial of daily mechanical loading (-2000με, 120cycles daily, "jump" waveform) and big ET1 (25ng/mL), 48 bovine sternal trabecular bone cores were maintained in bioreactor chambers for 23days. The bone cores' response to the treatment stimuli was assessed with percent change in core apparent elastic modulus (ΔEapp), static and dynamic histomorphometry, and prostaglandin E2 (PGE2) secretion. Two-way ANOVA with a post hoc Fisher's LSD test found no significant treatment effects on ΔEapp (p=0.25 and 0.51 for load and big ET1, respectively). The ΔEapp in the "no load + big ET1" (CE, 13±12.2%, p=0.56), "load + no big ET1" (LC, 17±3.9%, p=0.14) and "load + big ET1" (LE, 19±4.2%, p=0.13) treatment groups were not statistically different than the control group (CC, 3.3%±8.6%). Mineralizing surface (MS/BS), mineral apposition (MAR) and bone formation rates (BFR/BS) were significantly greater in LE than CC (p=0.037, 0.0040 and 0.019, respectively). While the histological bone formation markers in LC trended to be greater than CC (p=0.055, 0.11 and 0.074, respectively) there was no difference between CE and CC (p=0.61, 0.50 and 0.72, respectively). Cores in LE and LC had more than 50% greater MS/BS (p=0.037, p=0.055 respectively) and MAR (p=0.0040, p=0.11 respectively) than CC. The BFR/BS was more than two times greater in LE (p=0.019) and LC (p=0.074) than CC. The PGE2 levels were elevated at 8days post-osteotomy in all groups and the treatment groups remained elevated compared to the CC group on days 15

  17. Development of a device for the delivery of agents to bone during distraction osteogenesis.

    PubMed

    Grayson, B H; Rowe, N M; Hollier, L H; Williams, J K; McCormick, S; Longaker, M T; McCarthy, J G

    2001-01-01

    Various agents have been theoretically and experimentally implicated as mediators of distraction osteogenesis (DO). The purpose of this study was to develop a vehicle for the potential delivery of these factors to the region of the distraction site in an attempt to manipulate this biologic process. Three adult mongrel dogs (12 months old) had oblique osteotomies performed bilaterally through the gonial regions. In group I, the external distracter was affixed to the right hemimandible of two dogs (n = 2 hemimandibles) with cannulated pins (external diameter = 1.5 mm; lumen diameter = 1.0 mm; length = 60 mm), whereas the distracter on the left was affixed with standard, noncannulated pins of the same dimensions. In group II, cannulated pins were used to affix the external distracter to both hemimandibles (n = 2 hemimandibles) of a dog. The devices were activated after a 5-day latency period and were lengthened at a rate of 1 mm/day for 20 days. During the distraction period, 0.1 ml/d of sterile india ink was injected into the cannulated pins, after which the sterile stylet was replaced. The activation protocol was followed by 28 days of fixation (consolidation period). The hemimandibles from group I underwent removal of soft tissues, acetone fixation, and gross examination/photography, whereas the hemimandibles from group II were prepared for histologic evaluation (whole mount, hematoxylin and eosin staining). All dogs survived to the end of the study and demonstrated successful DO without evidence of complications. Hemimandibles in group I displayed evidence of india ink on both the lingual and buccal cortex around the cannulated pin site, in the regenerate and on the neocortices of the distracted segment. Hemimandibles of group II showed histologic evidence of the india ink being deposited densely around the cannulated pin site and extending in a radial fashion around the pin site into the regenerate. This study demonstrates for the first time a vehicle device for

  18. Evaluation of mild skin cleansers.

    PubMed

    Wortzman, M S

    1991-01-01

    Each person makes the decision of how best to care for his or her own skin. Among the prime concerns, especially for facial skin, is the type of dirt, debris, or make-up to be removed. In most cases, all products do an adequate job in the removal of dirt; if not, the washing techniques can be modified to accomplish the task at hand. What cannot be controlled are the adverse side effects inherent in the use of that product. These adverse properties include damages to the barrier function of the skin; increased susceptibility to environmental sources of irritation and sensitization; frank irritation responses, such as erythema and edema; and reduction of the cosmetic qualities of the skin, such as degree of moisture and smoothness. Part of the problem is that most of these changes are subtle, occurring slowly over time. Often, the association of these problems with the use of a particular facial cleansing regimen is overlooked. The typical woman uses as many as 10 to 15 facial cosmetic and cleansing products each day, making the identification of a problem even more difficult. It is important to identify the risks associated with individual products and with product categories in general. Although the identification of a safe group of products to use for facial cleansing is desirable, the results of this investigation indicate that there are no simple answers. It has been assumed that because moisturizing cream formulations are routinely safe and mild in general use, a cleansing product in the same general form would share these attributes. We can see from the results in Table 2 and Figures 2, 3, 5, 7, and 9 that cleansing creams are not uniformly superior to cleansing bars in the key attributes that are used to evaluate mildness. In each evaluation there were individual cleansing creams that demonstrated statistically weaker performance than did cleansing bars in general. As a group, cleansing creams did well in the cosmetic categories of dryness and texture but

  19. Ethanol extract of Fructus Ligustri Lucidi promotes osteogenesis of mesenchymal stem cells.

    PubMed

    Li, Guo; Zhang, Xiao-ai; Zhang, Jin-fang; Chan, Chu-yan; Yew, David Tai Wai; He, Ming-liang; Lin, Marie Chia-mi; Leung, Ping-chung; Kung, Hsiang-fu

    2010-04-01

    Fructus Ligustri Lucidi (FLL) has been used in traditional Chinese medicine for over 1000 years. The ethanol extract of FLL (EFLL) has been shown to be a potential candidate in the prevention and treatment of osteoporosis. The present study aimed to determine whether EFLL carries out the effect by promoting osteogenesis in mesenchymal stem cells (MSCs). The osteogenic differentiation of MSCs was evaluated by their alkaline phosphatase (ALP) activities and mineralization. Expression of genes was detected by RT-PCR. We found that EFLL significantly stimulated the ALP activities and shortened the time needed for the mineralization of MSCs during osteogenic differentiation. The expression of several osteoblast differentiation regulators was also upregulated by EFLL during this process. Our study demonstrated that the EFLL is capable of enhancing osteogenic differentiation of MSCs. It might be useful for treating diseases with inadequate bone formation, including osteoporosis. PMID:19813230

  20. Experiment K-310: The effect of spaceflight on osteogenesis and dentinogenesis in the mandibles of rats

    NASA Technical Reports Server (NTRS)

    Simmons, D. J.; Russell, J. E.; Winter, F.; Rosenberg, G. D.; Walker, W. V.

    1981-01-01

    Normal rates of dentinogenesis and osteogenesis in the body of the mandible were observed. The total calcium, inorganic phosphorus and hydroxyproline levels in the jaws and incisors of the flight rats were normal. Gravity density fractionation studies suggested, however, that spaceflight caused a delay in the normal maturation of bone mineral and matrix; normal values were reestablished by 6 days postflight. The teeth were spared. The circadian and ultradian patterns of dentin calcification were normal during spaceflight and recovery periods, but the enamel rhythms displayed a greater amplitude of sulfur concentrations and this abnormal calcium to sulfur ratios only during exposure to zero gravity. The rat mandible and teeth do not suffer the deficits of bone formation common to weight bearing parts of the skeleton during spaceflight. The only derangements detected were in the quality of the matrix and mineral moieties.

  1. Advances in the Treatment of Syndromic Midface Hypoplasia Using Monobloc and Facial Bipartition Distraction Osteogenesis

    PubMed Central

    Kumar, Anand R.; Steinbacher, Derek

    2014-01-01

    Midface hypoplasia or retrusion remains a persistent feature of syndromic craniosynostosis years after successful treatment of the cranium. Although expansion of the cranial vault in infancy by traditional fronto-orbital advancement, posterior expansion, or both, can treat the immediate intracranial constriction, midface hypoplasia and its stigmata of exorbitism, sleep apnea, central face concavity, and malocclusion remain suboptimally treated. Initial enthusiasm for the procedures was tempered due to a high rate of infectious complications; timing and indications for surgery continue to stir controversy. During the last decade renewed interest with the monobloc and facial bipartition procedure using distraction osteogenesis with either an internal or external distraction system has decreased morbidity significantly. These procedures have re-emerged as powerful and comprehensive tools in the treatment of syndromic midface hypoplasia. PMID:26417208

  2. Nonvascularized Free Transport Distraction Osteogenesis to Reconstruct the Mandibular Defect of a Patient With an Ossifying Fibroma: A Case Report.

    PubMed

    Wang, Yan; Huang, Xuanping; Liang, Feixin; Zhou, Nuo

    2016-09-01

    We report on a case in which trifocal distraction osteogenesis was applied in a patient with a mandibular defect caused by resection of an ossifying fibroma. During the surgical procedure, we accidentally dissected the surrounding periosteal tissue of the left transport completely in the process of transport disc preparation and made the disc into a free bone graft. However, we still used this transport and successfully completed the distraction osteogenesis. The patient's facial and occlusal function were regained after treatment. PMID:27292526

  3. Scaffold pore size modulates in vitro osteogenesis of human adipose-derived stem/stromal cells.

    PubMed

    Huri, Pinar Yilgor; Ozilgen, B Arda; Hutton, Daphne L; Grayson, Warren L

    2014-08-01

    Trabecular bone has an interconnected porous structure, which influences cellular responses, biochemical transport and mechanical strength. Appropriately mimicking this structural organization in biomaterial scaffolds can facilitate more robust bone tissue regeneration and integration by providing a native microenvironment to the cells. This study examined the effect of pore size on human adipose-derived stem/stromal cell (ASC) osteogenesis within poly(ε-caprolactone) (PCL) scaffolds. Scaffold pore size was controlled by porogen leaching of custom-made paraffin particles with three different size ranges: P200 (< 500 µm), P500 (500-1000 µm), and P1000 (1000-1500 µm). Scaffolds produced by leaching these particles exhibited highly interconnected pores and rough surface structures that were favorable for cell attachment and ingrowth. The osteogenic response of ASCs was evaluated following 3 weeks of in vitro culture using biochemical (ALP, Ca(2+)/DNA content), mechanical (compression test) and histological (H&E and von Kossa staining) analyses. It was observed that while the total number of cells was similar for all scaffolds, the cell distributions and osteogenic properties were affected by the scaffold pore size. ASCs were able to bridge smaller pores and grow uniformly within these scaffolds (P200) while they grew as a layer along the periphery of the largest pores (P1000). The cell-biomaterial interactions specific to the latter case led to enhanced osteogenic responses. The ALP activity and Ca(2+) deposition were doubled in P1000 scaffolds as compared to P200 scaffolds. A significant difference was observed between the compressive strength of unseeded and seeded P1000 scaffolds. Therefore, we demonstrated that the use of scaffolds with pores that are in the range of 1 mm enhances in vitro ASC osteogenesis, which may improve their performance in engineered bone substitutes. PMID:24945873

  4. Collagens VI and XII form complexes mediating osteoblast interactions during osteogenesis.

    PubMed

    Izu, Yayoi; Ezura, Yoichi; Koch, Manuel; Birk, David E; Noda, Masaki

    2016-06-01

    Bone formation is precisely regulated by cell-cell communication in osteoblasts. We have previously demonstrated that genetic deletion of Col6a1 or Col12a1 impairs osteoblast connections and/or communication in mice, resulting in bone mass reduction and bone fragility. Mutations of the genes encoding collagen VI cause Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM), which have overlapping phenotypes involving connective tissue and muscle. Recent studies have identified COL12A1 gene mutations in patients with UCMD- and BM-like disorders harboring no COL6 mutations, indicating the shared functions of these collagens in connective tissue homeostasis. The purpose of this investigation has been to test the hypothesis that collagens VI and XII have coordinate regulatory role(s) during bone formation. We analyzed the localization of collagens VI and XII relative to primary osteoblasts during osteogenesis. Immunofluorescence analysis demonstrated that collagens VI and XII colocalized in matrix bridges between adjacent cells during periods when osteoblasts were establishing cell-cell connections. Quantification of cells harboring collagen bridges demonstrated that matrix bridges were composed of collagens VI and XII but not collagen I. Interestingly, matrix bridge formation was impaired in osteoblasts deficient in either Col6a1 or Col12a1, suggesting that both collagens were indispensable for matrix bridge formation. These data demonstrate, for the first time, a functional relationship between collagens VI and XII during osteogenesis and indicate that a complex containing collagens VI and XII is essential for the formation of a communicating cellular network during bone formation. PMID:26753503

  5. 3D-printed dimethyloxallyl glycine delivery scaffolds to improve angiogenesis and osteogenesis.

    PubMed

    Min, Zhu; Shichang, Zhao; Chen, Xin; Yufang, Zhu; Changqing, Zhang

    2015-08-01

    Angiogenesis-osteogenesis coupling processes are vital in bone tissue engineering. Normal biomaterials implanted in bone defects have issues in the sufficient formation of blood vessels, especially in the central part. Single delivery of vascular endothelial growth factors (VEGF) to foci in previous studies did not show satisfactory results due to low loading doses, a short protein half-life and low efficiency. Development of a hypoxia-mimicking microenvironment for cells by local prolyl-4-hydroxylase inhibitor release, which can stabilize hypoxia-inducible factor 1α (HIF-1α) expression, is an alternative method. The aim of this study was to design a dimethyloxallyl glycine (DMOG) delivering scaffold composed of mesoporous bioactive glasses and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) polymers (MPHS scaffolds), so as to investigate whether the sustained release of DMOG promotes local angiogenesis and bone healing. The morphology and microstructure of composite scaffolds were characterized. The DMOG release patterns from scaffolds loaded with different DMOG dosages were evaluated, and the effects of DMOG delivery on human bone marrow stromal cell (hBMSC) adhesion, viability, proliferation, osteogenic differentiation and angiogenic-relative gene expressions with scaffolds were also investigated. In vivo studies were carried out to observe vascular formations and new bone ingrowth with DMOG-loaded scaffolds. The results showed that DMOG could be released in a sustained manner over 4 weeks from MPHS scaffolds and obviously enhance the angiogenesis and osteogenesis in the defects. Microfil perfusion showed a significantly increased formation of vessels in the defects with DMOG delivery. Furthermore, micro-CT imaging and fluorescence labeling indicated larger areas of bone formation for DMOG-loaded scaffolds. It is concluded that MPHS-DMOG scaffolds are promising for enhancing bone healing of osseous defects. PMID:26222039

  6. Surgical Management of Pierre Robin Sequence: Using Mandibular Distraction Osteogenesis to Address Hypoventilation and Failure to Thrive in Infancy.

    PubMed

    Scott, Andrew R

    2016-04-01

    Mandibular hypoplasia may present in isolation or in the context of glossoptosis and a U-shaped, incomplete cleft palate. This latter triad is referred to as Pierre Robin sequence. Deleterious effects of micrognathia that may present during infancy are due primarily to glossoptosis or posterior displacement of the tongue. This tongue base prolapse may cause varying degrees of upper airway obstruction. A surgical option for management of tongue base airway obstruction secondary to mandibular hypoplasia is neonatal mandibular distraction osteogenesis. Herein, the author seeks to outline the benefits and limitations of early mandibular distraction osteogenesis as a way of managing airway obstruction and feeding difficulty in newborns with micrognathia. A description of the author's operative technique as well as potential complications and pitfalls will also be discussed. PMID:27097139

  7. miR-199b-5p modulates BMSC osteogenesis via suppressing GSK-3β/β-catenin signaling pathway.

    PubMed

    Zhao, Ruibo; Li, Yusheng; Lin, Zhangyuan; Wan, Jun; Xu, Can; Zeng, Yong; Zhu, Yong

    2016-09-01

    miR-199b-5p is up-regulated significantly during the osteogenesis process in human bone marrow stromal cells (BMSCs). Inhibiting miR-199b-5p notably reduces while over-expressing miR-199b-5p promotes the BMSCs osteoblast differentiation, suggested by the alternations of osteogenic genes expression, ALP activity and the ARS-stained mineral nodules. miR-199b-5p exerts its role in BMSC osteogenesis most probably through the GSK-3β/β-catenin signaling pathway. In conclusion, the present study revealed for the first time that miR-199b-5p plays a positive role in osteoblast differentiation. PMID:27363340

  8. [Mild brain injuries in emergency medicine].

    PubMed

    Liimatainen, Suvi; Niskakangas, Tero; Ohman, Juha

    2011-01-01

    Diagnostics and correct classification of mild brain injuries is challenging. Problems caused by insufficient documentation at the acute phase become more obvious in situations in which legal insurance issues are to be considered. A small proportion of patients with mild brain injury suffer from prolonged symptoms. Medical recording and classification of the brain injury at the initial phase should therefore be carried out in a structured manner. The review deals with the diagnostic problems of mild brain injuries and presents a treatment protocol for adult patients at the acute phase, aiming at avoiding prolonged problems. PMID:22238915

  9. Bilateral Mandibular Distraction Osteogenesis in the Neonate with Pierre Robin Sequence and Airway Obstruction: A Primary Option

    PubMed Central

    Zenha, Horácio; Azevedo, Luis; Rios, Leonor; Pereira, Alberto; Pinto, Armindo; Barroso, Maria Luz; Costa, Horácio

    2012-01-01

    Children with craniofacial abnormalities associated with retromicrognathia and glossoptosis often have compromised upper airway flow. In severe cases, emergency intubation is necessary immediately after birth, and tracheostomy is advocated to manage the airway in the neonatal period and to allow for feeding. Early intervention with bilateral mandibular osteogenesis avoids the need for tracheostomy, along with its complications, and it targets the primary etiologic factor of the problem—the anomalous anatomy of the mandible. We report two neonates with severe Pierre Robin sequence managed with bilateral mandibular distraction osteogenesis on day 9 and day 11 of life. The surgical techniques and distraction and consolidation periods were similar apart from the distraction devices used. The procedures were successful with early extubation (day 5 and day 7), oral feeding tolerance (day 11 and day 13) and hospital discharge (day 19 and day 18). Total mandibular distraction was 19 mm and 23.45 mm, respectively. No major complications were reported. Medium to long-term results were good. Bilateral mandibular distraction osteogenesis in the neonate is a safe and accurate procedure and is the primary option in cases of selected severe Pierre Robin sequence. PMID:23450076

  10. Bone morphogenetic protein-2-induced signaling and osteogenesis is regulated by cell shape, RhoA/ROCK, and cytoskeletal tension.

