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Sample records for connective tissue growth

  1. Connective tissue growth factor is a substrate of ADAM28

    SciTech Connect

    Mochizuki, Satsuki; Tanaka, Rena; Shimoda, Masayuki; Onuma, Junko; Fujii, Yutaka; Jinno, Hiromitsu; Okada, Yasunori

    2010-11-26

    Research highlights: {yields} The hyper-variable region in the cysteine-rich domain of ADAM28 binds to C-terminal domain of CTGF. {yields} ADAM28 cleaves CTGF alone and CTGF in the CTGF/VEGF{sub 165} complex. {yields} CTGF digestion by ADAM28 releases biologically active VEGF{sub 165} from the complex. {yields} ADAM28, CTGF and VEGF{sub 165} are commonly co-expressed by carcinoma cells in human breast carcinoma tissues. {yields} These suggest that ADAM28 promotes VEGF{sub 165}-induced angiogenesis in the breast carcinomas by selective CTGF digestion in the CTGF/VEGF{sub 165} complex. -- Abstract: ADAM28, a member of the ADAM (a disintegrin and metalloproteinase) gene family, is over-expressed by carcinoma cells and the expression correlates with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, information about substrates of ADAM28 is limited. We screened interacting molecules of ADAM28 in human lung cDNA library by yeast two-hybrid system and identified connective tissue growth factor (CTGF). Binding of CTGF to proADAM28 was demonstrated by yeast two-hybrid assay and protein binding assay. ADAM28 cleaved CTGF in dose- and time-dependent manners at the Ala{sup 181}-Tyr{sup 182} and Asp{sup 191}-Pro{sup 192} bonds in the hinge region of the molecule. ADAM28 selectively digested CTGF in the complex of CTGF and vascular endothelial growth factor{sub 165} (VEGF{sub 165}), releasing biologically active VEGF{sub 165} from the complex. RT-PCR and immunohistochemical analyses demonstrated that ADAM28, CTGF and VEGF are commonly co-expressed in the breast carcinoma tissues. These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF{sub 165}-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF{sub 165} complex.

  2. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  3. Mechanical tension as a driver of connective tissue growth in vitro.

    PubMed

    Wilson, Cameron J; Pearcy, Mark J; Epari, Devakara R

    2014-07-01

    We propose the progressive mechanical expansion of cell-derived tissue analogues as a novel, growth-based approach to in vitro tissue engineering. The prevailing approach to producing tissue in vitro is to culture cells in an exogenous "scaffold" that provides a basic structure and mechanical support. This necessarily pre-defines the final size of the implantable material, and specific signals must be provided to stimulate appropriate cell growth, differentiation and matrix formation. In contrast, surgical skin expansion, driven by increments of stretch, produces increasing quantities of tissue without trauma or inflammation. This suggests that connective tissue cells have the innate ability to produce growth in response to elevated tension. We posit that this capacity is maintained in vitro, and that order-of-magnitude growth may be similarly attained in self-assembling cultures of cells and their own extracellular matrix. The hypothesis that growth of connective tissue analogues can be induced by mechanical expansion in vitro may be divided into three components: (1) tension stimulates cell proliferation and extracellular matrix synthesis; (2) the corresponding volume increase will relax the tension imparted by a fixed displacement; (3) the repeated application of static stretch will produce sustained growth and a tissue structure adapted to the tensile loading. Connective tissues exist in a state of residual tension, which is actively maintained by resident cells such as fibroblasts. Studies in vitro and in vivo have demonstrated that cellular survival, reproduction, and matrix synthesis and degradation are regulated by the mechanical environment. Order-of-magnitude increases in both bone and skin volume have been achieved clinically through staged expansion protocols, demonstrating that tension-driven growth can be sustained over prolonged periods. Furthermore, cell-derived tissue analogues have demonstrated mechanically advantageous structural adaptation in

  4. Changes in connective tissue of M. semitendinosus as a response to different growth paths in steers.

    PubMed

    Harper, G S; Allingham, P G; Le Feuvre, R P

    1999-10-01

    The effect of growth path, as opposed to advancing age, on the biophysical and biochemical properties of muscle connective tissue was investigated. Nine-month old Brahman-cross steers were grown across either an uninterrupted path, or paths that incorporated weight-loss and then weight gain on two different diets: one group was realimented on pasture, whilst the other was realimented on a grain-based diet. Biophysical attributes of connective tissue toughness (Compression and Adhesion) in the semitendinosus muscle, were significantly reduced by treatment (P<0.05): weight loss with grain realimentation being the least tough in regard to the connective tissue component. Variance within the biophysical attributes was modelled statistically. Statistically significant models included terms for the post-slaughter connective tissue content as well as tissue contents of the enzymes lactate dehydrogenase and isocitrate dehydrogenase. The data suggest that biochemical measurements made up to 100 days prior to slaughter, may have value as indicators of final connective tissue toughness. PMID:22063087

  5. Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

    PubMed

    Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan; Ford, Jette; Charles, Adrian K; Lyons, Karen M; Brigstock, David R; Goldschmeding, Roel; Cole, Catherine H; Alexander, Warren S; Kees, Ursula R

    2014-07-01

    Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis.