    PubMed

    Wang, Yang-Kao; Yu, Xiang; Cohen, Daniel M; Wozniak, Michele A; Yang, Michael T; Gao, Lin; Eyckmans, Jeroen; Chen, Christopher S

    2012-05-01

    Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is classically thought to be mediated by different cytokines such as the bone morphogenetic proteins (BMPs). Here, we report that cell adhesion to extracellular matrix (ECM), and its effects on cell shape and cytoskeletal mechanics, regulates BMP-induced signaling and osteogenic differentiation of hMSCs. Using micropatterned substrates to progressively restrict cell spreading and flattening against ECM, we demonstrated that BMP-induced osteogenesis is progressively antagonized with decreased cell spreading. BMP triggered rapid and sustained RhoA/Rho-associated protein kinase (ROCK) activity and contractile tension only in spread cells, and this signaling was required for BMP-induced osteogenesis. Exploring the molecular basis for this effect, we found that restricting cell spreading, reducing ROCK signaling, or inhibiting cytoskeletal tension prevented BMP-induced SMA/mothers against decapentaplegic (SMAD)1 c-terminal phosphorylation, SMAD1 dimerization with SMAD4, and SMAD1 translocation into the nucleus. Together, these findings demonstrate the direct involvement of cell spreading and RhoA/ROCK-mediated cytoskeletal tension generation in BMP-induced signaling and early stages of in vitro osteogenesis, and highlight the essential interplay between biochemical and mechanical cues in stem cell differentiation. PMID:21967638

  11. Focal Adhesion Kinase Signaling Mediated the Enhancement of Osteogenesis of Human Mesenchymal Stem Cells Induced by Extracorporeal Shockwave

    PubMed Central

    Hu, Jun; Liao, Haojie; Ma, Zebin; Chen, Hongjiang; Huang, Zhonglian; Zhang, Yuantao; Yu, Menglei; Chen, Youbin; Xu, Jiankun

    2016-01-01

    Extracorporeal shockwave (ESW) has been shown of great potential in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but it is unknown whether this osteogenic promotion effect can also be achieved in other MSCs (i.e., tendon-derived stem cells (TDSCs) and adipose-derived stem cells (ADSCs)). In the current study, we aimed not only to compare the osteogenic effects of BMSCs induced by ESW to those of TDSCs and ADSCs; but also to investigate the underlying mechanisms. We show here that ESW (0.16 mj/mm2) significantly promoted the osteogenic differentiation in all the tested types of MSCs, accompanied with the downregulation of miR-138, but the activation of FAK, ERK1/2, and RUNX2. The enhancement of osteogenesis in these MSCs was consistently abolished when the cells were pretreated with one of the following conditions: overexpression of miR-138, FAK knockdown using specific siRNA, and U0126, implying that all of these elements are indispensable for mediating the effect of ESW. Moreover, our study provides converging genetic and molecular evidence that the miR-138-FAK-ERK1/2-RUNX2 machinery can be generally activated in ESW-preconditioned MSCs, suggesting that ESW may be a promising therapeutic strategy for the enhancement of osteogenesis of MSCs, regardless of their origins. PMID:26863924

  12. Focal Adhesion Kinase Signaling Mediated the Enhancement of Osteogenesis of Human Mesenchymal Stem Cells Induced by Extracorporeal Shockwave

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Liao, Haojie; Ma, Zebin; Chen, Hongjiang; Huang, Zhonglian; Zhang, Yuantao; Yu, Menglei; Chen, Youbin; Xu, Jiankun

    2016-02-01

    Extracorporeal shockwave (ESW) has been shown of great potential in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but it is unknown whether this osteogenic promotion effect can also be achieved in other MSCs (i.e., tendon-derived stem cells (TDSCs) and adipose-derived stem cells (ADSCs)). In the current study, we aimed not only to compare the osteogenic effects of BMSCs induced by ESW to those of TDSCs and ADSCs; but also to investigate the underlying mechanisms. We show here that ESW (0.16 mj/mm2) significantly promoted the osteogenic differentiation in all the tested types of MSCs, accompanied with the downregulation of miR-138, but the activation of FAK, ERK1/2, and RUNX2. The enhancement of osteogenesis in these MSCs was consistently abolished when the cells were pretreated with one of the following conditions: overexpression of miR-138, FAK knockdown using specific siRNA, and U0126, implying that all of these elements are indispensable for mediating the effect of ESW. Moreover, our study provides converging genetic and molecular evidence that the miR-138-FAK-ERK1/2-RUNX2 machinery can be generally activated in ESW-preconditioned MSCs, suggesting that ESW may be a promising therapeutic strategy for the enhancement of osteogenesis of MSCs, regardless of their origins.

  13. Characterization of BMP signaling dependent osteogenesis using a BMP depletable avianized bone marrow stromal cell line (TVA-BMSC).

    PubMed

    Yadav, Prem Swaroop; Khan, Mohd Parvez; Prashar, Paritosh; Duggal, Shivali; Rath, Srikanta Kumar; Chattopadhyay, Naibedya; Bandyopadhyay, Amitabha

    2016-10-01

    Adipogenesis, chondrogenesis and osteogenesis are BMP signaling dependent differentiation processes. However, the molecular networks operating downstream of BMP signaling to bring about these distinct fates are yet to be fully elucidated. We have developed a novel Bone Marrow Stromal Cell (BMSC) derived mouse cell line as a powerful in vitro platform to conduct such experiments. This cell line is a derivative of BMSCs isolated from a tamoxifen inducible Bmp2 and Bmp4 double conditional knock-out mouse strain. These BMSCs are immortalized and stably transfected with avian retroviral receptor TVA (TVA-BMSCs), enabling an easy method for stable transduction of multiple genes in these cells. In TVA-BMSCs multiple components of BMP signaling pathway can be manipulated simultaneously. Using this cell line we have demonstrated that for osteogenesis, BMP signaling is required only for the first three days. We have further demonstrated that Klf10, an osteogenic transcription factor which is transcribed in developing bones in a BMP signaling dependent manner, can largely compensate for the loss of BMP signaling during osteogenesis of BMSCs. TVA-BMSCs can undergo chondrogenesis and adipogenesis, and hence may be used for dissection of the molecular networks downstream of BMP signaling in these differentiation processes as well. PMID:27424936

  14. The Possible Roles of Biological Bone Constructed with Peripheral Blood Derived EPCs and BMSCs in Osteogenesis and Angiogenesis.

    PubMed

    Wu, Li; Zhao, Xian; He, Bo; Jiang, Jie; Xie, Xiao-Jie; Liu, Liu

    2016-01-01

    This study aimed to determine the possible potential of partially deproteinized biologic bone (PDPBB) seeded with bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs) in osteogenesis and angiogenesis. BMSCs and EPCs were isolated, identified, and cocultured in vitro, followed by seeding on the PDPBB. Expression of osteogenesis and vascularization markers was quantified by immunofluorescence (IF) staining, immunohistochemistry (IHC), and quantitive real-time polymerase chain reaction (qRT-PCR). Scanning electron microscope (SEM) was also employed to further evaluate the morphologic alterations of cocultured cells in the biologic bone. Results demonstrated that the coculture system combined with BMSCs and EPCs had significant advantages of (i) upregulating the mRNA expression of VEGF, Osteonectin, Osteopontin, and Collagen Type I and (ii) increasing ALP and OC staining compared to the BMSCs or EPCs only group. Moreover, IHC staining for CD105, CD34, and ZO-1 increased significantly in the implanted PDPBB seeded with coculture system, compared to that of BMSCs or EPCs only, respectively. Summarily, the present data provided evidence that PDPBB seeded with cocultured system possessed favorable cytocompatibility, provided suitable circumstances for different cell growth, and had the potential to provide reconstruction for cases with bone defection by promoting osteogenesis and angiogenesis. PMID:27195296

  15. Melatonin reversed tumor necrosis factor-alpha-inhibited osteogenesis of human mesenchymal stem cells by stabilizing SMAD1 protein.

    PubMed

    Lian, Chengjie; Wu, Zizhao; Gao, Bo; Peng, Yan; Liang, Anjing; Xu, Caixia; Liu, Lei; Qiu, Xianjian; Huang, Junjun; Zhou, Hang; Cai, Yifeng; Su, Peiqiang; Huang, Dongsheng

    2016-10-01

    Tumor necrosis factor-alpha (TNFα) plays a pivotal role in inflammation-related osteoporosis through the promotion of bone resorption and suppression of bone formation. Numerous drugs have been produced to treat osteoporosis by inhibiting bone resorption, but they offer few benefits to bone formation, which is what is needed by patients with severe bone loss. Melatonin, which can exert both anti-inflammatory and pro-osteogenic effects, shows promise in overcoming TNFα-inhibited osteogenesis and deserves further research. This study demonstrated that melatonin rescued TNFα-inhibited osteogenesis of human mesenchymal stem cells and that the interactions between SMURF1 and SMAD1 mediated the crosstalk between melatonin signaling and TNFα signaling. Additionally, melatonin treatment was found to downregulate TNFα-induced SMURF1 expression and then decrease SMURF1-mediated ubiquitination and degradation of SMAD1 protein, leading to steady bone morphogenetic protein-SMAD1 signaling activity and restoration of TNFα-impaired osteogenesis. Thus, melatonin has prospects for treating osteoporosis caused by inflammatory factors due to its multifaceted functions on regulation of bone formation, bone resorption, and inflammation. Further studies will focus on unveiling the specific mechanisms by which melatonin downregulates SMURF1 expression and confirming the clinical therapeutic value of melatonin in the prevention and therapy of bone loss associated with inflammation. PMID:27265199

  16. The Possible Roles of Biological Bone Constructed with Peripheral Blood Derived EPCs and BMSCs in Osteogenesis and Angiogenesis

    PubMed Central

    Wu, Li; Zhao, Xian; He, Bo; Jiang, Jie; Xie, Xiao-Jie; Liu, Liu

    2016-01-01

    This study aimed to determine the possible potential of partially deproteinized biologic bone (PDPBB) seeded with bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs) in osteogenesis and angiogenesis. BMSCs and EPCs were isolated, identified, and cocultured in vitro, followed by seeding on the PDPBB. Expression of osteogenesis and vascularization markers was quantified by immunofluorescence (IF) staining, immunohistochemistry (IHC), and quantitive real-time polymerase chain reaction (qRT-PCR). Scanning electron microscope (SEM) was also employed to further evaluate the morphologic alterations of cocultured cells in the biologic bone. Results demonstrated that the coculture system combined with BMSCs and EPCs had significant advantages of (i) upregulating the mRNA expression of VEGF, Osteonectin, Osteopontin, and Collagen Type I and (ii) increasing ALP and OC staining compared to the BMSCs or EPCs only group. Moreover, IHC staining for CD105, CD34, and ZO-1 increased significantly in the implanted PDPBB seeded with coculture system, compared to that of BMSCs or EPCs only, respectively. Summarily, the present data provided evidence that PDPBB seeded with cocultured system possessed favorable cytocompatibility, provided suitable circumstances for different cell growth, and had the potential to provide reconstruction for cases with bone defection by promoting osteogenesis and angiogenesis. PMID:27195296

  17. LGR4 acts as a key receptor for R-spondin 2 to promote osteogenesis through Wnt signaling pathway.

    PubMed

    Zhu, Chao; Zheng, Xin-Feng; Yang, Yue-Hua; Li, Bo; Wang, Yu-Ren; Jiang, Sheng-Dan; Jiang, Lei-Sheng

    2016-08-01

    R-spondin proteins are identified as secreted agonists of the canonical Wnt/β-catenin signaling pathway, and leucine-rich repeat-containing G-protein-coupled receptors (LGR) are recognized as R-spondin receptors. The potential role of R-spondin 2 (Rspo2) and LGR4 in mediating osteogenesis remains poorly understood. In our in vitro experiments, we found that Rspo2 could promote osteogenesis through activating the Wnt signaling pathway in MC3T3-E1 cells. However, this effect of Rsop2 disappeared in the cells with functional disruption of LGR4. Meanwhile, Rspo2 significantly inhibited osteoclastogenesis and this effect of Rspo2 was dependent on the presence of osteoblasts with normal function of LGR4. In our in vivo experiments, we found that application of exogenous Rspo2 rescued the bone loss and improved the microarchitecture of bone in OVX mice. Rspo2 could be a positive regulator of bone metabolism through activating the canonical Wnt/β-catenin signaling, and LGR4 acted as a key receptor for Rspo2 to promote osteogenesis. PMID:27140682

  18. Hydrogels functionalized with N-cadherin mimetic peptide enhance osteogenesis of hMSCs by emulating the osteogenic niche.

    PubMed

    Zhu, Meiling; Lin, Sien; Sun, Yuxin; Feng, Qian; Li, Gang; Bian, Liming

    2016-01-01

    N-cadherin is considered to be the key factor in directing cell-cell interactions during mesenchymal condensation, which is essential to osteogenesis. In this study, hyaluronic acid (HA) hydrogels are biofunctionalized with an N-cadherin mimetic peptide to mimic the pro-osteogenic niche in the endosteal space to promote the osteogenesis of human mesenchymal stem cells (hMSCs). Results show that the conjugation of the N-cadherin peptide in the HA hydrogels enhances the expression of the osteogenic marker genes in the seeded hMSCs. Furthermore, the biofunctionalized HA hydrogels promote the alkaline phosphatase activity, type I collagen deposition, and matrix mineralization by the seeded hMSCs under both in vitro and in vivo condition. We postulate that the biofunctionalized hydrogels emulates the N-cadherin-mediated homotypic cell-cell adhesion among MSCs and the "orthotypic" interaction between the osteoblasts and MSCs. These findings demonstrate that the biofunctionalized HA hydrogels provide a supportive niche microenvironment for the osteogenesis of hMSCs. PMID:26580785

  19. Kids with Mild Asthma Can Take Acetaminophen

    MedlinePlus

    ... gov/news/fullstory_160475.html Kids With Mild Asthma Can Take Acetaminophen: Study Finding counters past research ... 17, 2016 (HealthDay News) -- Acetaminophen does not worsen asthma symptoms in young children, a new study finds. ...

  20. Mild Air Pollution of Concern in Pregnancy

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_158558.html Mild Air Pollution of Concern in Pregnancy Study found risk for ... Being exposed to just a small amount of air pollution during pregnancy ups the risk of a pregnancy ...

  1. Mild Air Pollution of Concern in Pregnancy

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_158558.html Mild Air Pollution of Concern in Pregnancy Study found risk for ... Being exposed to just a small amount of air pollution during pregnancy ups the risk of a pregnancy ...

  2. Treatment Alternatives Following Mild Head Injury.

    ERIC Educational Resources Information Center

    Novack, Thomas A.; And Others

    1988-01-01

    Discusses treatment alternatives which may alleviate problems in recovery following mild head injury, including providing education, cognitive stimulation, stress management training, individual counseling, group discussion, and physical activity in a day treatment setting. (Author/ABL)

  3. A regulatory loop containing miR-26a, GSK3β and C/EBPα regulates the osteogenesis of human adipose-derived mesenchymal stem cells

    PubMed Central

    Wang, Zi; Xie, Qing; Yu, Zhang; Zhou, Huifang; Huang, Yazhuo; Bi, Xiaoping; Wang, Yefei; Shi, Wodong; Sun, Hao; Gu, Ping; Fan, Xianqun

    2015-01-01

    Elucidating the molecular mechanisms responsible for osteogenesis of human adipose-derived mesenchymal stem cells (hADSCs) will provide deeper insights into the regulatory mechanisms of this process and help develop more efficient methods for cell-based therapies. In this study, we analysed the role of miR-26a in the regulation of hADSC osteogenesis. The endogenous expression of miR-26a increased during the osteogenic differentiation. The overexpression of miR-26a promoted hADSC osteogenesis, whereas osteogenesis was repressed by miR-26a knockdown. Additionally, miR-26a directly targeted the 3′UTR of the GSK3β, suppressing the expression of GSK3β protein. Similar to the effect of overexpressing miR-26a, the knockdown of GSK3β promoted osteogenic differentiation, whereas GSK3β overexpression inhibited this process, suggesting that GSK3β acted as a negative regulator of hADSC osteogenesis. Furthermore, GSK3β influences Wnt signalling pathway by regulating β-catenin, and subsequently altered the expression of its downstream target C/EBPα. In turn, C/EBPα transcriptionally regulated the expression of miR-26a by physically binding to the CTDSPL promoter region. Taken together, our data identified a novel feedback regulatory circuitry composed of miR-26a, GSK3β and C/EBPα, the function of which might contribute to the regulation of hADSC osteogenesis. Our findings provided new insights into the function of miR-26a and the mechanisms underlying osteogenesis of hADSCs. PMID:26469406

  4. Classification and management of mild head trauma

    PubMed Central

    Andrade, Almir F; Paiva, Wellingson S; Soares, Matheus S; De Amorim, Robson LO; Tavares, Wagner M; Teixeira, Manoel J

    2011-01-01

    Mild head trauma had been defined in patients with direct impact or deceleration effect admitted with a Glasgow Coma Scale score of 13–15. It is one of the most frequent causes of morbidity in emergency medicine. Although common, several controversies persist about its clinical management. In this paper, we describe the Brazilian guidelines for mild head trauma, based on a critical review of the relevant literature. PMID:21475628

  5. Fetal biometry of skeletal dysplasias: a multicentric study.

    PubMed

    Goncalves, L; Jeanty, P

    1994-10-01

    Twenty-three diagnostic centers worldwide contributed 127 cases of 17 skeletal dysplasias. Discriminant analysis showed that the femur length was the best biometric parameter to distinguish among the five most common disorders in this series (thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, achondroplasia and hypochondroplasia). Fifty-four percent of fetuses with femur length below 30% of the mean for gestational age had achondrogenesis. Seventy-eight percent of measurements between 40 and 60% of the mean for gestational age represented either thanatophoric dysplasia or osteogenesis imperfecta type II. Fetuses who had over 80% of the mean for gestational age had predominantly hypochondroplasia, achondroplasia, and osteogenesis imperfecta type III. PMID:7880297

  6. Fetal biometry of skeletal dysplasias: a multicentric study.

    PubMed

    Goncalves, L; Jeanty, P

    1994-12-01

    Twenty-three diagnostic centers worldwide contributed 127 cases of 17 skeletal dysplasias. Discriminant analysis showed that the femur length was the best biometric parameter to distinguish among the five most common disorders in this series (thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, achondroplasia and hypochondroplasia). Fifty-four percent of fetuses with femur length below 30% of the mean for gestational age had achondrogenesis. Seventy-eight percent of measurements between 40 and 60% of the mean for gestational age represented either thanatophoric dysplasia or osteogenesis imperfecta type II. Fetuses who had over 80% of the mean for gestational age had predominantly hypochondroplasia, achondroplasia, and osteogenesis imperfecta type III. PMID:7877211

  7. Effect of distraction osteogenesis of the mandible on upper airway volume and resistance in children with micrognathia.

    PubMed

    Perlyn, Chad A; Schmelzer, Rodney E; Sutera, Salvatore P; Kane, Alex A; Govier, Dan; Marsh, Jeffrey L

    2002-05-01

    Children with craniofacial anomalies often have compromise of the upper airway, a condition with potential for morbidity and mortality. In children with microretrognathia, the diminutive size and retruded position of the mandible reduces the size of the oropharynx, thereby predisposing to glossoptosis and airway obstruction. Although several authors have reported successful use of mandibular distraction osteogenesis to alleviate this type of upper airway obstruction, the physiologic relationship between changes in mandibular shape, size, and position and upper airway dynamics remains undefined. The purpose of this study was to develop methodologies to quantitatively evaluate upper airway dynamics in children with micrognathia both before and after mandibular distraction osteogenesis. The patient population consisted of four children with micrognathia who had successfully undergone upper airway stabilization by bilateral mandibular distraction osteogenesis. The data used were digitally archived computed tomographic scan data from high-resolution, thin-slice head computed tomographic scans obtained before and after mandibular distraction. Upper airway evaluation was performed in two ways: static and dynamic. Static analysis consisted of computer quantification of predistraction and postdistraction mandibular and upper airway volumes using Analyze imaging software. Dynamic analysis consisted of fabrication of rigid stereolithographic hollow cast models of the upper airway produced from computed tomographic scan data. Models were used for characterization of upper airway resistance and flow patterns as related to respiration. After distraction osteogenesis, mandibular total volume increased 32, 32, 18, and 25 percent (mean, 27 percent) and upper airway volume increased by 20, 31, 23, and 71 percent (mean, 37 percent). A significant decrease in flow resistance, both inspiratory and expiratory, was observed in the patient with the greatest upper airway volume increase

  8. Acceleration of osteogenesis by using barium titanate piezoelectric ceramic as an implant material

    NASA Astrophysics Data System (ADS)

    Furuya, K.; Morita, Y.; Tanaka, K.; Katayama, T.; Nakamachi, E.

    2011-04-01

    As bone has piezoelectric properties, it is expected that activity of bone cells and bone formation can be accelerated by applying piezoelectric ceramics to implants. Since lead ions, included in ordinary piezoelectric ceramics, are harmful, a barium titanate (BTO) ceramic, which is a lead-free piezoelectric ceramic, was used in this study. The purpose of this study was to investigate piezoelectric effects of surface charge of BTO on cell differentiation under dynamic loading in vitro. Rat bone marrow cells seeded on surfaces of BTO ceramics were cultured in culture medium supplemented with dexamethasone, β-glycerophosphate and ascorbic acid while a dynamic load was applied to the BTO ceramics. After 10 days of cultivation, the cell layer and synthesized matrix on the BTO surfaces were scraped off, and then DNA content, alkaline phosphtase (ALP) activity and calcium content were measured, to evaluate osteogenic differentiation. ALP activity on the charged BTO surface was slightly higher than that on the non-charged BTO surface. The amount of calcium on the charged BTO surface was also higher than that on the non-charged BTO surface. These results showed that the electric charged BTO surface accelerated osteogenesis.

  9. Strontium eluting nanofibers augment stem cell osteogenesis for bone tissue regeneration.

    PubMed

    Meka, Sai Rama Krishna; Jain, Shubham; Chatterjee, Kaushik

    2016-10-01

    Strontium is known to offer a therapeutic benefit to osteoporotic patients by promoting bone formation. Thus, toward engineering scaffolds for bone tissue regeneration we have prepared polymer nanocomposite scaffolds by electrospinning. Strontium carbonate nanoparticles (nSrCO3) were added to poly(ε-caprolactone) (PCL) at 10 and 20wt% to develop nanocomposite fibrous scaffolds (PCL/SrC10 and PCL/SrC20) with fiber diameter in the range of 300-500nm. Incorporation of nSrCO3 decreased crystallinity and the elastic modulus of PCL. The composite scaffolds released Sr(2+) ions with up to 65ppm in 4days from the PCL/SrC20 scaffolds. Cell studies confirmed that the composite scaffold with 20% nSrCO3 enhanced proliferation of human mesenchymal stem cells in vitro. There was marked increase in mineral deposition up to four folds in PCL/SrC20 suggesting enhanced osteogenesis. This was corroborated by increased mRNA and protein expression of various osteogenic markers such as BMP-2, Osterix and Runx2 in the PCL/SrC20 fibers. Thus, incorporation of nSrCO3 in polymer scaffolds is a promising strategy for bone tissue engineering as an alternative to the use of labile growth factors to impart bioactivity to polymer scaffolds. PMID:27429299

  10. Bilateral sagittal split osteotomy versus distraction osteogenesis of the mandible: a randomized clinical trial.

    PubMed

    Baas, E M; Bierenbroodspot, F; de Lange, J

    2015-02-01

    A randomized clinical trial was performed to evaluate differences in postoperative neurosensory disturbance (NSD) between two methods of mandibular advancement surgery. A total of 66 non-syndromal class II patients with mandibular hypoplasia were randomized for either distraction osteogenesis (DO) or bilateral sagittal split osteotomy (BSSO). Twenty-nine patients in the BSSO group and 34 patients in the DO group were available for evaluation. Objective assessment was performed by Semmes-Weinstein (SW) monofilament testing preoperatively and at least 1 year after surgery. Six of the 34 patients (17.6%) in the DO group experienced objective NSD, compared to 5/29 patients (17.2%) in the BSSO group. In the evaluation of nerve function by individual nerves, 8/68 nerves (11.8%) revealed objective NSD in the DO group, compared to 7/58 nerves (12.1%) in the BSSO group. A subjective NSD was reported in 11/34 patients (32.4%) in the DO group, compared to 9/29 patients (31.0%) in the BSSO group. In the evaluation of nerve function by individual nerves, a subjective NSD was reported for 13/68 nerves (19.1%) in the DO group, compared to 13/58 nerves (22.4%) in the BSSO group. None of the differences was significant. No differences in neurosensory disturbance could be found between the two study groups. Objective WS monofilament testing appeared to underestimate NSD compared to subjective patient report. PMID:25457820

  11. Peptide-incorporated 3D porous alginate scaffolds with enhanced osteogenesis for bone tissue engineering.

    PubMed

    Luo, Zuyuan; Yang, Yue; Deng, Yi; Sun, Yuhua; Yang, Hongtao; Wei, Shicheng

    2016-07-01

    Good bioactivity and osteogenesis of three-dimensional porous alginate scaffolds (PAS) are critical for bone tissue engineering. In this work, alginate and bone-forming peptide-1 (BFP-1), derived from bone morphogenetic protein-7 (BMP-7), have been combined together (without carbodiimide chemistry treatment) to develop peptide-incorporated PAS (p-PAS) for promoting bone repairing ability. The mechanical properties and SEM images show no difference between pure PAS and p-PAS. The release kinetics of the labeled peptide with 6-carboxy tetramethyl rhodamine from the PAS matrix suggests that the peptide is released in a relatively sustained manner. In the cell experiment, p-PAS show higher cell adhesion, spreading, proliferation and alkaline phosphatase (ALP) activity than the pristine PAS group, indicating that the BFP-1 released from p-PAS could significantly promote the aggregation and differentiation of osteoblasts, especially at 10μg/mL of trapped peptide concentration (p-PAS-10). Furthermore, p-PAS-10 was implanted into Beagle calvarial defects and bone regeneration was analyzed after 4 weeks. New bone formation was assessed by calcein and Masson's trichrome staining. The data reveal that p-PAS group exhibits significantly enhanced oseto-regenerative capability in vivo. The peptide-modified PAS with promoted bioactivity and osteogenic differentiation in vitro as well as bone formation ability in vivo could be promising tissue engineering materials for repairing and regeneration of bone defects. PMID:27022863

  12. MicroRNAs Regulate Osteogenesis and Chondrogenesis of Mouse Bone Marrow Stromal Cells

    PubMed Central

    Suomi, Salla; Taipaleenmäki, Hanna; Seppänen, Anne; Ripatti, Tommi; Väänänen, Kalervo; Hentunen, Teuvo; Säämänen, Anna-Marja; Laitala-Leinonen, Tiina

    2008-01-01

    MicroRNAs (miRNAs) are non-coding RNAs that bind to target mRNA leading to translational arrest or mRNA degradation. To study miRNA-mediated regulation of osteogenesis and chondrogenesis, we compared the expression of 35 miRNAs in osteoblasts and chondroblasts derived from mouse marrow stromal cells (MSCs). Differentiation of MSCs resulted in up- or downregulation of several miRNAs, with miR-199a expression being over 10-fold higher in chondroblasts than in undifferentiated MSCs. In addition, miR-124a was strongly upregulated during chondrogenesis while the expression of miR-96 was substantially suppressed. A systems biological analysis of the potential miRNA target genes and their interaction networks was combined with promoter analysis. These studies link the differentially expressed miRNAs to collagen synthesis and hypoxia, key pathways related to bone and cartilage physiology. The global regulatory networks described here suggest for the first time how miRNAs and transcription factors are capable of fine-tuning the osteogenic and chondrogenic differentiation of mouse MSCs. PMID:19787082

  13. Severe proliferative congenital temporomandibular joint ankylosis: a proposed treatment protocol utilizing distraction osteogenesis.

    PubMed

    Bartlett, Scott P; Reid, Russell R; Losee, Joseph E; Quinn, Peter D

    2006-05-01

    The classical treatment for temporomandibular joint (TMJ) ankylosis in children: 1) joint release; 2) arthroplasty; 3) reconstruction; and 4) postoperative physical therapy (PT), is often unsuccessful. Postoperative physical therapy is difficult in the young patient due to poor cooperation. Moreover, there is a subgroup of patients who have a refractory congenital proliferative bony process that is the cause of their disease. In these patients, a role for distraction osteogenesis (DO) has been defined. We present a series of young patients with congenital proliferative TMJ ankylosis. Some have failed classic treatment. In such cases, DO is used to expand the mandibular size and soft tissue matrix. This creates a static open bite, facilitates mid-facial growth, and avoids compromise of the airway, speech, nutrition, and oral hygiene. To maintain these objectives, mandibular DO may be repeated as the child matures. Once skeletal maturity is reached, DO is used to normalize occlusion and further expand the soft tissue envelope prior to definitive reconstruction and aggressive post-op PT. In seven patients, this protocol has been used. Five patients are currently in the active phase of growth and undergoing interim treatment with mandibular DO. Two patients have reached skeletal maturity and have completed the protocol of DO with definitive arthroplasty and reconstruction. DO is a valuable aid in the treatment of the problematic child with congenital proliferative TMJ ankylosis. Interim DO, prior to definitive arthroplasty and reconstruction, can provide a static open bite that prevents progressive deformity and its associated functional disturbances. PMID:16770209

  14. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

    SciTech Connect

    Wahl, Elizabeth C.; Aronson, James; Liu, Lichu; Liu, Zhendong; Perrien, Daniel S.; Skinner, Robert A.; Badger, Thomas M.; Ronis, Martin J.J.; Lumpkin, Charles K. . E-mail: lumpkincharlesk@uams.edu

    2007-05-01

    Tumor necrosis factor-alpha (TNF-{alpha}) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-{alpha} signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-{alpha} (rmTNF-{alpha}) to ethanol naive mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-{alpha} (10 {mu}g/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model.

  15. Prostaglandin E2 and Connexin 43 crosstalk in the osteogenesis induced by extracorporeal shockwave.

    PubMed

    Chen, Youbin; Xu, Jiankun; Liao, Haojie; Ma, Zebin; Zhang, Yuantao; Chen, Hongjiang; Huang, Zhonglian; Hu, Jun

    2016-09-01

    As a type of mechanical stimulation, extracorporeal shockwave (ESW) has been widely used in the clinic to treat bone fracture delayed union and non-unions. A large number of studies have shown beneficial effects of ESW in promoting fracture healing by inducing bone regeneration; however, the underlying mechanisms remain unclear. ESW has been shown to induce the production of prostaglandin E2 (PGE2), which is essential for gap junction intercellular communication in response to mechanical stress. Among the 19 known gap junction subunits, connexin43 (Cx43) is the most prevalent for mediating the response of mechanical stress. However, to our knowledge, the effect of ESW on Cx43 expression has not been reported before. Herein, we propose that a crosstalk between PGE2 and Cx43 is involved in the enhancement of osteogenesis induced by ESW. We review the currently available data to propose an unrevealed, but important mechanism via which ESW treatment affects osteogenic differentiation of bone marrow stromal cells. PMID:27515217

  16. Enhanced Osteogenesis of Adipose Derived Stem Cells with Noggin Suppression and Delivery of BMP-2

    PubMed Central

    Fan, Jiabing; Park, Hyejin; Tan, Steven; Lee, Min

    2013-01-01

    Bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors. However, BMPs are highly pleiotropic molecules and their supra-physiological high dose requirement leads to adverse side effects and inefficient bone formation. Thus, there is a need to develop alternative osteoinductive growth factor strategies that can effectively complement BMP activity. In this study, we intrinsically stimulated BMP signaling in adipose derived stem cells (ASCs) by downregulating noggin, a potent BMP antagonist, using an RNAi strategy. ASCs transduced with noggin shRNA significantly enhanced osteogenic differentiation of cells. The potency of endogenous BMPs was subsequently enhanced by stimulating ASCs with exogenous BMPs at a significantly reduced dose. The level of mineralization in noggin shRNA treated ASCs when treated with BMP-2 was comparable to that of control shRNA treated cell treated with 10-fold more BMP-2. The complementary strategy of noggin suppression + BMP-2 to enhance osteogenesis was further confirmed in 3D in vitro environments using scaffolds consisting of chitosan (CH), chondroitin sulfate (CS), and apatite layer on their surfaces designed to slowly release BMP-2. This finding supports the novel therapeutic potential of this complementary strategy in bone regeneration. PMID:23977305

  17. Choice of osteoblast model critical for studying the effects of electromagnetic stimulation on osteogenesis in vitro.

    PubMed

    Bique, Anna-Maria; Kaivosoja, Emilia; Mikkonen, Marko; Paulasto-Kröckel, Mervi

    2016-01-01

    The clinical benefits of electromagnetic field (EMF) therapy in enhancing osteogenesis have been acknowledged for decades, but agreement regarding the underlying mechanisms continues to be sought. Studies have shown EMFs to promote osteoblast-like cell proliferation, or contrarily, to induce differentiation and enhance mineralization. Typically these disparities have been attributed to methodological differences. The present paper argues the possibility that the chosen osteoblast model impacts stimulation outcome. Phenotypically immature cells, particularly at low seeding densities, appear to be prone to EMF-amplified proliferation. Conversely, mature cells at higher densities seem to be predisposed to earlier onset differentiation and mineralization. This suggests that EMFs augment ongoing processes in cell populations. To test this hypothesis, mature SaOS-2 cells and immature MC3T3-E1 cells at various densities, with or without osteo-induction, were exposed to sinusoidal 50 Hz EMF. The exposure stimulated the proliferation of MC3T3-E1 and inhibited the proliferation of SaOS-2 cells. Baseline alkaline phosphatase (ALP) expression of SaOS-2 cells was high and rapidly further increased with EMF exposure, whereas ALP effects in MC3T3-E1 cells were not seen until the second week. Thus both cell types responded differently to EMF stimulation, corroborating the hypothesis that the phenotypic maturity and culture stage of cells influence stimulation outcome. PMID:27355896

  18. Secondary mandibular reconstruction after oral squamous cell carcinoma resection: clinical reevaluation of transport disk distraction osteogenesis.

    PubMed

    Seitz, Oliver; Harth, Marc; Ghanaati, Shahram; Lehnert, Thomas; Vogl, Thomas J; Sader, Robert; Klein, Cornelius M

    2010-01-01

    Besides bone grafting, transport disk distraction osteogenesis (TDDO) is an alternative approach that can be used for the reconstruction of the mandibular arch after neoplastic surgery. Although several animal experiments are reporting about the applicability of this technique, little is known about its long-term success in human beings. In this study, we report about the successful treatment of patients with defects of their mandibular arch due to tumor resection by means of the external bifocal TDDO. A total of 7 patients (n = 3 with lateral, n = 4 with anterior defects) were followed up for a mean period of 56 months. Although neither adjuvant nor neoadjuvant chemotherapy negatively influenced callus formation, prereconstructive radiation with a dose of 51 Gy led to an insufficient callus formation. The reconstruction of anterior defects was unsatisfying because tensions from the soft tissue on the fragile and rubber-like callus negatively influenced the natural arch shaping.In these cases, additional surgery was often required. However, reconstruction of lateral defects of the mandibular arch was more successful and resulted in functional bone with good quality, in which dental implants could be inserted. The results of this study emphasize that TDDO by means of bifocal distraction provides functional bone comparable to residual bone.Lateral defects of mandibular arch can be better reconstructed, whereas anterior defects often require additional surgery. PMID:20061975

  19. Histological and physical analysis of bone neoformation by osteogenesis distraction: A preliminary report

    PubMed Central

    Vannucci, Marcello Gaieta; Dreyer, Juliana; Kreisner, Paulo; Gaião, Leonilson; Moraes, João Feliz Duarte; de Oliveira, Marilia Gerhardt

    2011-01-01

    Introduction: Osteogenesis distraction (OD) is a mainstream technique in maxillofacial surgical reconstruction with varied applications. OD technique employs a distractor with the aim to get new bone in the site of interest. Osseous maturation time is necessary before the device can be removed and few patients’ complaint of related discomfort, especially when these devices are external, and induces superficial infections, paresthesia, hypertrophic scars and social relationship difficulties. The use of Low Level Laser Therapy (LLLT) has been proved beneficial to soft tissue and osseous repairs. Materials and Method: 12 rabbits were randomly divided in to two groups. In all animals, distractor was placed and one group was exposed to LLLT while the other group served as control. After consolidation, animals were sacrificed, the new bone formed were subjected to investigations including histomorphometric, physical analysis and tomographical analysis. Statistical analyses were performed using SPSS software. Result: Newly formed bone was significantly different between the groups. The physical properties of the neobone were comparatively better when the animals were exposed to LLLT with varying statistical significance. Conclusion: The results obtained with smaller sample size in this study need to be interpreted with care. The results of this preliminary pilot study encourage the use of LLLT during healing period. However the histological, tomographical and physical findings need to be ascertained using a larger sample size to study the bio-stimulatory effects with laser therapy from basics to clinical relevance on wound and bone healing. PMID:23482632

  20. Vascular endothelial growth factor signaling affects both angiogenesis and osteogenesis during the development of scleral ossicles.

    PubMed

    Jabalee, James; Franz-Odendaal, Tamara A

    2015-10-01

    Intramembranous ossification is a complex multi-step process which relies on extensive interactions among bone cells and surrounding tissues. The embryonic vasculature is essential in regulating endochondral ossification; however, its role during intramembranous ossification remains poorly understood, and in vivo studies are lacking. Previous research from our lab on the development of the intramembranous scleral ossicles has demonstrated an intriguing pattern of vascular development in which the areas of future osteogenesis remain avascular until after bone induction has occurred. Such avascular zones are located directly beneath each of the conjunctival papillae, epithelial structures which provide osteogenic signals to the underlying mesenchyme. Here we provide a high-resolution map of the developing vasculature from the time of ossicle induction to mineralization using a novel technique. We show that vegfa is expressed by the papillae and nearby mesenchymal tissue throughout HH 34-37, when vascular growth is taking place, and is down-regulated thereafter. Localized inhibition of Vegf results in expansion of the avascular zone surrounding the implanted papilla and mispatterning of the scleral ossicles. These results demonstrate that Vegf signaling could provide important insights into the complex relationship between bone and vasculature during intramembranous bone development. PMID:26210172

  1. Therapeutic effect of deferoxamine on iron overload-induced inhibition of osteogenesis in a zebrafish model.

    PubMed

    Chen, Bin; Yan, Yi-Lin; Liu, Chen; Bo, Lin; Li, Guang-Fei; Wang, Han; Xu, You-Jia

    2014-03-01

    Osteoporosis results from an imbalance in bone remodeling, in which osteoclastic bone resorption exceeds osteoblastic bone formation. Iron has recently been recognized as an independent risk factor for osteoporosis. Reportedly, excess iron could promote osteoclast differentiation and bone resorption through the production of reactive oxygen species (ROS). We evaluated the effect of iron on osteoblast differentiation and bone formation in zebrafish and further investigated the potential benefits of deferoxamine (DFO), a powerful iron chelator, in iron-overloaded zebrafish. The zebrafish model of iron overload described in this study demonstrated an apparent inhibition of bone formation, accompanied by decreased expression of osteoblast-specific genes (runx2a, runx2b, osteocalcin, osteopontin, ALP, and collagen type I). The negative effect of iron on osteoblastic activity and bone formation could be attributed to increased ROS generation and oxidative stress. Most importantly, we revealed that DFO was capable of removing whole-body iron and attenuating oxidative stress in iron-overloaded larval zebrafish, which facilitated larval recovery from the reductions in bone formation and osteogenesis induced by iron overload. PMID:24414856

  2. Biomimetic scaffolds containing nanofibers coated with willemite nanoparticles for improvement of stem cell osteogenesis.

    PubMed

    Ramezanifard, Rouhallah; Seyedjafari, Ehsan; Ardeshirylajimi, Abdolreza; Soleimani, Masoud

    2016-05-01

    Nowadays, discovering osteogenesis stimulating effectors is one of the major topics in bone tissue engineering and regenerative medicine. In this study, the proliferation rate and osteogenic differentiation potency of adipose-derived mesenchymal stem cells (AT-MSCs) cultured on poly (l-lactide acid) (PLLA) and willemite-coated PLLA were investigated by MTT assay and common osteogenic markers such as alkaline phosphatase (ALP) activity, calcium mineral deposition and bone-related genes expression. Willemite-coated PLLA showed a higher proliferation support to AT-MSCs in comparison to PLLA and TCPS. During the period of study, AT-MSCs cultured on willemite-coated PLLA scaffolds exhibited the greatest ALP activity and mineralization. Gene expression analysis demonstrated that the highest expression of four important osteogenic-related genes, osteonectin, Runx2, collagen type 1 and osteocalcin was observed in stem cells cultured on willemite-coated PLLA nanofibrous scaffolds. According to the results, willemite-coated PLLA could be a suitable substrate to support the proliferation and osteogenic differentiation of stem cells and holds promising potential for bone tissue engineering and regenerative medicine applications. PMID:26952439

  3. Degradability, cytocompatibility, and osteogenesis of porous scaffolds of nanobredigite and PCL–PEG–PCL composite

    PubMed Central

    Hou, Jun; Fan, Donghui; Zhao, Lingming; Yu, Baoqin; Su, Jiacan; Wei, Jie; Shin, Jung-Woog

    2016-01-01

    Biocomposite scaffolds were fabricated by incorporation of nanobredigite (n-BD) into the polymer of poly(ε-caprolactone)–poly(ethyleneglycol)–poly(ε-caprolactone) (PCL–PEG–PCL). The results revealed that the addition of n-BD into PCL–PEG–PCL significantly improved water absorption, compressive strength, and degradability of the scaffolds of n-BD/PCL–PEG–PCL composite (n-BPC) compared with PCL–PEG–PCL scaffolds alone. In addition, the proliferation and alkaline phosphatase activity of MG63 cells cultured on n-BPC scaffolds were obviously higher than that cultured on PCL–PEG–PCL scaffolds. Moreover, the results of the histological evaluation from the animal model revealed that the n-BPC scaffolds significantly improved new bone formation compared with the PCL–PEG–PCL scaffolds, indicating good osteogenesis. The n-BPC scaffolds with good biocompatibility could stimulate cell proliferation, differentiation, and bone tissue regeneration and would be an excellent candidate for bone defect repair. PMID:27555774

  4. Recapitulating cranial osteogenesis with neural crest cells in 3-D microenvironments.

    PubMed

    Namkoong, Bumjin; Güven, Sinan; Ramesan, Shwathy; Liaudanskaya, Volha; Abzhanov, Arhat; Demirci, Utkan

    2016-02-01

    The experimental systems that recapitulate the complexity of native tissues and enable precise control over the microenvironment are becoming essential for the pre-clinical tests of therapeutics and tissue engineering. Here, we described a strategy to develop an in vitro platform to study the developmental biology of craniofacial osteogenesis. In this study, we directly osteo-differentiated cranial neural crest cells (CNCCs) in a 3-D in vitro bioengineered microenvironment. Cells were encapsulated in the gelatin-based photo-crosslinkable hydrogel and cultured up to three weeks. We demonstrated that this platform allows efficient differentiation of p75 positive CNCCs to cells expressing osteogenic markers corresponding to the sequential developmental phases of intramembranous ossification. During the course of culture, we observed a decrease in the expression of early osteogenic marker Runx2, while the other mature osteoblast and osteocyte markers such as Osterix, Osteocalcin, Osteopontin and Bone sialoprotein increased. We analyzed the ossification of the secreted matrix with alkaline phosphatase and quantified the newly secreted hydroxyapatite. The Field Emission Scanning Electron Microscope (FESEM) images of the bioengineered hydrogel constructs revealed the native-like osteocytes, mature osteoblasts, and cranial bone tissue morphologies with canaliculus-like intercellular connections. This platform provides a broadly applicable model system to potentially study diseases involving primarily embryonic craniofacial bone disorders, where direct diagnosis and adequate animal disease models are limited. PMID:26675129

  5. Amifostine Treatment Mitigates the Damaging Effects of Radiation on Distraction Osteogenesis in the Murine Mandible.

    PubMed

    Monson, Laura A; Nelson, Noah S; Donneys, Alexis; Farberg, Aaron S; Tchanque-Fossuo, Catherine N; Deshpande, Sagar S; Buchman, Steven R

    2016-08-01

    According to the American Society of Clinical Oncology, in 2012, more than 53,000 new cases of head and neck cancers (HNCs) were reported in the United States alone and nearly 12,000 deaths occurred relating to HNC. Although radiotherapy (XRT) has increased survival, the adverse effects can be unrelenting and their management is rarely remedial. Current treatment dictates surgical mandibular reconstruction using free tissue transfer. These complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of adjuvant therapy, jeopardizing prognosis as well as quality of life. The creation of new bone by distraction osteogenesis (DO) generates a replacement of deficient tissue from local substrate and could have immense potential therapeutic ramifications. Radiotherapy drastically impairs bone healing, precluding its use as a reconstructive method for HNC. We posit that the deleterious effects of XRT on bone formation could be pharmacologically mitigated. To test this hypothesis, we used a rodent model of DO and treated with amifostine, a radioprotectant, to assuage the XRT-induced injury on new bone formation. Amifostine had a profound salutary effect on bone regeneration, allowing the successful implementation of DO as a reconstructive technique. The optimization of bone regeneration in the irradiated mandible has immense potential for translation from the bench to the bedside, providing improved therapeutic options for patients subjected to XRT. PMID:27070667

  6. Use of anterior maxillary distraction osteogenesis in two cleft lip and palate patients

    PubMed Central

    Srivastava, Dhirendra; Ghassemi, Alireza; Ghassemi, Mehrangiz; Showkatbakhsh, Rahman; Jamilian, Abdolreza

    2015-01-01

    Distraction osteogenesis (DO) has become a mainstream surgical technique for patients with jaw deformities. The aim of this study was to report the effect of DO done by a hyrax screw incorporated in an acrylic plate in the treatment of two maxillary deficient cases with cleft lip and palate. Two patients, a 24-year-old female and a 29-year-old male who suffered from maxillary deficiency and cleft lip and palate, were treated by DO. After making vertical cuts between the premolars on both sides and horizontal cuts similar to Le Fort 1, a hyrax screw was mounted on an acrylic plate for the slow anteroposterior expansion of maxillary arch. The expansion was achieved by turning the hyrax screw 0.8 mm per day after the latency period. Treatment was discontinued after achieving satisfactory over jet and occlusion. This study showed that anterior maxillary distraction is a reliable technique for correction of midfacial deformity arising out of cleft lip and palate. Incidences of complications are negligible compared to total maxillary distraction. PMID:26668459

  7. Mice Deficient in AKAP13 (BRX) Are Osteoporotic and Have Impaired Osteogenesis.

    PubMed

    Koide, Hisashi; Holmbeck, Kenn; Lui, Julian C; Guo, Xiaoxiao C; Driggers, Paul; Chu, Tiffany; Tatsuno, Ichiro; Quaglieri, Caroline; Kino, Tomoshige; Baron, Jeffrey; Young, Marian F; Robey, Pamela G; Segars, James H

    2015-10-01

    Mechanical stimulation is crucial to bone growth and triggers osteogenic differentiation through a process involving Rho and protein kinase A. We previously cloned a gene (AKAP13, aka BRX) encoding a protein kinase A-anchoring protein in the N-terminus, a guanine nucleotide-exchange factor for RhoA in the mid-section, coupled to a carboxyl region that binds to estrogen and glucocorticoid nuclear receptors. Because of the critical role of Rho, estrogen, and glucocorticoids in bone remodeling, we examined the multifunctional role of Akap13. Akap13 was expressed in bone, and mice haploinsufficient for Akap13 (Akap13(+/-)) displayed reduced bone mineral density, reduced bone volume/total volume, and trabecular number, and increased trabecular spacing; resembling the changes observed in osteoporotic bone. Consistent with the osteoporotic phenotype, Colony forming unit-fibroblast numbers were diminished in Akap13(+/-) mice, as were osteoblast numbers and extracellular matrix production when compared to control littermates. Transcripts of Runx2, an essential transcription factor for the osteogenic lineage, and alkaline phosphatase (Alp), an indicator of osteogenic commitment, were both reduced in femora of Akap13(+/-) mice. Knockdown of Akap13 reduced levels of Runx2 and Alp transcripts in immortalized bone marrow stem cells. These findings suggest that Akap13 haploinsufficient mice have a deficiency in early osteogenesis with a corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity. PMID:25892096

  8. Enhancement of osteogenesis on micro/nano-topographical carbon fiber-reinforced polyetheretherketone-nanohydroxyapatite biocomposite.

    PubMed

    Xu, Anxiu; Liu, Xiaochen; Gao, Xiang; Deng, Feng; Deng, Yi; Wei, Shicheng

    2015-03-01

    As an FDA-approved implantable material, carbon fiber-reinforced polyetheretherketone (CFRPEEK) possesses excellent mechanical properties similar to those of human cortical bone and is a prime candidate to replace conventional metallic implants. The bioinertness and inferior osteogenic properties of CFRPEEK, however, limit its clinical application as orthopedic/dental implants. The present work aimed at developing a novel carbon fiber-reinforced polyetheretherketone-nanohydroxyapatite (PEEK/CF/n-HA) ternary biocomposite with micro/nano-topographical surface for the enhancement of the osteogenesis as a potential bioactive material for bone grafting and bone tissue-engineering applications. The combined modification of oxygen plasma and sand-blasting could improve the hydrophily and generate micro/nano-topographical structures on the surface of the CFRPEEK-based ternary biocomposite. The results clearly showcased that the micro-/nano-topographical PEEK/n-HA/CF ternary biocomposite demonstrated the outstanding ability to promote the proliferation and differentiation of MG-63 cells in vitro as well as to boost the osseointegration between implant and bone in vivo, thereby boding well application to bone tissue engineering. PMID:25579962

  9. Distraction osteogenesis device to estimate the axial stiffness of the callus in Vivo.

    PubMed

    Mora-Macías, J; Reina-Romo, E; Domínguez, J

    2015-10-01

    Knowing the evolution of callus stiffness is very important in distraction osteogenesis and bone healing. It allows the characterization of the bone maturation process and the assessment of the moment to retire the fixator. A new distractor device that monitors the callus axial stiffness is presented in this study. It quantifies the callus stiffness during the bone transport process with some advantages over previous methods to assess stiffness during simple distraction and bone healing. This device avoids a misalignment between bone segments, uses real load conditions, monitors forces continuously, does not involve radiation for patients, and allows the study of the complete distraction process, i.e., the distraction and consolidation phases. The device was calibrated in vitro simulating different real bone load conditions depending on the stage of the process. The stiffness of the callus could be estimated for values between 4.2 N/mm and 9066.8 N/mm. The average relative error in measurements carried out in in vitro calibration tests was 7.8% during the distraction phase and 9.5% during the consolidation phase. These results improve the accuracy and increase the callus stiffness range of estimation with respect to other devices in the literature. In addition, the device was used successfully in vivo in a preliminary experiment. PMID:26320818

  10. Histological evaluation of condylar hyperplasia model of rabbit following distraction osteogenesis of the condylar neck.

    PubMed

    Meng, Q; Chen, G; Long, X; Deng, M; Cai, H; Li, J

    2011-01-01

    Condylar hyperplasia is the excessive unilateral growth of mandibular leading to facial asymmetry, occlusal disturbance, joint pain and dysfunction. The aim of this study is to evaluate the histological presence of temporomandibular joint in model of condylar hyperplasia by lengthening unilateral condylar neck of distraction osteogenesis. An extra oral distractor was employed to achieve unilateral condylar neck distraction (1·0 mm daily for 7 days). The experimental condylar necks were elongated by 7 mm compared to the contralateral. Eleven adult white rabbits were used. Eight rabbits were, respectively, sacrificed after the post-distraction period (4 or 8 weeks). All animals were evaluated clinically and histomorphometrically. The condyles radiologically showed remodelling, flattening and sclerosis. In 4-week group, thinning of the cartilage was evident, and the trabeculae were long, not multiply connected. A thin, dense fibrous layer covered all over the surface of cartilage. In 8-week group, the cartilaginous layer was similar to thickness of the normal cartilage, but still thinner than control. However, the fibrous layers covering condyle manifested slight degenerative changes, and even depressions and erosions were seen in the cartilage and subchondral bone. The trabeculae showed denser and multiply connected. In 8-week group, the cartilaginous thickness of surgical condyles was significantly thinner than the contralateral. This study indicates that unilateral distraction of condylar neck loads the condyles asymmetrically. Asymmetrical loads affect more on the surgical condyles than the contralateral, and after 8 weeks of the post-distraction, condyle could recover from asymmetrical loads in some degree. PMID:20626572

  11. Distraction osteogenesis in the treatment of temporomandibular joint ankylosis with mandibular micrognathia

    PubMed Central

    Giraddi, Girish B.; Arora, Kirti; Sai Anusha, A. J.

    2016-01-01

    Aims: The aims of the study were to evaluate the efficacy of simultaneous interpositional arthroplasty with distraction osteogenesis (DO) as a single procedure and to give the patient acceptable functional rehabilitation with correction of the gross facial asymmetry. Materials and Methods: Nine patients of temporomandibular joint (TMJ) ankylosis with micrognathia were treated with interpositional arthroplasty and simultaneous DO and followed for a period of minimum 3 years. Preoperative, immediate postoperative, at the end of distraction, at 6 months and 3 years postdistraction consolidation radiographs were taken along with the clinical examination for mouth opening, deviation, length of the mandible and ramus, midline shift, occlusal cant, and occlusion. Results: The results showed an increase in the mouth opening, length of the mandible and ramus height, correction of deviation, occlusion, and midline shift. Relapse was not seen in any case, rather one patient developed infection at the distractor site and two patients had fracture of the roots of the teeth at the osteotomy site. There was an overall improvement in the facial asymmetry. Conclusion: Simultaneous interpositional arthroplasty with DO should be used to correct TMJ ankylosis associated with facial asymmetry/micrognathia, as it reduces the need for second surgery, thereby saving the trauma of a second surgery and difficulty in intubation, increases the length of the mandible, corrects the deformity, thereby resulting in an acceptable facial esthetics and function.

  12. Pre-arthroplasty simultaneous maxillomandibular distraction osteogenesis for the correction of post-ankylotic dentofacial deformities.

    PubMed

    Mehrotra, D; Vishwakarma, K; Chellapa, A L; Mahajan, N

    2016-07-01

    The aim of this study was to evaluate the hard and soft tissue changes after pre-arthroplasty simultaneous maxillomandibular distraction osteogenesis for the correction of post-ankylotic dentofacial deformities. This prospective study included 10 patients with unilateral temporomandibular joint (TMJ) ankylosis who presented with a facial deformity and a maxillary cant. Informed patient consent was obtained for participation. Simultaneous maxillomandibular distraction was planned based on clinical and radiographic examinations. A horizontal mandibular osteotomy was performed in the ramus and the distractor device was fixed. A bilateral Le Fort I osteotomy was then performed and a four-hole straight plate was fixed on the contralateral zygomatic buttress to act as a fulcrum. After a latency period of 5 days, the distractor was activated twice daily by 0.5mm until the required vertical lengthening was achieved. Intermaxillary fixation was maintained during the entire distraction period. After a consolidation period of 8-12 weeks, the distractor was removed. The TMJ ankylosis was released and a temporal fascia interpositional arthroplasty was performed as second surgery, along with a genioplasty if needed. All patients were followed up for a period of 12-24 months. A marked improvement in the facial asymmetry was noted in all cases. The occlusal cant and mandibular retrusion improved satisfactorily, and the average postoperative inter-incisal opening was 35.6mm. Pre-arthroplasty simultaneous maxillomandibular distraction offers a good treatment outcome, as it allows improvements in facial aesthetics as well as function. PMID:26780926

  13. Genomic organization of the human osteopontin gene: Exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.

    SciTech Connect

    Crosby, A.H.; Edwards, S.J.; Murray, J.C.

    1995-05-01

    Osteopontin (SPP1) is the principal phosphorylated glycoprotein of bone that is also expressed in a limited number of other tissues including dentine. In the current investigation the authors report the genomic organization of the SPP1 gene, which comprises seven exons, six of which contain coding sequence. The splice sites for exon donor and acceptor positions are in close agreement with previously published consensus sequences. Comparison of the human gene with its murine and bovine counterparts revealed a highly homologous organization. A highly informative short tandem repeat polymorphism isolated at the SPP1 locus showed no recombination with the autosomal dominant disorder dentinogenesis imperfecta type II. Nevertheless, sequencing of each exon in individuals affected by this disorder failed to reveal any disease-specific mutations. 25 refs., 2 figs., 2 tabs.

  14. Automatic Prosodic Analysis to Identify Mild Dementia

    PubMed Central

    Gonzalez-Moreira, Eduardo; Torres-Boza, Diana; Kairuz, Héctor Arturo; Ferrer, Carlos; Garcia-Zamora, Marlene; Espinoza-Cuadros, Fernando; Hernandez-Gómez, Luis Alfonso

    2015-01-01

    This paper describes an exploratory technique to identify mild dementia by assessing the degree of speech deficits. A total of twenty participants were used for this experiment, ten patients with a diagnosis of mild dementia and ten participants like healthy control. The audio session for each subject was recorded following a methodology developed for the present study. Prosodic features in patients with mild dementia and healthy elderly controls were measured using automatic prosodic analysis on a reading task. A novel method was carried out to gather twelve prosodic features over speech samples. The best classification rate achieved was of 85% accuracy using four prosodic features. The results attained show that the proposed computational speech analysis offers a viable alternative for automatic identification of dementia features in elderly adults. PMID:26558287

  15. Automatic Prosodic Analysis to Identify Mild Dementia.

    PubMed

    Gonzalez-Moreira, Eduardo; Torres-Boza, Diana; Kairuz, Héctor Arturo; Ferrer, Carlos; Garcia-Zamora, Marlene; Espinoza-Cuadros, Fernando; Hernandez-Gómez, Luis Alfonso

    2015-01-01

    This paper describes an exploratory technique to identify mild dementia by assessing the degree of speech deficits. A total of twenty participants were used for this experiment, ten patients with a diagnosis of mild dementia and ten participants like healthy control. The audio session for each subject was recorded following a methodology developed for the present study. Prosodic features in patients with mild dementia and healthy elderly controls were measured using automatic prosodic analysis on a reading task. A novel method was carried out to gather twelve prosodic features over speech samples. The best classification rate achieved was of 85% accuracy using four prosodic features. The results attained show that the proposed computational speech analysis offers a viable alternative for automatic identification of dementia features in elderly adults. PMID:26558287

  16. Bilateral internuclear ophthalmoplegia following mild head injury.

    PubMed

    Muthukumar, N; Veerarajkumar, N; Madeswaran, K

    2001-05-01

    A 7-year-old child presented with bilateral internuclear ophthalmoplegia (INO) following a trivial head injury. CT was normal. MRI revealed a pontine lesion. Two months after the injury the patient was neurologically normal. INO following head injury is rare. Rarer still is INO following mild head injury. To date, only four cases of INO had been reported following mild head injury; the present case is the fifth and the first in which the lesion was documented using MRI. The relevant literature is reviewed. PMID:11417420

  17. Stimulatory effects of the degradation products from Mg-Ca-Sr alloy on the osteogenesis through regulating ERK signaling pathway.

    PubMed

    Li, Mei; He, Peng; Wu, Yuanhao; Zhang, Yu; Xia, Hong; Zheng, Yufeng; Han, Yong

    2016-01-01

    The influence of Mg-1Ca-xwt.% Sr (x = 0.2, 0.5, 1.0, 2.0) alloys on the osteogenic differentiation and mineralization of pre-osteoblast MC3T3-E1 were studied through typical differentiation markers, such as intracellular alkaline phosphatase (ALP) activity, extracellular collagen secretion and calcium nodule formation. It was shown that Mg-1Ca alloys with different content of Sr promoted cell viability and enhanced the differentiation and mineralization levels of osteoblasts, and Mg-1Ca-2.0Sr alloy had the most remarkable and significant effect among all. To further investigate the underlying mechanisms, RT-PCR and Western Blotting assays were taken to analyze the mRNA expression level of osteogenesis-related genes and intracellular signaling pathways involved in osteogenesis, respectively. RT-PCR results showed that Mg-1Ca-2.0Sr alloy significantly up-regulated the expressions of the transcription factors of Runt-related transcription factor 2 (RUNX2) and Osterix (OSX), Integrin subunits, as well as alkaline phosphatase (ALP), Bone sialoprotein (BSP), Collagen I (COL I), Osteocalcin (OCN) and Osteopontin (OPN). Western Blotting results suggested that Mg-1Ca-2.0Sr alloy rapidly induced extracellular signal-regulated kinase (ERK) activation but showed no obvious effects on c-Jun N terminal kinase (JNK) and p38 kinase of MAPK. Taken together, our results demonstrated that Mg-1Ca-2.0Sr alloy had excellent biocompatibility and osteogenesis via the ERK pathway and is expected to be promising as orthopedic implants and bone repair materials. PMID:27580744

  18. Stimulatory effects of the degradation products from Mg-Ca-Sr alloy on the osteogenesis through regulating ERK signaling pathway

    PubMed Central

    Li, Mei; He, Peng; Wu, Yuanhao; Zhang, Yu; Xia, Hong; Zheng, Yufeng; Han, Yong

    2016-01-01

    The influence of Mg-1Ca-xwt.% Sr (x = 0.2, 0.5, 1.0, 2.0) alloys on the osteogenic differentiation and mineralization of pre-osteoblast MC3T3-E1 were studied through typical differentiation markers, such as intracellular alkaline phosphatase (ALP) activity, extracellular collagen secretion and calcium nodule formation. It was shown that Mg-1Ca alloys with different content of Sr promoted cell viability and enhanced the differentiation and mineralization levels of osteoblasts, and Mg-1Ca-2.0Sr alloy had the most remarkable and significant effect among all. To further investigate the underlying mechanisms, RT-PCR and Western Blotting assays were taken to analyze the mRNA expression level of osteogenesis-related genes and intracellular signaling pathways involved in osteogenesis, respectively. RT-PCR results showed that Mg-1Ca-2.0Sr alloy significantly up-regulated the expressions of the transcription factors of Runt-related transcription factor 2 (RUNX2) and Osterix (OSX), Integrin subunits, as well as alkaline phosphatase (ALP), Bone sialoprotein (BSP), Collagen I (COL I), Osteocalcin (OCN) and Osteopontin (OPN). Western Blotting results suggested that Mg-1Ca-2.0Sr alloy rapidly induced extracellular signal-regulated kinase (ERK) activation but showed no obvious effects on c-Jun N terminal kinase (JNK) and p38 kinase of MAPK. Taken together, our results demonstrated that Mg-1Ca-2.0Sr alloy had excellent biocompatibility and osteogenesis via the ERK pathway and is expected to be promising as orthopedic implants and bone repair materials. PMID:27580744

  19. Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner

    PubMed Central

    Lohanatha, Ferenz L.; Hahne, Martin; Strehl, Cindy; Fangradt, Monique; Tran, Cam Loan; Schönbeck, Kerstin; Hoff, Paula; Ode, Andrea; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

    2012-01-01

    Background Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages. Methodology/Principal Findings Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O2) or hypoxic (less than 2% O2) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis. Conclusions/Significance Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches. PMID:23029528

  20. Hierarchical bioceramic scaffolds with 3D-plotted macropores and mussel-inspired surface nanolayers for stimulating osteogenesis.

    PubMed

    Xu, Mengchi; Zhai, Dong; Xia, Lunguo; Li, Hong; Chen, Shiyi; Fang, Bing; Chang, Jiang; Wu, Chengtie

    2016-07-14

    The hierarchical structure of biomaterials plays an important role in the process of tissue reconstruction and regeneration. 3D-plotted scaffolds have been widely used for bone tissue engineering due to their controlled macropore structure and mechanical properties. However, the lack of micro- or nano-structures on the strut surface of 3D-plotted scaffolds, especially for bioceramic scaffolds, limits their biological activity. Inspired by the adhesive versatility of mussels and the active ion-chelating capacity of polydopamine, we set out to prepare a hierarchical bioceramic scaffold with controlled macropores and mussel-inspired surface nanolayers by combining the 3D-plotting technique with the polydopamine/apatite hybrid strategy in order to synergistically accelerate the osteogenesis and angiogenesis. β-Tricalcium phosphate (TCP) scaffolds were firstly 3D-plotted and then treated in dopamine-Tris/HCl and dopamine-SBF solutions to obtain TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds, respectively. It was found that polydopamine/apatite hybrid nanolayers were formed on the surface of both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds and TCP-DOPA-SBF scaffolds induced apatite mineralization for the second time during the cell culture. As compared to TCP scaffolds, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly promoted the osteogenesis of bone marrow stromal cells (BMSCs) as well as the angiogenesis of human umbilical vein endothelial cells (HUVECs), and the TCP-DOPA-SBF group presented the highest in vitro osteogenic/angiogenic activity among the three groups. Furthermore, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly improved the formation of new bone in vivo as compared to TCP scaffolds without a nanostructured surface. Our results suggest that the utilization of a mussel-inspired Ca, P-chelated polydopamine nanolayer on 3D-plotted bioceramic scaffolds is a viable and effective strategy to construct a hierarchical structure for synergistically

  1. Enhancement of osteogenesis and biodegradation control by brushite coating on Mg-Nd-Zn-Zr alloy for mandibular bone repair.

    PubMed

    Guan, Xingmin; Xiong, Meiping; Zeng, Feiyue; Xu, Bin; Yang, Lingdi; Guo, Han; Niu, Jialin; Zhang, Jian; Chen, Chenxin; Pei, Jia; Huang, Hua; Yuan, Guangyin

    2014-12-10

    To diminish incongruity between bone regeneration and biodegradation of implant magnesium alloy applied for mandibular bone repair, a brushite coating was deposited on a matrix of a Mg-Nd-Zn-Zr (hereafter, denoted as JDBM) alloy to control the degradation rate of the implant and enhance osteogenesis of the mandible bone. Both in vitro and in vivo evaluations were carried out in the present work. Viability and adhesion assays of rabbit bone marrow mesenchyal stem cells (rBM-MSCs) were applied to determine the biocompatibility of a brushite-coated JDBM alloy. Osteogenic gene expression was characterized by quantitative real-time polymerase chain reaction (RT-PCR). Brushite-coated JDBM screws were implanted into mandible bones of rabbits for 1, 4, and 7 months, respectively, using 316L stainless steel screws as a control group. In vivo biodegradation rate was determined by synchrotron radiation X-ray microtomography, and osteogenesis was observed and evaluated using Van Gieson's picric acid-fuchsin. Both the naked JDBM and brushite-coated JDBM samples revealed adequate biosafety and biocompatibility as bone repair substitutes. In vitro results showed that brushite-coated JDBM considerably induced osteogenic differentiation of rBM-MSCs. And in vivo experiments indicated that brushite-coated JDBM screws presented advantages in osteoconductivity and osteogenesis of mandible bone of rabbits. Degradation rate was suppressed at a lower level at the initial stage of implantation when new bone tissue formed. Brushite, which can enhance oeteogenesis and partly control the degradation rate of an implant, is an appropriate coating for JDBM alloys used for mandibular repair. The Mg-Nd-Zn-Zr alloy with brushite coating possesses great potential for clinical applications for mandibular repair. PMID:25343576

  2. Osteogenesis and cytotoxicity of a new Carbon Fiber/Flax/Epoxy composite material for bone fracture plate applications.

    PubMed

    Bagheri, Zahra S; Giles, Erica; El Sawi, Ihab; Amleh, Asma; Schemitsch, Emil H; Zdero, Radovan; Bougherara, Habiba

    2015-01-01

    This study is part of an ongoing program to develop a new CF/Flax/Epoxy bone fracture plate to be used in orthopedic trauma applications. The purpose was to determine this new plate's in-vitro effects on the level of bone formation genes, as well as cell viability in comparison with a medical grade metal (i.e. stainless steel) commonly employed for fabrication of bone plates (positive control). Cytotoxicity and osteogenesis induced by wear debris of the material were assessed using Methyl Tetrazolium (MTT) assay and reverse transcription polymerase chain reaction (RT-PCR) for 3 osteogenesis specific gene markers, including bone morphogenetic proteins (BMP2), runt-related transcription factor 2 (Runx2) and Osterix. Moreover, the Flax/Epoxy and CF/Epoxy composites were examined separately for their wettability properties by water absorption and contact angle (CA) tests using the sessile drop technique. The MTT results for indirect and direct assays indicated that the CF/Flax/Epoxy composite material showed comparable cell viability with no cytotoxicity at all incubation times to that of the metal group (p≥0.05). Osteogenesis test results showed that the expression level of Runx2 marker induced by CF/Flax/Epoxy were significantly higher than those induced by metal after 48 h (p=0.57). Also, the Flax/Epoxy composite revealed a hydrophilic character (CA=68.07°±2.05°) and absorbed more water up to 17.2% compared to CF/Epoxy, which reached 1.25% due to its hydrophobic character (CA=93.22°±1.95°) (p<0.001). Therefore, the new CF/Flax/Epoxy may be a potential candidate for medical applications as a bone fracture plate, as it showed similar cell viability with no negative effect on gene expression levels responsible for bone formation compared to medical grade stainless steel. PMID:25492008

  3. Cyclic stretch promotes osteogenesis-related gene expression in osteoblast-like cells through a cofilin-associated mechanism.

    PubMed

    Gao, Jie; Fu, Shanmin; Zeng, Zhaobin; Li, Feifei; Niu, Qiannan; Jing, Da; Feng, Xue

    2016-07-01

    Osteoblasts have the capacity to perceive and transduce mechanical signals, and thus, regulate the mRNA and protein expression of a variety of genes associated with osteogenesis. Cytoskeletal reconstruction, as one of the earliest perception events for external mechanical stimulation, has previously been demonstrated to be essential for mechanotransduction in bone cells. However, the mechanism by which mechanical signals induce cytoskeletal deformation remains poorly understood. The actin‑binding protein, cofilin, promotes the depolymerization of actin and is understood to be important in the regulation of activities in various cell types, including endothelial, neuronal and muscle cells. However, to the best of our knowledge, the importance of cofilin in osteoblastic mechanotransduction has not been previously investigated. In the present study, osteoblast‑like MG‑63 cells were subjected to physiological cyclic stretch stimulation (12% elongation) for 1, 4, 8, 12 and 24 h, and the expression levels of cofilin and osteogenesis-associated genes were quantified with reverse transcription‑quantitative polymerase chain reaction, immunofluorescence staining and western blotting analyses. Additionally, knockdown of cofilin using RNA interference was conducted, and the mRNA levels of osteogenesis‑associated genes were compared between osteoblast‑like cells in the presence and absence of cofilin gene knockdown. The results of the present study demonstrated that cyclic stretch stimulates the expression of genes associated with osteoblastic activities in MG‑63 cells, including alkaline phosphatase (ALP), osteocalcin (OCN), runt‑related transcription factor 2 (Runx2) and collagen‑1 (COL‑1). Cyclic stretch also regulates the mRNA and protein expression of cofilin in MG‑63 cells. Furthermore, stretch‑induced increases in the levels of osteogenesis-associated genes, including ALP, OCN, Runx2 and COL‑1, were reduced following cofilin gene knockdown

  4. Beyond osteogenesis: an in vitro comparison of the potentials of six bone morphogenetic proteins.

    PubMed

    Rivera, Jessica C; Strohbach, Cassandra A; Wenke, Joseph C; Rathbone, Christopher R

    2013-01-01

    Bone morphogenetic proteins (BMPs) other than the clinically available BMP-2 and BMP-7 may be useful for improving fracture healing through both increasing osteogenesis and creating a favorable healing environment by altering cytokine release by endogenous cells. Given the spectrum of potential applications for BMPs, the objective of this study was to evaluate various BMPs under a variety of conditions to provide further insight into their therapeutic capabilities. The alkaline phosphatase (ALP) activity of both C2C12 and human adipose-derived stem cells (hASCs) was measured after exposure of increasing doses of recombinant human BMP-2, -4, -5, -6, -7, or -9 for 3 and 7 days. BMPs-2, -4, -5, -6, -7, and -9 were compared in terms of their ability to affect the release of stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (b-FGF) from human bone marrow stromal cells (hBMSCs). Gene expression of ALP, osteocalcin, SDF-1, VEGF, and b-FGF following shRNA-mediated knockdown of BMP-2 and BMP-6 in hBMSCs or human osteoblasts under osteogenic differentiation conditions was also evaluated. Collectively, BMPs-6 and -9 produced the greatest osteogenic differentiation of C2C12 and hASCs as determined by ALP. The hBMSC secretion of SDF-1 was most affected by BMP-5, VEGF by BMP-4, and b-FGF by BMP-2. The knockdown of BMP-2 in BMSCs had no effect on any of the genes measured whereas BMP-6 knockdown in hBMSCs caused a significant increase in VEGF gene expression. BMP-2 and BMP-6 knockdown in human osteoblasts caused significant increases in VEGF gene expression and trends toward decreases in osteocalcin expression. These findings support efforts to study other BMPs as potential bone graft supplements, and to consider combined BMP delivery for promotion of multiple aspects of fracture healing. PMID:24101902

  5. Minocycline Loaded Hybrid Composites Nanoparticles for Mesenchymal Stem Cells Differentiation into Osteogenesis.

    PubMed

    Tham, Allister Yingwei; Gandhimathi, Chinnasamy; Praveena, Jayaraman; Venugopal, Jayarama Reddy; Ramakrishna, Seeram; Kumar, Srinivasan Dinesh

    2016-01-01

    Bone transplants are used to treat fractures and increase new tissue development in bone tissue engineering. Grafting of massive implantations showing slow curing rate and results in cell death for poor vascularization. The potentials of biocomposite scaffolds to mimic extracellular matrix (ECM) and including new biomaterials could produce a better substitute for new bone tissue formation. A purpose of this study is to analyze polycaprolactone/silk fibroin/hyaluronic acid/minocycline hydrochloride (PCL/SF/HA/MH) nanoparticles initiate human mesenchymal stem cells (MSCs) proliferation and differentiation into osteogenesis. Electrospraying technique was used to develop PCL, PCL/SF, PCL/SF/HA and PCL/SF/HA/MH hybrid biocomposite nanoparticles and characterization was analyzed by field emission scanning electron microscope (FESEM), contact angle and Fourier transform infrared spectroscopy (FT-IR). The obtained results proved that the particle diameter and water contact angle obtained around 0.54 ± 0.12 to 3.2 ± 0.18 µm and 43.93 ± 10.8° to 133.1 ± 12.4° respectively. The cell proliferation and cell-nanoparticle interactions analyzed using (3-(4,5-dimethyl thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt) MTS assay (Promega, Madison, WI, USA), FESEM for cell morphology and 5-Chloromethylfluorescein diacetate (CMFDA) dye for imaging live cells. Osteogenic differentiation was proved by expression of osteocalcin, alkaline phosphatase activity (ALP) and mineralization was confirmed by using alizarin red (ARS). The quantity of cells was considerably increased in PCL/SF/HA/MH nanoparticles when compare to all other biocomposite nanoparticles and the cell interaction was observed more on PCL/SF/HA/MH nanoparticles. The electrosprayed PCL/SF/HA/MH biocomposite nanoparticle significantly initiated increased cell proliferation, osteogenic differentiation and mineralization, which provide huge potential for bone tissue engineering. PMID

  6. Combined use of alveolar distraction osteogenesis and segmental osteotomy in anterior vertical ridge augmentation

    PubMed Central

    Öncü, Elif; Isik, Kubilay; Alaaddinoğlu, E. Emine; Uçkan, Sina

    2015-01-01

    Introduction Vertical defects of the anterioral veolar ridge are challenging cases in implant dentistry. Various techniques, such as onlay bone grafting, segmental osteotomy (SO) oral veolar distraction osteogenesis (ADO), have been suggested to manage those situations. ADO has an advantage of being capable of enhancing both hard and soft tissue simultaneously. Presentation of case One of the possible complications of ADO is rotation ortilting the transport segment (TS). In this report, we present a 30-year old woman who had a severe anterior vertical deficiency. ADO was started to manage the case, but advancement of the TS lagged on the left side and the segment rotated. A SO was planned and the lagged side was corrected. Two years after the surgery, hard and soft tissue gains were found to be preserved. Discussion Vertical alveolar bone deficiencies are challenging cases for dental implantology. Alveolar DO promotes soft tissue along with hard tissue, and the bone regeneration process and shows lower infection rates and greater stability over the long term. However, the technique has some disadvantages and can lead to complications, such as breaking of the distraction device, nerve injury or paresthesia, fracture of transport bone, hematoma, wound dehiscence, severe bleeding, and even jaw fractures. Deviation of the TS from the distraction path is another undesired situation. The rigidity of the device, the width of the mucosa, the volume of the transport and anchor segments, and the amount of augmentation can affect vector deviation. Conclusion We suggest that SO can be used in similar cases in which TS could not be distracted on a straight vector line. PMID:25661636

  7. BONE REGENERATION AND DOCKING SITE HEALING AFTER BONE TRANSPORT DISTRACTION OSTEOGENESIS IN THE CANINE MANDIBLE

    PubMed Central

    Nagashima, Lucy K; Newby, Michelle Rondon; Zakhary, Ibrahim E; Nagy, William W; Zapata, Uriel; Dechow, Paul C; Opperman, Lynne A; Elsalanty, Mohammed E

    2011-01-01

    Purpose Bone transport distraction osteogenesis (BTDO) provides a promising alternative to traditional grafting techniques. However, existing BTDO devices have many limitations. The purpose of this research was to test a new device, the mandibular bone transport reconstruction plate (BTRP), in an animal model with comparable mandible size to humans and to histologically and mechanically examine the regenerate bone. Materials and methods Eleven adult foxhound dogs were divided into an unreconstructed control group of 5 animals, and an experimental group of 6 animals. In each animal, a 34 mm segmental defect was created in the mandible. The defect was reconstructed with BTRP. Histological and biomechanical characteristics of the regenerate and un-repaired defect were analyzed and compared to bone on the contralateral side of the mandible after 4 weeks of consolidation. Results The reconstructed defect was bridged with new bone, with little bone in the control defect. Regenerate density and microhardness were 22.3% and 42.6% lower than the contralateral normal bone, respectively. Likewise, the anisotropy of the experimental group was statistically lower than in the contralateral bone. Half the experimental animals showed non-union at the docking site. Conclusion The device was very stable and easy to install and activate. After one month of consolidation, the defect has been bridged with new bone with evidence of active bone formation. Regenerate bone was less mature than the control bone. Studies are underway to identify when the regenerate properties compare to normal bone, and to identify methods to augment bone union at the docking site. PMID:21601342

  8. Bioactive cell-derived matrices combined with polymer mesh scaffold for osteogenesis and bone healing.

    PubMed

    Kim, In Gul; Hwang, Mintai P; Du, Ping; Ko, Jaehoon; Ha, Chul-won; Do, Sun Hee; Park, Kwideok

    2015-05-01

    Successful bone tissue engineering generally requires an osteoconductive scaffold that consists of extracellular matrix (ECM) to mimic the natural environment. In this study, we developed a PLGA/PLA-based mesh scaffold coated with cell-derived extracellular matrix (CDM) for the delivery of bone morphogenic protein (BMP-2), and assessed the capacity of this system to provide an osteogenic microenvironment. Decellularized ECM from human lung fibroblasts (hFDM) was coated onto the surface of the polymer mesh scaffolds, upon which heparin was then conjugated onto hFDM via EDC chemistry. BMP-2 was subsequently immobilized onto the mesh scaffolds via heparin, and released at a controlled rate. Human placenta-derived mesenchymal stem cells (hPMSCs) were cultured in such scaffolds and subjected to osteogenic differentiation for 28 days in vitro. The results showed that alkaline phosphatase (ALP) activity, mineralization, and osteogenic marker expression were significantly improved with hPMSCs cultured in the hFDM-coated mesh scaffolds compared to the control and fibronectin-coated ones. In addition, a mouse ectopic and rat calvarial bone defect model was used to examine the feasibility of current platform to induce osteogenesis as well as bone regeneration. All hFDM-coated mesh groups exhibited a significant increase of newly formed bone and in particular, hFDM-coated mesh scaffold loaded with a high dose of BMP-2 exhibited a nearly complete bone defect healing as confirmed via micro-CT and histological observation. This work proposes a great potency of using hFDM (biophysical) coupled with BMP-2 (biochemical) as a promising osteogenic microenvironment for bone tissue engineering applications. PMID:25736498

  9. Comparison of two protocols of periosteal distraction osteogenesis in a rabbit calvaria model.

    PubMed

    Saulacic, Nikola; Nakahara, Ken; Iizuka, Tateyuki; Haga-Tsujimura, Maiko; Hofstetter, Willy; Scolozzi, Paolo

    2016-08-01

    The regenerative pathways during periosteal distraction osteogenesis may be influenced by the local environment composed by cells, growth factors, nutrition and mechanical load. The aim of the present study was to evaluate the influence of two protocols of periosteal distraction on bone formation. Custom made distraction devices were surgically fixed onto the calvariae of 60 rabbits. After an initial healing period of 7 days, two groups of animals were submitted to distraction rates of 0.25 and 0.5 mm/24 h for 10 days, respectively. Six animals per group were sacrificed 10 (mid-distraction), 17 (end-distraction), 24 (1-week consolidation), 31 (2-week consolidation) and 77 days (2-month consolidation) after surgery. Newly formed bone was assessed by means of micro-CT and histologically. Expression of transcripts encoding tissue-specific genes (BMP-2, RUNX2, ACP5, SPARC, collagen I α1, collagen II α1 and SOX9) was analyzed by quantitative PCR. Two patterns of bone formation were observed, originating from the old bone surface in Group I and from the periosteum in Group II. Bone volume (BV) and bone mineral density (BMD) significantly increased up to the 2-month consolidation period within the groups (p < 0.05). Significantly more bone was observed in Group II compared to Group I at the 2-month consolidation period (p < 0.001). Expression of transcripts encoding osteogenic genes in bone depended on the time-point of observation (p < 0.05). Low level of transcripts reveals an indirect role of periosteum in the osteogenic process. Two protocols of periosteal distraction in the present model resulted in moderate differences in terms of bone formation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1121-1131, 2016. PMID:26036193

  10. Enhanced osteogenesis on titanium implants by UVB photofunctionalization of hydrothermally grown TiO₂ coatings.

    PubMed

    Lorenzetti, Martina; Dakischew, Olga; Trinkaus, Katja; Lips, Katrin Susanne; Schnettler, Reinhard; Kobe, Spomenka; Novak, Saša

    2015-07-01

    Even though Ti-based implants are the most used materials for hard tissue replacement, they may present lack of osseointegration on the long term, due to their inertness. Hydrothermal treatment (HT) is a useful technique for the synthesis of firmly attached, highly crystalline coatings made of anatase titanium dioxide (TiO2), providing favorable nanoroughness and higher exposed surface area, as well as greater hydrophilicity, compared to the native amorphous oxide on pristine titanium. The hydrophilicity drops even more by photofunctionalization of the nanostructured TiO2-anatase coatings under UV light. Human mesenchymal stem cells exhibited a good response to the combination of the positive surface characteristics, especially in respect to the UVB pre-irradiation. The results showed that the cells were not harmed in terms of viability; even more, they were encouraged to differentiate in osteoblasts and to become osteogenically active, as confirmed by the calcium ion uptake and the formation of well-mineralized, bone-like nodule structures. In addition, the enrichment of hydroxyl groups on the HT-surfaces by UVB photofunctionalization accelerated the cell differentiation process and greatly improved the osteogenesis in comparison with the nonirradiated samples. The optimal surface characteristics of the HT-anatase coatings as well as the high potentiality of the photo-induced hydrophilicity, which was reached during a relatively short pre-irradiation time (5 h) with UVB light, can be correlated with better osseointegration ability in vivo; among the samples, the superior biological behavior of the roughest and most hydrophilic HT coating makes it a good candidate for further studies and applications. PMID:25633960

  11. Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice

    PubMed Central

    Du, Er-Xia; Wang, Xiao-Fang; Yang, Wu-Chen; Kaback, Deborah; Yee, Siu-Pok; Qin, Chun-Lin; George, Anne; Hao, Jian-Jun

    2015-01-01

    Our previous studies have demonstrated that Fam20C promotes differentiation and mineralization of odontoblasts, ameloblasts, osteoblasts and osteocytes during tooth and bone development. Ablation of the Fam20C gene inhibits bone and tooth growth by increasing fibroblast growth factor 23 in serum and causing hypophosphatemia in conditional knockout mice. However, control and regulation of the expression of Fam20C are still unknown. In this study, we generated a transgenic reporter model which expresses green fluorescence protein (GFP) driven by the Fam20C promoter. Recombineering was used to insert a 16 kb fragment of the mouse Fam20C gene (containing the 15 kb promoter and 1.1 kb of exon 1) into a pBluescript SK vector with the topaz variant of GFP and a bovine growth hormone polyadenylation sequence. GFP expression was subsequently evaluated by histomorphometry on cryosections from E14 to adult mice. Fluorescence was evident in the bone and teeth as early as E17.5. The GFP signal was maintained stably in odontoblasts and osteoblasts until 4 weeks after birth. The expression of GFP was significantly reduced in teeth, alveolar bone and muscle by 8 weeks of age. We also observed colocalization of the GFP signal with the Fam20C antibody in postnatal 1- and 7-day-old animals. Successful generation of Fam20C-GFP transgenic mice will provide a unique model for studying Fam20C gene expression and the biological function of this gene during odontogenesis and osteogenesis. PMID:25537657

  12. Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice.

    PubMed

    Du, Er-Xia; Wang, Xiao-Fang; Yang, Wu-Chen; Kaback, Deborah; Yee, Siu-Pok; Qin, Chun-Lin; George, Anne; Hao, Jian-Jun

    2015-06-01

    Our previous studies have demonstrated that Fam20C promotes differentiation and mineralization of odontoblasts, ameloblasts, osteoblasts and osteocytes during tooth and bone development. Ablation of the Fam20C gene inhibits bone and tooth growth by increasing fibroblast growth factor 23 in serum and causing hypophosphatemia in conditional knockout mice. However, control and regulation of the expression of Fam20C are still unknown. In this study, we generated a transgenic reporter model which expresses green fluorescence protein (GFP) driven by the Fam20C promoter. Recombineering was used to insert a 16 kb fragment of the mouse Fam20C gene (containing the 15 kb promoter and 1.1 kb of exon 1) into a pBluescript SK vector with the topaz variant of GFP and a bovine growth hormone polyadenylation sequence. GFP expression was subsequently evaluated by histomorphometry on cryosections from E14 to adult mice. Fluorescence was evident in the bone and teeth as early as E17.5. The GFP signal was maintained stably in odontoblasts and osteoblasts until 4 weeks after birth. The expression of GFP was significantly reduced in teeth, alveolar bone and muscle by 8 weeks of age. We also observed colocalization of the GFP signal with the Fam20C antibody in postnatal 1- and 7-day-old animals. Successful generation of Fam20C-GFP transgenic mice will provide a unique model for studying Fam20C gene expression and the biological function of this gene during odontogenesis and osteogenesis. PMID:25537657

  13. Simulated Body Fluid Nucleation of Three-Dimensional Printed Elastomeric Scaffolds for Enhanced Osteogenesis.

    PubMed

    Castro, Nathan J; Tan, Wilhelmina Nanrui; Shen, Charlie; Zhang, Lijie Grace

    2016-07-01

    Osseous tissue defects caused by trauma present a common clinical problem. Although traditional clinical procedures have been successfully employed, several limitations persist with regards to insufficient donor tissue, disease transmission, and inadequate host-implant integration. Therefore, this work aims to address current limitations regarding inadequate host tissue integration through the use of a novel elastomeric material for three-dimensional (3D) printing biomimetic and bioactive scaffolds. A novel thermoplastic polyurethane-based elastomeric composite filament (Gel-Lay) was used to manufacture porous scaffolds. In an effort to render the scaffolds more bioactive, the flexible scaffolds were subsequently incubated in simulated body fluid at various time points and evaluated for enhanced mechanical properties along with the effects on cell adhesion, proliferation, and 3-week osteogenesis. This work is the first reported use of a novel class of flexible elastomeric materials for the manufacture of 3D printed bioactive scaffold fabrication allowing efficient and effective nucleation of hydroxyapatite (HA) leading to increased nanoscale surface roughness while retaining the bulk geometry of the predesigned structure. Scaffolds with interconnected microfibrous filaments of ∼260 μm were created and nucleated in simulated body fluid that facilitated cell adhesion and spreading after only 24 h in culture. The porous structure further allowed efficient nucleation, exchange of nutrients, and metabolic waste removal during new tissue formation. Through the incorporation of osteoconductive HA, human fetal osteoblast adhesion and differentiation were greatly enhanced thus setting the tone for further exploration of this novel material for biomedical and tissue regenerative applications. PMID:27298115

  14. Beneficial role of periosteum in distraction osteogenesis of mandible: its preservation prevents the external bone resorption.

    PubMed

    Takeuchi, Sawako; Matsuo, Akira; Chiba, Hiroshige

    2010-01-01

    Distraction osteogenesis (DO) is a surgical process of new bone generation through the gradual extension of two segments of existing bone. DO is applied for maxillofacial surgeries to manage defects in mandibular continuity. Vertical DO with an oral device is often employed to augment the alveolar bone height for better implant anchorage for esthetic purposes or functional prosthetic requirements. To determine how the periosteum affects the vertical DO in mandibular reconstruction, we extracted the teeth and resected the alveolar parts of the mandible on both sides of dogs, along with removal of the surrounding periosteum in the right, but not left side. Three months later, box-shaped bone segments (vectors) were prepared from the resected alveolar part, and the segments were vertically elongated using a distraction device on both sides at 0.9 mm/day for one week. The extent of bone formation after distraction was determined with micro-focused computed tomography and by measuring incorporation of tetracycline and calcein with confocal laser scanning microscopy. During the initial two months after distraction, new bone formation was observed more prominently in the left side than in the right side of mandible with the periosteum. However, this difference was less clear during the bone-remodeling period. One notable change was the reduced height of the alveolar part of the right-side mandible, a sign of external bone resorption, observed in two out of three dogs at 6-month post-consolidation. These findings suggest that preservation of periosteum prevents the external bone resorption during the vertical DO of mandible. PMID:20046054

  15. Minocycline Loaded Hybrid Composites Nanoparticles for Mesenchymal Stem Cells Differentiation into Osteogenesis

    PubMed Central

    Tham, Allister Yingwei; Gandhimathi, Chinnasamy; Praveena, Jayaraman; Venugopal, Jayarama Reddy; Ramakrishna, Seeram; Kumar, Srinivasan Dinesh

    2016-01-01

    Bone transplants are used to treat fractures and increase new tissue development in bone tissue engineering. Grafting of massive implantations showing slow curing rate and results in cell death for poor vascularization. The potentials of biocomposite scaffolds to mimic extracellular matrix (ECM) and including new biomaterials could produce a better substitute for new bone tissue formation. A purpose of this study is to analyze polycaprolactone/silk fibroin/hyaluronic acid/minocycline hydrochloride (PCL/SF/HA/MH) nanoparticles initiate human mesenchymal stem cells (MSCs) proliferation and differentiation into osteogenesis. Electrospraying technique was used to develop PCL, PCL/SF, PCL/SF/HA and PCL/SF/HA/MH hybrid biocomposite nanoparticles and characterization was analyzed by field emission scanning electron microscope (FESEM), contact angle and Fourier transform infrared spectroscopy (FT-IR). The obtained results proved that the particle diameter and water contact angle obtained around 0.54 ± 0.12 to 3.2 ± 0.18 µm and 43.93 ± 10.8° to 133.1 ± 12.4° respectively. The cell proliferation and cell-nanoparticle interactions analyzed using (3-(4,5-dimethyl thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt) MTS assay (Promega, Madison, WI, USA), FESEM for cell morphology and 5-Chloromethylfluorescein diacetate (CMFDA) dye for imaging live cells. Osteogenic differentiation was proved by expression of osteocalcin, alkaline phosphatase activity (ALP) and mineralization was confirmed by using alizarin red (ARS). The quantity of cells was considerably increased in PCL/SF/HA/MH nanoparticles when compare to all other biocomposite nanoparticles and the cell interaction was observed more on PCL/SF/HA/MH nanoparticles. The electrosprayed PCL/SF/HA/MH biocomposite nanoparticle significantly initiated increased cell proliferation, osteogenic differentiation and mineralization, which provide huge potential for bone tissue engineering. PMID

  16. An animal experimental study of porous magnesium scaffold degradation and osteogenesis

    PubMed Central

    Liu, Y.J.; Yang, Z.Y.; Tan, L.L.; Li, H.; Zhang, Y.Z.

    2014-01-01

    Our objective was to observe the biodegradable and osteogenic properties of magnesium scaffolding under in vivo conditions. Twelve 6-month-old male New Zealand white rabbits were randomly divided into two groups. The chosen operation site was the femoral condyle on the right side. The experimental group was implanted with porous magnesium scaffolds, while the control group was implanted with hydroxyapatite scaffolds. X-ray and blood tests, which included serum magnesium, alanine aminotransferase (ALT), creatinine (CREA), and blood urea nitrogen (BUN) were performed serially at 1, 2, and 3 weeks, and 1, 2, and 3 months. All rabbits were killed 3 months postoperatively, and the heart, kidney, spleen, and liver were analyzed with hematoxylin and eosin (HE) staining. The bone samples were subjected to microcomputed tomography scanning (micro-CT) and hard tissue biopsy. SPSS 13.0 (USA) was used for data analysis, and values of P<0.05 were considered to be significant. Bubbles appeared in the X-ray of the experimental group after 2 weeks, whereas there was no gas in the control group. There were no statistical differences for the serum magnesium concentrations, ALT, BUN, and CREA between the two groups (P>0.05). All HE-stained slices were normal, which suggested good biocompatibility of the scaffold. Micro-CT showed that magnesium scaffolds degraded mainly from the outside to inside, and new bone was ingrown following the degradation of magnesium scaffolds. The hydroxyapatite scaffold was not degraded and had fewer osteoblasts scattered on its surface. There was a significant difference in the new bone formation and scaffold bioabsorption between the two groups (9.29±1.27 vs 1.40±0.49 and 7.80±0.50 vs 0.00±0.00 mm3, respectively; P<0.05). The magnesium scaffold performed well in degradation and osteogenesis, and is a promising material for orthopedics. PMID:25098717

  17. Quantitative Histologic Evidence of Amifostine Induced Cytoprotection in an Irradiated Murine Model of Mandibular Distraction Osteogenesis

    PubMed Central

    Tchanque-Fossuo, Catherine N.; Donneys, Alexis; Razdolsky, Elizabeth R.; Monson, Laura; Farberg, Aaron S.; Deshpande, Sagar S.; Sarhaddi, Deniz; Poushanchi, Behdod; Goldstein, Steven A.; Buchman, Steven R.

    2012-01-01

    Background Head and neck cancer (HNC) management requires adjuvant radiation therapy (XRT). The authors have previously demonstrated the damaging effect of a human equivalent dose of radiation (HEDR) on a murine mandibular model of distraction osteogenesis (DO). Utilizing quantitative histomorphometry (QHM), our specific aim is to objectively measure the radio-protective effects of Amifostine (AMF) on the cellular integrity and tissue quality of an irradiated and distracted regenerate. Methods Sprague Dawley rats were randomly assigned into 2 groups: XRT/DO and AMF/XRT/DO, which received AMF prior to XRT. Both groups were given HEDR in 5 fractionated doses and underwent a left mandibular osteotomy with bilateral fixator placement. Distraction to 5.1mm was followed by a 28-day consolidation period. Left hemimandibles were harvested. QHM was performed for osteocyte count (Oc), empty lacunae (EL), Bone Volume/Tissue Volume (BV/TV) and Osteoid Volume/Tissue Volume (OV/TV) ratios. Results AMF/XRT/DO exhibited bony bridging as opposed to XRT/DO fibrous unions. QHM analysis revealed statistically significant higher Oc and BV/TV ratio in AMF-treated mandibles compared with irradiated mandibles. There was a corresponding decrease in EL and the ratio of OV/TV between AMF/XRT/DO and XRT/DO. Conclusion We have successfully established the significant osseous cytoprotective and histoprotective capacity of AMF on DO in the face of XRT. AMF-sparing effect on bone cellularity correlated with an increase in bony union and elimination of fibrous union. We posit that the demonstration of similar efficacy of AMF in the clinic may allow the successful implementation of DO as a viable reconstructive option for HNC in the future. PMID:22878481

  18. Peroxisome proliferator activated receptor gamma loaded dental implant improves osteogenesis of rat mandible.

    PubMed

    Bhattarai, Govinda; Lee, Young-Hee; Yi, Ho-Keun

    2015-04-01

    Peroxisome proliferator activated receptor gamma (PPARγ) has been known for their anti-inflammatory effects. But the application of this molecule in implant-induced inflammation has not been clearly studied yet. Here, we determined in vivo anti-inflammatory and osteogenic effects of PPARγ coated dental implant in the rat mandible. We used chitosan gold nanoparticles (Ch-GNPs) as a non viral vector to carry PPARγ plasmid DNA. Ch-GNPs were conjugated with PPARγ plasmid DNA through a coacervation process. Conjugation was cast over titanium (Ti) implants (4.5 × 0.8 mm) by dipping, and implants were installed in rat mandibles. One, 2, 3, and 6 weeks post-implantation, mandibles were examined by microcomputed tomography (µCT), immunohistochemistry, hematoxylin & eosin, and tartrate resistance acid phosphatase (TRAP) staining. In vivo Ch-GNPs/PPARγcoated implants were associated with inhibition of implant induced inflammatory molecules interleukin-1β and receptor activator of nuclear factor kappa-B ligand and enhanced expression of osteogenic molecules like bone morphogenetic protein 2 and 7 (BMP-2/-7) by up-regulating anti-oxidant molecules heme oxygenase-1. µCT demonstrated that PPARγ overexpression increased the density and volume of newly formed bone surrounding the implants compared to control (n = 4; p < 0.05). Also, PPARγ reduced the number of TRAP positive cells. These results support the view that PPARγ overexpression diminishes inflammation and enhances osteogenesis around the dental implants. Thus, implant coated with anti-inflammatory molecules could have a significant utilization for the preparation of new biomaterials and may serve as prosthetic materials in patients suffering from inflammatory bone disease. PMID:24962969

  19. Automating skeletal expansion: An implant for distraction osteogenesis of the mandible

    PubMed Central

    Magill, John C.; Byl, Marten F.; Goldwaser, Batya; Papadaki, Maria; Kromann, Roger; Yates, Brent; Morency, Joseph R.; Kaban, Leonard B.; Troulis, Maria J.

    2010-01-01

    Background Distraction osteogenesis (DO) is a technique of bone lengthening that makes use of the body’s natural healing capacity. An osteotomy is created and a rigid distraction device is attached to the bone. After a latency period, the device is activated 2–4 times per day for a total of 1 mm/day of bone lengthening. This technique is used to correct a variety of congenital and acquired deformities of the mandible, midface and long bones. To shorten the treatment period and to eliminate the complications of patient activation of the device, an automated continuous distraction device would be desirable. It has been reported that continuous distraction generates adequate bone with lengthening at a rate of 2 mm/day, thereby reducing the treatment time. Method of Approach The device we describe here uses miniature high-pressure hydraulics, position feedback, and a digital controller to achieve closed-loop control of the distraction process. The implanted actuator can produce up to 40N of distraction force on linear trajectories as well as curved distraction paths. In the paper we detail the spring-powered hydraulic reservoir, controller, and user interface. Results Experiments to test the new device design were performed in a porcine cadaver head and in live pigs. In the cadaver head, the device performed an 11-day/11 mm distraction with a root-mean-squared position error of 0.09 mm. The device functioned for periods of several days in each of five live animals, though some component failures occurred, leading to design revisions. Conclusions The test series showed that the novel design of this system provides the capabilities necessary to automate distraction of the mandible. Further developments will focus on making the implanted position sensor more robust and then carrying out clinical trials. PMID:20740071

  20. Mild fetal hydronephrosis indicating vesicoureteric reflux.

    PubMed Central

    Marra, G; Barbieri, G; Moioli, C; Assael, B M; Grumieri, G; Caccamo, M L

    1994-01-01

    The management of neonates with mild hydronephrosis diagnosed antenatally is still debated. Although some of these infants are normal, it is recognised that others will have mild obstruction of the ureteropelvic junction or vesicoureteric reflux (VUR). A prospective study was performed in all newborn infants with an antenatal diagnosis of mild hydronephrosis (47 babies, 62 kidneys) born over a two year period in order to assess the frequency of VUR. Voiding cystography in 14 patients with 21 renal units showed VUR. Two patients underwent surgery and the VUR resolved; the other 12 received medical treatment. Repeat cystography was scheduled for 12-18 months later, when a high rate of spontaneous cure was observed. The remaining patients were monitored by ultrasonography but only in one case did hydronephrosis deteriorate because of the presence of severe ureteropelvic junction obstruction. It is concluded that mild dilatation of the pelvis might be an expression of a potentially severe malformation such as VUR, and a careful follow up of these cases is mandatory. Images PMID:7802758

  1. Learning Strategies for Adolescents with Mild Disabilities

    ERIC Educational Resources Information Center

    Conderman, Greg; Koman, Kara; Schibelka, Mary; Higgin, Karen; Cooper, Cody; Butler, Jordyn

    2013-01-01

    Learning strategy instruction is an evidence-based practice for teaching adolescents with mild disabilities. However, researchers have not developed strategies for every content area or skill. Therefore, teachers need to be able develop strategies based on the needs of their students. This article reviews the process for developing and teaching…

  2. Mild Traumatic Brain Injury: Facilitating School Success.

    ERIC Educational Resources Information Center

    Hux, Karen; Hacksley, Carolyn

    1996-01-01

    A case study is used to demonstrate the effects of mild traumatic brain injury on educational efforts. Discussion covers factors complicating school reintegration, ways to facilitate school reintegration, identification of cognitive and behavioral consequences, minimization of educators' discomfort, reintegration program design, and family…

  3. Hypophosphatasia

    MedlinePlus

    ... osteogenesis imperfecta. It is an inherited metabolic (chemical) bone disease that results from low levels of an enzyme ... Dr. Michael Whyte, Medical Director, Center for Metabolic Bone Disease Research at Shriners Hospital, St. Louis, Missouri, and ...

  4. Surgery Considerations for Adults and Children

    MedlinePlus

    Surgery Considerations for Adults and Children 804 W. Diamond Ave., Ste. 210 Gaithersburg, MD 20878 (800) 981- ... orbdnrc@nof.org Osteogenesis Imperfecta Foundation 804 W. Diamond Avenue Suite 210 Gaithersburg, MD 20878 Tel (800) ...

  5. Get in the Swim: Gaining Access to Recreational Facilities.

    ERIC Educational Resources Information Center

    Richard, Jean-Paul

    1980-01-01

    The father of a child with osteogenesis imperfecta, an orthopedic condition, recounts his struggles to convince local agencies to operate a swimming program for disabled students. He offers eight guidelines for advocating such programs in other areas. (CL)

  6. Bone x-ray

    MedlinePlus

    ... or broken bone Bone tumors Degenerative bone conditions Osteomyelitis (inflammation of the bone caused by an infection) ... Multiple myeloma Osgood-Schlatter disease Osteogenesis imperfecta Osteomalacia Osteomyelitis Paget disease of the bone Rickets X-ray ...

  7. Bone Diseases

    MedlinePlus

    ... avoid smoking and drinking too much alcohol. Bone diseases can make bones easy to break. Different kinds ... break Osteogenesis imperfecta makes your bones brittle Paget's disease of bone makes them weak Bones can also ...

  8. Adults Living with OI

    MedlinePlus

    ... to encourage/assist people attending conference, but it's applicable to any future travel plans. Airb ags Information ... Click here for details about the Oregon Health Science University, Portland, OR trial . © Osteogenesis Imperfecta Foundation, 2015 ...

  9. Mortality associated with mild, untreated xerophthalmia.

    PubMed Central

    Sommer, A

    1983-01-01

    The high mortality rate among children with severe corneal xerophthalmia is well recognized. The present study investigates, for the first time, mortality among the very much larger number of otherwise healthy free-living children with mild xerophthalmia (night blindness and Bitot's spots). An average of 3481 children (under 6 years of age) living in six Indonesian villages were reexamined by an ophthalmologist, pediatrician, and nutritionist every 3 months for 18 months. The overall prevalence of mild xerophthalmia was 4.9%. During the 18 months of observation, 132 children died. Of these, 24 had mild xerophthalmia and 108 had normal eyes at the 3-monthly examination preceding their death. Mortality rates were calculated for each 3-month interval by classifying all children by their ocular status at the start of the interval, and then dividing the number of deaths within the interval by the number of children of the same ocular status followed up for that interval. Mortality rates for the six 3-month intervals were then added together, and the results expressed as deaths per 1000 "child-intervals" of follow-up. Overall mortality rates for children with mild xerophthalmia and for children with normal eyes were 23.3 and 5.3, respectively, a ratio of 4 to 1. Excess mortality among the mildly xerophthalmic children increased with the severity of their xerophthalmia. Mortality rates for children with night blindness, with Bitot's spots, and with the two conditions concurrently were 2.7, 6.6, and 8.6 times the mortality rate of non-xerophthalmic children. This direct, almost linear relation between mortality and the severity of mild xerophthalmia was still present after standardizing for age and for the presence or absence of respiratory infection and protein-energy malnutrition. In the population studied, 16% of all deaths in children 1 to 6 years of age were directly related to vitamin A deficiency identified by the presence of mild xerophthalmia. These results

  10. Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis

    PubMed Central

    Wang, Yu-gang; Han, Xiu-guo; Yang, Ying; Qiao, Han; Dai, Ke-rong; Fan, Qi-ming; Tang, Ting-ting

    2016-01-01

    The endocrine role of the skeleton-which is impaired in human diseases including osteoporosis, obesity and diabetes-has been highlighted previously. In these diseases, the role of AMPK, a sensor and regulator of energy metabolism, is of biological and clinical importance. Since AMPK’s main catalytic subunit α has two isoforms, it is unclear whether functional differences between them exist in the skeletal system. The current study overexpressed AMPKα1 and α2 in MC3T3-E1 cells, primary osteoblasts and mouse BMSCs by lentiviral transduction. Cells overexpressing AMPKα2 showed higher osteogenesis potential than AMPKα1, wherein androgen receptor (AR) and osteoactivin played important roles. RANKL and M-CSF were secreted at lower levels from cells overexpressing α2 than α1, resulting in decreased osteoblast-associated osteoclastogenesis. Adipogenesis was inhibited to a greater degree in 3T3-L1 cells overexpressing α2 than α1, which was modulated by AR. An abnormal downregulation of AMPKα2 was observed in human BMSCs exhibiting the fibrous dysplasia (FD) phenotype. Overexpression of AMPKα2 in these cells rescued the defect in osteogenesis, suggesting that AMPKα2 plays a role in FD pathogenesis. These findings highlight functional differences between AMPKα1 and α2, and provide a basis for investigating the molecular mechanisms of diseases associated with impaired functioning of the skeletal system. PMID:27600021

  11. Enhanced interfacial adhesion and osteogenesis for rapid "bone-like" biomineralization by PECVD-based silicon oxynitride overlays.

    PubMed

    Ilyas, Azhar; Lavrik, Nickolay V; Kim, Harry K W; Aswath, Pranesh B; Varanasi, Venu G

    2015-07-22

    Structurally unstable fracture sites require metal fixative devices, which have long healing times due to their lack of osteoinductivity. Bioactive glass coatings lack in interfacial bonding, delaminate, and have reduced bioactivity due to the high temperatures used for their fabrication. Here, we test the hypothesis that low-temperature PECVD amorphous silica can enhance adhesion to the underlying metal surface and that N incorporation enhances osteogenesis and rapid biomineralization. A model Ti/TiO2-SiOx interface was formed by first depositing Ti onto Si wafers, followed by surface patterning, thermal annealing to form TiO2, and depositing SiOx/Si(ON)x overlays. TEM micrographs showed conformal SiOx layers on Ti/TiO2 overlays while XPS data revealed the formation of an elemental Ti-O-Si interface. Nanoscratch testing verified strong SiOx bonding with the underlying TiO2 layers. In vitro studies showed that the surface properties changed significantly to reveal the formation of hydroxycarbonate apatite within 6 h, and Si(ON)x surface chemistry induced osteogenic gene expression of human periosteal cells and led to a rapid "bone-like" biomineral formation within 4 weeks. XANES data revealed that the incorporation of N increased the surface HA bioactivity by increasing the carbonate to phosphate ratio. In conclusion, silicon oxynitride overlays on bone-implant systems enhance osteogenesis and biomineralization via surface nitrogen incorporation. PMID:26095187

  12. Inhibition of histone deacetylase activity in reduced oxygen environment enhances the osteogenesis of mouse adipose-derived stromal cells.

    PubMed

    Xu, Yue; Hammerick, Kyle E; James, Aaron W; Carre, Antoine L; Leucht, Philipp; Giaccia, Amato J; Longaker, Michael T

    2009-12-01

    Recent studies suggest that oxygen tension has a great impact on the osteogenic differentiation capacity of mesenchymal cells derived from adipose tissue: reduced oxygen impedes osteogenesis. We have found that expansion of mouse adipose-derived stromal cells (mASCs) in reduced oxygen tension (10%) results in increased cell proliferation along with induction of histone deacetylase (HDAC) activity. In this study, we utilized two HDAC inhibitors (HDACi), sodium butyrate (NaB) and valproic acid (VPA), and studied their effects on mASCs expanded in various oxygen tensions (21%, 10%, and 1% O(2)). Significant growth inhibition was observed with NaB or VPA treatment in each oxygen tension. Osteogenesis was enhanced by treatment with NaB or VPA, particularly in reduced oxygen tensions (10% and 1% O(2)). Conversely, adipogenesis was decreased with treatments of NaB or VPA at all oxygen tensions. Finally, NaB- or VPA-treated, reduced oxygen tension-exposed (1% O(2)) ASCs were grafted into surgically created mouse tibial defects and resulted in significantly increased bone regeneration. In conclusion, HDACi significantly promote the osteogenic differentiation of mASCs exposed to reduced oxygen tension; HDACi may hold promise for future clinical applications of ASCs for skeletal regeneration. PMID:19505250

  13. Inhibition of Histone Deacetylase Activity in Reduced Oxygen Environment Enhances the Osteogenesis of Mouse Adipose-Derived Stromal Cells

    PubMed Central

    Xu, Yue; Hammerick, Kyle E.; James, Aaron W.; Carre, Antoine L.; Leucht, Philipp; Giaccia, Amato J.

    2009-01-01

    Recent studies suggest that oxygen tension has a great impact on the osteogenic differentiation capacity of mesenchymal cells derived from adipose tissue: reduced oxygen impedes osteogenesis. We have found that expansion of mouse adipose-derived stromal cells (mASCs) in reduced oxygen tension (10%) results in increased cell proliferation along with induction of histone deacetylase (HDAC) activity. In this study, we utilized two HDAC inhibitors (HDACi), sodium butyrate (NaB) and valproic acid (VPA), and studied their effects on mASCs expanded in various oxygen tensions (21%, 10%, and 1% O2). Significant growth inhibition was observed with NaB or VPA treatment in each oxygen tension. Osteogenesis was enhanced by treatment with NaB or VPA, particularly in reduced oxygen tensions (10% and 1% O2). Conversely, adipogenesis was decreased with treatments of NaB or VPA at all oxygen tensions. Finally, NaB- or VPA-treated, reduced oxygen tension–exposed (1% O2) ASCs were grafted into surgically created mouse tibial defects and resulted in significantly increased bone regeneration. In conclusion, HDACi significantly promote the osteogenic differentiation of mASCs exposed to reduced oxygen tension; HDACi may hold promise for future clinical applications of ASCs for skeletal regeneration. PMID:19505250

  14. Apocynin suppression of NADPH oxidase reverses the aging process in mesenchymal stem cells to promote osteogenesis and increase bone mass

    PubMed Central

    Sun, Jinlong; Ming, Leiguo; Shang, Fengqing; Shen, Lijuan; Chen, Jihua; Jin, Yan

    2015-01-01

    Because of the reduced potential for osteogenesis in aging bone marrow stromal cells, the balance of bone metabolism becomes disrupted, leading to various bone diseases. An increase in reactive oxygen species has been determined to be one of the key factors that accelerates the aging process in BMSCs. In these cells, increased expression of NADPH oxidases is the major source of ROS. In the current study, we suppressed the expression of NOX using apocynin, an effective antioxidant and free radical scavenger, and the results showed that aging BMSCs exhibited an enhanced potential for osteogenesis. The expression of potential key targets influencing this reversal was evaluated using qRT-PCR, and the expression of p53 was shown to be reduced with the suppression of NOX. We speculate that this may be one of the major reasons for the reversal of the aging process. We also examined the effect of apocynin in vivo, and the results showed that in SAMP6 mice, bone mineral density and total bone volume were increased after 3 months of apocynin treatment. In conclusion, our results demonstrate that in aging BMSCs, suppression of NADPH oxidase by apocynin partially reverses the aging process and enhances osteogenic potential. PMID:26686764

  15. Functional differences between AMPK α1 and α2 subunits in osteogenesis, osteoblast-associated induction of osteoclastogenesis, and adipogenesis.

    PubMed

    Wang, Yu-Gang; Han, Xiu-Guo; Yang, Ying; Qiao, Han; Dai, Ke-Rong; Fan, Qi-Ming; Tang, Ting-Ting

    2016-01-01

    The endocrine role of the skeleton-which is impaired in human diseases including osteoporosis, obesity and diabetes-has been highlighted previously. In these diseases, the role of AMPK, a sensor and regulator of energy metabolism, is of biological and clinical importance. Since AMPK's main catalytic subunit α has two isoforms, it is unclear whether functional differences between them exist in the skeletal system. The current study overexpressed AMPKα1 and α2 in MC3T3-E1 cells, primary osteoblasts and mouse BMSCs by lentiviral transduction. Cells overexpressing AMPKα2 showed higher osteogenesis potential than AMPKα1, wherein androgen receptor (AR) and osteoactivin played important roles. RANKL and M-CSF were secreted at lower levels from cells overexpressing α2 than α1, resulting in decreased osteoblast-associated osteoclastogenesis. Adipogenesis was inhibited to a greater degree in 3T3-L1 cells overexpressing α2 than α1, which was modulated by AR. An abnormal downregulation of AMPKα2 was observed in human BMSCs exhibiting the fibrous dysplasia (FD) phenotype. Overexpression of AMPKα2 in these cells rescued the defect in osteogenesis, suggesting that AMPKα2 plays a role in FD pathogenesis. These findings highlight functional differences between AMPKα1 and α2, and provide a basis for investigating the molecular mechanisms of diseases associated with impaired functioning of the skeletal system. PMID:27600021

  16. Polydopamine-Templated Hydroxyapatite Reinforced Polycaprolactone Composite Nanofibers with Enhanced Cytocompatibility and Osteogenesis for Bone Tissue Engineering.

    PubMed

    Gao, Xiang; Song, Jinlin; Ji, Ping; Zhang, Xiaohong; Li, Xiaoman; Xu, Xiao; Wang, Mengke; Zhang, Siqi; Deng, Yi; Deng, Feng; Wei, Shicheng

    2016-02-10

    Nanohydroxyapatite (HA) synthesized by biomimetic strategy is a promising nanomaterial as bone substitute due to its physicochemical features similar to those of natural nanocrystal in bone tissue. Inspired by mussel adhesive chemistry, a novel nano-HA was synthesized in our work by employing polydopamine (pDA) as template under weak alkaline condition. Subsequently, the as-prepared pDA-templated HA (tHA) was introduced into polycaprolactone (PCL) matrix via coelectrospinning, and a bioactive tHA/PCL composite nanofiber scaffold was developed targeted at bone regeneration application. Our research showed that tHA reinforced PCL composite nanofibers exhibited favorable cytocompatibility at given concentration of tHA (0-10 w.t%). Compared to pure PCL and traditional nano-HA enriched PCL (HA/PCL) composite nanofibers, enhanced cell adhesion, spreading and proliferation of human mesenchymal stem cells (hMSCs) were observed on tHA/PCL composite nanofibers on account of the contribution of pDA present in tHA. More importantly, tHA nanoparticles exposed on the surface of composite nanofibers could further promote osteogenesis of hMSCs in vitro even in the absence of osteogenesis soluble inducing factors when compared to traditional HA/PCL scaffolds, which was supported by in vivo test as well according to the histological analysis. Overall, our study demonstrated that the developed tHA/PCL composite nanofibers with enhanced cytocompatibility and osteogenic capacity hold great potential as scaffolds for bone tissue engineering. PMID:26756224

  17. Micro-CT evaluation of in vivo osteogenesis at implants processed by wire-type electric discharge machining.

    PubMed

    Yamaki, Koichi; Kataoka, Yu; Ohtsuka, Fukunaga; Miyazaki, Takashi

    2012-01-01

    Titanium surfaces processed by wire-type electric discharge machining (EDM) are microfabricated surfaces with an irregular morphology, and they exhibited excellent in vitro bone biocompatibility. In this study, the efficiency of in vivo osteogenesis on EDM surfaces was investigated by surgically placing screw-shaped EDM-processed and machined-surface implants into the femurs of four Japanese white rabbits. The volume and process of new bone formation were evaluated by an X-ray micro-CT scanner, coupled with histopathological observations at 1, 2, and 4 weeks post-implantation. Before surgical implantation, the surface topography and contact angle of each implant surface were examined. Bone formation increased over time on both implant surfaces, with both implant types yielding statistically equivalent bone volume at 4 weeks post-implementation. However, at 1 week post-implantation, amount of new bone at EDM-processed implant was markedly greater than that at machined-surface implant. Moreover, new bone appeared to initiate directly from the EDM surfaces, while new bone appeared to generate from pre-existing host bone to the machined surfaces. Thus, EDM seemed to be a promising method for surface modification of titanium implants to support enhanced osteogenesis. PMID:22673455

  18. Osteogenesis of peripheral blood mesenchymal stem cells in self assembling peptide nanofiber for healing critical size calvarial bony defect

    PubMed Central

    Wu, Guofeng; Pan, Mengjie; Wang, Xianghai; Wen, Jinkun; Cao, Shangtao; Li, Zhenlin; Li, Yuanyuan; Qian, Changhui; Liu, Zhongying; Wu, Wutian; Zhu, Lixin; Guo, Jiasong

    2015-01-01

    Peripheral blood mesenchymal stem cells (PBMSCs) may be easily harvested from patients, permitting autologous grafts for bone tissue engineering in the future. However, the PBMSC’s capabilities of survival, osteogenesis and production of new bone matrix in the defect area are still unclear. Herein, PBMSCs were seeded into a nanofiber scaffold of self-assembling peptide (SAP) and cultured in osteogenic medium. The results indicated SAP can serve as a promising scaffold for PBMSCs survival and osteogenic differentiation in 3D conditions. Furthermore, the SAP seeded with the induced PBMSCs was splinted by two membranes of poly(lactic)-glycolic acid (PLGA) to fabricate a composited scaffold which was then used to repair a critical-size calvarial bone defect model in rat. Twelve weeks later the defect healing and mineralization were assessed by H&E staining and microcomputerized tomography (micro-CT). The osteogenesis and new bone formation of grafted cells in the scaffold were evaluated by immunohistochemistry. To our knowledge this is the first report with solid evidence demonstrating PBMSCs can survive in the bone defect area and directly contribute to new bone formation. Moreover, the present data also indicated the tissue engineering with PBMSCs/SAP/PLGA scaffold can serve as a novel prospective strategy for healing large size cranial defects. PMID:26568114

  19. PDGF-BB secreted by preosteoclasts induces CD31hiEmcnhi vessel subtype in coupling osteogenesis

    PubMed Central

    Xie, Hui; Cui, Zhuang; Wang, Long; Xia, Zhuying; Hu, Yin; Xian, Lingling; Li, Changjun; Xie, Liang; Crane, Janet; Wan, Mei; Zhen, Gehua; Bian, Qin; Yu, Bin; Chang, Weizhong; Qiu, Tao; Pickarski, Maureen; Duong, Le Thi; Windle, Jolene J.; Luo, Xianghang; Liao, Eryuan; Cao, Xu

    2014-01-01

    Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study shows that the specific vessel subtype, strongly positive for CD31 and Endomucin (CD31hiEmcnhi), couples angiogenesis and osteogenesis. We found that preosteoclasts secrete platelet derived growth factor-BB (PDGF-BB), inducing CD31hiEmcnhi vessels during bone modeling and remodeling. Mice with depletion of PDGF-BB in tartrate-resistant acid phosphatase positive (TRAP+) cell lineage (Pdgfb–/–) show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and CD31hiEmcnhi vessels compared to wild-type mice. In the ovariectomized (OVX) osteoporotic mouse model, concentrations of serum and bone marrow PDGF-BB and CD31hiEmcnhi vessels are significantly decreased. Inhibition of cathepsin K (CTSK) increases preosteoclast numbers, resulting in higher levels of PDGF-BB to stimulate CD31hiEmcnhi vessels and bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a novel therapeutic target for osteoporosis to promote angiogenesis for bone formation. PMID:25282358

  20. Direct bone formation during distraction osteogenesis does not require TNF alpha receptors and elevated serum TNF alpha fails to inhibit bone formation in TNFR1 deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated th...

  1. Downregulated microRNA-23b promotes BMP9-mediated osteogenesis in C2C12 myoblast cells by targeting Runx2

    PubMed Central

    CHEN, CHU; TANG, ZUCHUAN; SONG, QILING; YANG, MIN; SHI, QIONG; WENG, YAGUANG

    2016-01-01

    MicroRNAs are identified as negative regulators in gene expression through silencing gene expression at the post-transcriptional and translational levels. Bone morphogenetic protein 9 (BMP9) is the most effective in inducing osteogenesis in the BMP family, the members of which were originally identified as osteoinductive cytokines. In the current study, the role of miR-23b in the progression of BMP9-induced C2C12 myoblasts was investigated. The results indicated that miR-23b was significantly downregulated in C2C12 myoblasts induced by BMP9. Overexpression of miR-23b significantly inhibited osteogenesis in the C2C12 myoblasts. In addition, it was observed that Runx2 was negatively regulated by miR-23b at the post-transcriptional level, via a specific target site within the 3′UTR of Runx2. Knockdown of Runx2 promoted miR-23b-induced inhibition of osteogenesis in C2C12 myoblasts. The expression of Runx2 was observed to be frequently upregulated in osteoblast cell lines and inversely correlated with miR-23b expression. Thus, the results of the present study suggest that miR-23b inhibits BMP9-induced C2C12 myoblast osteogenesis via targeting of the Runx2 gene, acting as a suppressor. The current study contributes to the understanding of the functions of BMP9 in ossification. PMID:26820568

  2. The ENCOAL Mild Gasification Demonstration Project

    SciTech Connect

    Not Available

    1990-07-01

    The DOE plans to enter into a Cooperative Agreement with ENCOAL Corporation, a wholly owned subsidiary of Shell Mining Company, for the cost-shared design, construction and operation of a mild gasification facility based on Liquids-from-Coal (LFC) technology. The facility is planned to be located at the Triton Coal Company's Buckskin Mine near Gillette, Wyoming. The mild gasification process to be demonstrated will produce two new, low-sulfur fuel forms (a solid and a liquid) from subbituminous coal. The new fuel forms would be suitable for combustion in commercial, industrial, and utility boilers. This environmental assessment has been prepared by the DOE to comply with the requirements of the NEPA. Pollutant emissions, land use, water, and waste management are briefly discussed. 3 figs., 5 tabs.

  3. [Nonsurgical management of mild primary hyperparathyroidism].

    PubMed

    Imanishi, Yasuo

    2016-06-01

    Primary hyperparathyroidism(PHPT)is one of the common endocrine disorders, which results clinically in nephrolithiasis, osteoporosis, muscle weakness, cardiac and psychiatric abnormalities even in a mild or asymptomatic disease. Parathyroidectomy(PTX)is the only definitive treatment for PHPT, however, some patients with sporadic PHPT refuse surgery, are medically unfit, or have residual or recurrent disease inaccessible to further surgery. These patients may require intervention for management of symptomatic or moderate to severe hypercalcemia, bone loss or kidney calculi. PMID:27230840

  4. Disposable baby wipes: efficacy and skin mildness.

    PubMed

    Odio, M; Streicher-Scott, J; Hansen, R C

    2001-04-01

    The results of a series of four clinical studies demonstrated that disposable baby wipes were milder to the skin than use of a cotton washcloth and water, recognized as a "gold standard" for skin mildness. Importantly, the baby wipes caused no significant change from the baseline value in any of the skin parameters examined. This observation verified that the test wipes are minimally disruptive to the epidermal barrier and thus suitable for use on intact or compromised, irritated skin. PMID:11917305

  5. Perinatal Risk Factors for Mild Motor Disability

    ERIC Educational Resources Information Center

    Hands, Beth; Kendall, Garth; Larkin, Dawne; Parker, Helen

    2009-01-01

    The aetiology of mild motor disability (MMD) is a complex issue and as yet is poorly understood. The aim of this study was to identify the prevalence of perinatal risk factors in a cohort of 10-year-old boys and girls with (n = 362) and without (n = 1193) MMD. Among the males with MMD there was a higher prevalence of postpartum haemorrhage,…

  6. Mesoporous bioactive glass nanolayer-functionalized 3D-printed scaffolds for accelerating osteogenesis and angiogenesis.

    PubMed

    Zhang, Yali; Xia, Lunguo; Zhai, Dong; Shi, Mengchao; Luo, Yongxiang; Feng, Chun; Fang, Bing; Yin, Jingbo; Chang, Jiang; Wu, Chengtie

    2015-12-01

    The hierarchical microstructure, surface and interface of biomaterials are important factors influencing their bioactivity. Porous bioceramic scaffolds have been widely used for bone tissue engineering by optimizing their chemical composition and large-pore structure. However, the surface and interface of struts in bioceramic scaffolds are often ignored. The aim of this study is to incorporate hierarchical pores and bioactive components into the bioceramic scaffolds by constructing nanopores and bioactive elements on the struts of scaffolds and further improve their bone-forming activity. Mesoporous bioactive glass (MBG) modified β-tricalcium phosphate (MBG-β-TCP) scaffolds with a hierarchical pore structure and a functional strut surface (∼100 nm of MBG nanolayer) were successfully prepared via 3D printing and spin coating. The compressive strength and apatite-mineralization ability of MBG-β-TCP scaffolds were significantly enhanced as compared to β-TCP scaffolds without the MBG nanolayer. The attachment, viability, alkaline phosphatase (ALP) activity, osteogenic gene expression (Runx2, BMP2, OPN and Col I) and protein expression (OPN, Col I, VEGF, HIF-1α) of rabbit bone marrow stromal cells (rBMSCs) as well as the attachment, viability and angiogenic gene expression (VEGF and HIF-1α) of human umbilical vein endothelial cells (HUVECs) in MBG-β-TCP scaffolds were significantly upregulated compared with conventional bioactive glass (BG)-modified β-TCP (BG-β-TCP) and pure β-TCP scaffolds. Furthermore, MBG-β-TCP scaffolds significantly enhanced the formation of new bone in vivo as compared to BG-β-TCP and β-TCP scaffolds. The results suggest that application of the MBG nanolayer to modify 3D-printed bioceramic scaffolds offers a new strategy to construct hierarchically porous scaffolds with significantly improved physicochemical and biological properties, such as mechanical properties, osteogenesis, angiogenesis and protein expression for bone tissue

  7. Mesoporous bioactive glass nanolayer-functionalized 3D-printed scaffolds for accelerating osteogenesis and angiogenesis

    NASA Astrophysics Data System (ADS)

    Zhang, Yali; Xia, Lunguo; Zhai, Dong; Shi, Mengchao; Luo, Yongxiang; Feng, Chun; Fang, Bing; Yin, Jingbo; Chang, Jiang; Wu, Chengtie

    2015-11-01

    The hierarchical microstructure, surface and interface of biomaterials are important factors influencing their bioactivity. Porous bioceramic scaffolds have been widely used for bone tissue engineering by optimizing their chemical composition and large-pore structure. However, the surface and interface of struts in bioceramic scaffolds are often ignored. The aim of this study is to incorporate hierarchical pores and bioactive components into the bioceramic scaffolds by constructing nanopores and bioactive elements on the struts of scaffolds and further improve their bone-forming activity. Mesoporous bioactive glass (MBG) modified β-tricalcium phosphate (MBG-β-TCP) scaffolds with a hierarchical pore structure and a functional strut surface (~100 nm of MBG nanolayer) were successfully prepared via 3D printing and spin coating. The compressive strength and apatite-mineralization ability of MBG-β-TCP scaffolds were significantly enhanced as compared to β-TCP scaffolds without the MBG nanolayer. The attachment, viability, alkaline phosphatase (ALP) activity, osteogenic gene expression (Runx2, BMP2, OPN and Col I) and protein expression (OPN, Col I, VEGF, HIF-1α) of rabbit bone marrow stromal cells (rBMSCs) as well as the attachment, viability and angiogenic gene expression (VEGF and HIF-1α) of human umbilical vein endothelial cells (HUVECs) in MBG-β-TCP scaffolds were significantly upregulated compared with conventional bioactive glass (BG)-modified β-TCP (BG-β-TCP) and pure β-TCP scaffolds. Furthermore, MBG-β-TCP scaffolds significantly enhanced the formation of new bone in vivo as compared to BG-β-TCP and β-TCP scaffolds. The results suggest that application of the MBG nanolayer to modify 3D-printed bioceramic scaffolds offers a new strategy to construct hierarchically porous scaffolds with significantly improved physicochemical and biological properties, such as mechanical properties, osteogenesis, angiogenesis and protein expression for bone tissue

  8. Constitutive activation of IKK2/NF-κB impairs osteogenesis and skeletal development.

    PubMed

    Swarnkar, Gaurav; Zhang, Kaihua; Mbalaviele, Gabriel; Long, Fanxin; Abu-Amer, Yousef

    2014-01-01

    Pathologic conditions impair bone homeostasis. The transcription factor NF-κB regulates bone homeostasis and is central to bone pathologies. Whereas contribution of NF-κB to heightened osteoclast activity is well-documented, the mechanisms underlying NF-κB impact on chondrocytes and osteoblasts are scarce. In this study, we examined the effect of constitutively active IKK2 (IKK2ca) on chondrogenic and osteogenic differentiation. We show that retroviral IKK2ca but not GFP, IKK2WT, or the inactive IKK2 forms IKK2KM and IKK2SSAA, strongly suppressed osteogenesis and chondrogenesis, in vitro. In order to explore the effect of constitutive NF-κB activation on bone formation in vivo, we activated this pathway in a conditional fashion. Specifically, we crossed the R26StopIKK2ca mice with mice carrying the Col2-cre in order to express IKK2ca in osteoblasts and chondrocytes. Both chondrocytes and osteoblasts derived from Col2Cre/IKK2ca expressed IKK2ca. Mice were born alive yet died shortly thereafter. Histologically, newborn Col2Cre+/RosaIKK2ca heterozygotes (Cre+IKK2ca_w/f (het)) and homozygotes (Cre+IKK2ca_f/f (KI)) showed smaller skeleton, deformed vertebrate and reduced or missing digit ossification. The width of neural arches, as well as ossification in vertebral bodies of Cre+IKK2ca_w/f and Cre+IKK2ca_f/f, was reduced or diminished. H&E staining of proximal tibia from new born pups revealed that Cre+IKK2ca_f/f displayed disorganized hypertrophic zones within the smaller epiphysis. Micro-CT analysis indicated that 4-wk old Cre+IKK2ca_w/f has abnormal trabecular bone in proximal tibia compared to WT littermates. Mechanistically, ex-vivo experiments showed that expression of differentiation markers in calvarial osteoblasts derived from newborn IKK2ca knock-in mice was diminished compared to WT-derived cells. In situ hybridization studies demonstrated that the hypertrophic chondrocyte marker type-X collagen, the pre-hypertrophic chondrocyte markers Indian hedgehog

  9. Subacute to chronic mild traumatic brain injury.

    PubMed

    Mott, Timothy F; McConnon, Michael L; Rieger, Brian P

    2012-12-01

    Although a universally accepted definition is lacking, mild traumatic brain injury and concussion are classified by transient loss of consciousness, amnesia, altered mental status, a Glasgow Coma Score of 13 to 15, and focal neurologic deficits following an acute closed head injury. Most patients recover quickly, with a predictable clinical course of recovery within the first one to two weeks following traumatic brain injury. Persistent physical, cognitive, or behavioral postconcussive symptoms may be noted in 5 to 20 percent of persons who have mild traumatic brain injury. Physical symptoms include headaches, dizziness, and nausea, and changes in coordination, balance, appetite, sleep, vision, and hearing. Cognitive and behavioral symptoms include fatigue, anxiety, depression, and irritability, and problems with memory, concentration and decision making. Women, older adults, less educated persons, and those with a previous mental health diagnosis are more likely to have persistent symptoms. The diagnostic workup for subacute to chronic mild traumatic brain injury focuses on the history and physical examination, with continuing observation for the development of red flags such as the progression of physical, cognitive, and behavioral symptoms, seizure, progressive vomiting, and altered mental status. Early patient and family education should include information on diagnosis and prognosis, symptoms, and further injury prevention. Symptom-specific treatment, gradual return to activity, and multidisciplinary coordination of care lead to the best outcomes. Psychiatric and medical comorbidities, psychosocial issues, and legal or compensatory incentives should be explored in patients resistant to treatment. PMID:23198672

  10. Mild Appendicitis Complication Rates Similar for Surgery, Antibiotics

    MedlinePlus

    ... html Mild Appendicitis Complication Rates Similar for Surgery, Antibiotics Decision not to operate might be matter of ... 25, 2016 FRIDAY, March 25, 2016 (HealthDay News) -- Antibiotics can be used to treat mild appendicitis, but ...

  11. The Relationship of Mild Depression to Stress and Coping.

    ERIC Educational Resources Information Center

    Kolenc, Koleen M.; And Others

    1990-01-01

    Investigated relationship of mild depression, stress, and coping based on Lazarus's model of stress and coping. Examined two coping styles (problem and emotion focused), two measures of stress, and mild depression in college students (N=227). Found mildly depressed persons relied more on emotion-focused coping and experience more stress than did…

  12. Writing Impairments in Japanese Patients with Mild Cognitive Impairment and with Mild Alzheimer's Disease

    PubMed Central

    Hayashi, Atsuko; Nomura, Hiroshi; Mochizuki, Ruriko; Ohnuma, Ayumu; Kimpara, Teiko; Suzuki, Kyoko; Mori, Etsuro

    2015-01-01

    Background/Aims We investigated writing abilities in patients with the amnestic type of mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). To examine the earliest changes in writing function, we used writing tests for both words and sentences with different types of Japanese characters (Hiragana, Katakana, and Kanji). Methods A total of 25 aMCI patients, 38 AD patients, and 22 healthy controls performed writing to dictation for Kana and Kanji words, copied Kanji words, and wrote in response to a picture story task. Analysis of variance was used to test the subject group effects on the scores in the above writing tasks. Results For the written Kanji words, the mild AD group performed worse than the aMCI group and the controls, but there was no difference between the aMCI group and the controls. For the picture story writing task, the mild AD and aMCI groups performed worse than the controls, but the difference between the AD and the aMCI groups was not significant. Conclusions The mild AD group showed defects in writing Kanji characters, and the aMCI group showed impairments in narrative writing. Our study suggests that narrative writing, which demands complex integration of multiple cognitive functions, can be used to detect the subtle writing deficits in aMCI patients. PMID:26483830

  13. BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis.

    PubMed

    Shea, Colleen M; Edgar, Cory M; Einhorn, Thomas A; Gerstenfeld, Louis C

    2003-12-15

    The molecular mechanisms by which bone morphogenetic proteins (BMPs) promote skeletal cell differentiation were investigated in the murine mesenchymal stem cell line C3H10T1/2. Both BMP-7 and BMP-2 induced C3H10T1/2 cells to undergo a sequential pattern of chondrogenic followed by osteogenic differentiation that was dependent on both the concentration and the continuous presence of BMP in the growth media. Differentiation was determined by the expression of chondrogenesis and osteogenesis associated matrix genes. Subsequent experiments using BMP-7 demonstrated that withdrawal of BMP from the growth media led to a complete loss of skeletal cell differentiation accompanied by adipogenic differentiation of these cells. Continuous treatment with BMP-7 increased the expression of Sox9, Msx 2, and c-fos during the periods of chondrogenic differentiation after which point their expression decreased. In contrast, Dlx 5 expression was induced by BMP-7 treatment and remained elevated throughout the time-course of skeletal cell differentiation. Runx2/Cbfa1 was not detected by ribonuclease protection assay (RPA) and did not appear to be induced by BMP-7. The sequential nature of differentiation of chondrocytic and osteoblastic cells and the necessity for continuous BMP treatment to maintain skeletal cell differentiation suggests that the maintenance of selective differentiation of the two skeletal cell lineages might be dependent on BMP-7-regulated expression of other morphogenetic factors. An examination of the expression of Wnt, transforming growth factor-beta (TGF-beta), and the hedgehog family of morphogens showed that Wnt 5b, Wnt 11, BMP-4, growth and differentiation factor-1 (GDF-1), Sonic hedgehog (Shh), and Indian hedgehog (Ihh) were endogenously expressed by C3H10T1/2 cells. Wnt 11, BMP-4, and GDF-1 expression were inhibited by BMP-7 treatment in a dose-dependent manner while Wnt 5b and Shh were selectively induced by BMP-7 during the period of chondrogenic

  14. Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool.

    PubMed

    Hentschel, Julia; Tatun, Dana; Parkhomchuk, Dmitri; Kurth, Ingo; Schimmel, Bettina; Heinrich-Weltzien, Roswitha; Bertzbach, Sabine; Peters, Hartmut; Beetz, Christian

    2016-09-15

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations. PMID:27259663

  15. Mapping of the human dentin matrix acidic phosphoprotein gene (DMP1) to the dentinogenesis imperfecta type II critical region at chromosome 4q21

    SciTech Connect

    Aplin, H.M.; Hirst, K.L.; Crosby, A.H.; Dixon, M.J.

    1995-11-20

    Dentinogenesis imperfecta type II (DGI1) is an autosomal dominant disorder of dentin formation, which has been mapped to human chromosome 4q12-q21. The region most likely to contain the DGI1 locus is a 3.2-cM region surrounding the osteopontin (SPP1) locus. Recently, a novel dentin-specific acidic phosphoprotein (dmp1) has been cloned in the rat and mapped to mouse chromosome 5q21. In the current investigation, we have isolated a cosmid containing the human DMP1 gene. The isolation of a short tandem repeat polymorphism at this locus has allowed us to map the DMP1 locus to human chromosome 4q21 and demonstrate that it is tightly linked to DGI1 in two families (Z{sub max} = 11.01, {theta} = 0.001). The creation of a yeast artificial chromosome contig around SPP1 has further allowed us to demonstrate that DMP1 is located within 150 kb of the bone sialoprotein and 490 kb of the SPP1 loci, respectively. DMP1 is therefore a strong candidate for the DGI1 locus. 12 refs., 2 figs., 1 tab.

  16. Mild hypoglycaemia and questionnaire measures of aggression.

    PubMed

    Benton, D; Kumari, N; Brain, P F

    1982-01-01

    A glucose-tolerance test was given to a group of males who did not have a history involving aggressive behaviour or abnormal glucose metabolism. In these subjects a significant correlation was found between the tendency to become mildly hypoglycaemic and scores on the Buss-Durkee Hostility Inventory and the Rosenzweig Picture Frustration Study. A factor analysis of the data found that both scores on the aggression questionnaires and the measure of hypoglycaemia were similarly weighted. These results extent to normal subjects the finding that there is a relationship between hypoglycaemia and aggressiveness, a result previously found in psychiatric patients. PMID:7104424

  17. Mild cognitive impairment is becoming more psychosocial.

    PubMed

    Verhey, Frans; de Vugt, Marjolein

    2013-01-01

    In recent years, researchers have underlined the need for more studies of early psychosocial interventions for patients with mild cognitive impairment (MCI) and early dementia (Moniz-Cook, Vernooij-Dassen, Woods, & Orrell, 2011 ). In the last 10 years, MCI has become more 'psychosocial' and a starting point for professionals to help patients and their nearest ones to deal with their handicaps, to cope with a future that is insecure and gloomy, and to get prepared for the possibility of further decline and dependency. It is timely that Aging & Mental Health is devoting this paper, a special section in this issue with contributions dealing with psychological and social aspects of MCI. PMID:23402425

  18. Fabrication of multi-biofunctional gelatin-based electrospun fibrous scaffolds for enhancement of osteogenesis of mesenchymal stem cells.

    PubMed

    Lin, Wei-Han; Yu, Jiashing; Chen, Guoping; Tsai, Wei-Bor

    2016-02-01

    Biofunctional scaffolds that support the adhesion, proliferation, and osteo-differentiation of mesenchymal stem cells (MSCs) are critical for bone tissue engineering. In this study, a simple in situ UV-crosslinking strategy was utilized to fabricate gelatin electrospun fibrous (GEF) scaffolds with multiple biosignals, including cell adhesive Arg-Gly-Asp (RGD) peptide, osteo-conductive hydroxyapatite (HAp) nanoparticles, and osteo-inductive bone morphogenic protein-2 (BMP-2). The adhesion and proliferation of MSCs on the GEF scaffolds were improved by the incorporation of RGD. Meanwhile, the incorporation of HAp and BMP-2 enhanced osteo-differentiation of MSCs. The three incorporated bio-factors exert a synergistic effect on osteogenesis of MSCs in the GEF scaffolds. This strategy of incorporating multiple biomolecules could be used to fabricate crosslinked electrospun scaffolds of natural polymers for tissue-engineering applications. PMID:26642073

  19. Maxillary distraction osteogenesis for treatment of cleft lip and palate in a patient with X-linked agammaglobulinemia.

    PubMed

    Sato, Yutaka; Mishimagi, Takashi; Katsuki, Yuko; Harada, Kiyoshi

    2014-07-01

    X-linked agammaglobulinemia (XLA) is a congenital immune deficiency disorder caused by abnormal antibody production. It is a rare disease with an estimated frequency of 1 in 379,000 that has X-linked recessive heredity and develops only in males. The clinical problems include bacterial infection such as otitis media, sinusitis, and bronchitis. In recent years it has become possible to diagnose XLA in the early stage and intravenous immunoglobulin replacement therapy has permitted survival to adulthood. However, there have been no reports of oral surgery in patients with XLA. Here, we describe a case in which immunoglobulin replacement therapy given pre- and postoperatively was used to control infection in oral surgery and maxillary distraction osteogenesis performed for improving occlusion and appearance of a cleft lip and palate in a patient with XLA. PMID:24947966

  20. Decreased extracellular pH inhibits osteogenesis through proton-sensing GPR4-mediated suppression of yes-associated protein

    PubMed Central

    Tao, Shi-Cong; Gao, You-Shui; Zhu, Hong-Yi; Yin, Jun-Hui; Chen, Yi-Xuan; Zhang, Yue-Lei; Guo, Shang-Chun; Zhang, Chang-Qing

    2016-01-01

    The pH of extracellular fluids is a basic property of the tissue microenvironment and is normally maintained at 7.40 ± 0.05 in humans. Many pathological circumstances, such as ischemia, inflammation, and tumorigenesis, result in the reduction of extracellular pH in the affected tissues. In this study, we reported that the osteogenic differentiation of BMSCs was significantly inhibited by decreases in the extracellular pH. Moreover, we demonstrated that proton-sensing GPR4 signaling mediated the proton-induced inhibitory effects on the osteogenesis of BMSCs. Additionally, we found that YAP was the downstream effector of GPR4 signaling. Our findings revealed that the extracellular pH modulates the osteogenic responses of BMSCs by regulating the proton-sensing GPR4-YAP pathway. PMID:27256071