  6. Undifferentiated Connective Tissue Disease

    MedlinePlus

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... L. Goldstein, MD, MMSc (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  7. Could aging human skin use a connective tissue growth factor boost to increase collagen content?

    PubMed

    Oliver, Noelynn; Sternlicht, Mark; Gerritsen, Karin; Goldschmeding, Roel

    2010-02-01

    The roles of connective tissue growth factor (CTGF) and transforming growth factor-beta (TGF-beta), both well-known collagen production stimulators, were examined in skin aging. Aged skin and fibroblasts exhibited a coordinate decrease in CTGF, TGF-beta, and type I procollagen expression and content. CTGF knockdown and TGF-beta blockade in normal dermal fibroblasts reduced procollagen expression, whereas overexpressing CTGF increased procollagen by a TGF-beta/Smad signaling-dependent mechanism without involving Smad2/3.

  8. Connective Tissue Disorders

    MedlinePlus

    Connective tissue is the material inside your body that supports many of its parts. It is the "cellular ... their work. Cartilage and fat are examples of connective tissue. There are over 200 disorders that impact connective ...

  9. [Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage].

    PubMed

    Sánchez-López, E; Rodrigues Díez, R; Rodríguez Vita, J; Rayego Mateos, S; Rodrigues Díez, R R; Rodríguez García, E; Lavoz Barria, C; Mezzano, S; Egido, J; Ortiz, A; Ruiz-Ortega, M; Selgas, R

    2009-01-01

    Connective tissue growth factor (CTGF) is increased in several pathologies associated with fibrosis, including multiple renal diseases. CTGF is involved in biological processes such as cell cycle regulation, migration, adhesion and angiogenesis. Its expression is regulated by various factors involved in renal damage, such as transforming growth factor- , Angiotensin II, high concentrations of glucose and cellular stress. CTGF is involved in the initiation and progression of renal damage to be able to induce an inflammatory response and promote fibrosis, identified as a potential therapeutic target in the treatment of kidney diseases. In this paper we review the main actions of CTGF in renal disease, the intracellular action mechanisms and therapeutic strategies for its blocking.

  10. [THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

    PubMed

    Rudoi, A S; Moskalev, A V; Sboitchakov, V B

    2016-02-01

    The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-β (TGFβ). The involvement of TGFβ in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.

  11. Cyclical cell stretching of skin-derived fibroblasts downregulates connective tissue growth factor (CTGF) production.

    PubMed

    Kanazawa, Yuichiro; Nomura, Jun; Yoshimoto, Shinya; Suzuki, Toshikazu; Kita, Kazuko; Suzuki, Nobuo; Ichinose, Masaharu

    2009-01-01

    Delayed healing of skin wounds can be caused by wound instability, whereas appropriate massage or exercise prevents sclerosis and scar contracture. However, the mechanism by which wound healing is related to mechanical stress has not been fully elucidated. The present study aimed to identify whether mechanical stretching of fibroblasts reduces their production of extracellular matrix. We transferred skin fibroblasts into collagen-coated elastic silicone chambers, cultured them on a stretching apparatus, and used RT-PCR to examine the effects of mechanical stretching on the expression levels of 17 genes related to extracellular matrix production and growth factor secretion. We found that connective tissue growth factor (CTGF) was downregulated after 24 hr of cell stretching. Specifically, the CTGF mRNA and protein levels were 50% and 48% of the control levels, respectively. These findings suggest that cyclic stretching of fibroblasts contributes to anti-fibrotic processes by reducing CTGF production.

  12. [THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

    PubMed

    Rudoi, A S; Moskalev, A V; Sboitchakov, V B

    2016-02-01

    The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-β (TGFβ). The involvement of TGFβ in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem. PMID:27455564

  13. Recombinant Expression, Purification, and Functional Characterisation of Connective Tissue Growth Factor and Nephroblastoma-Overexpressed Protein

    PubMed Central

    Bohr, Wilhelm; Kupper, Michael; Hoffmann, Kurt; Weiskirchen, Ralf

    2010-01-01

    The CCN family of proteins, especially its prominent member, the Connective tissue growth factor (CTGF/CCN2) has been identified as a possible biomarker for the diagnosis of fibrotic diseases. As a downstream mediator of TGF-β1 signalling, it is involved in tissue scarring, stimulates interstitial deposition of extracellular matrix proteins, and promotes proliferation of several cell types. Another member of this family, the Nephroblastoma-Overexpressed protein (NOV/CCN3), has growth-inhibiting properties. First reports further suggest that these two CCN family members act opposite to each other in regulating extracellular matrix protein expression and reciprocally influence their own expression when over-expressed. We have established stable HEK and Flp-In-293 clones as productive sources for recombinant human CCN2/CTGF. In addition, we generated an adenoviral vector for recombinant expression of rat NOV and established protocols to purify large quantities of these CCN proteins. The identity of purified human CCN2/CTGF and rat CCN3/NOV was proven by In-gel digest followed by ESI-TOF/MS mass spectrometry. The biological activity of purified proteins was demonstrated using a Smad3-sensitive reporter gene and BrdU proliferation assay in permanent cell line EA•hy 926 cells. We further demonstrate for the first time that both recombinant CCN proteins are N-glycosylated. PMID:21209863

  14. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy.

    PubMed

    Sun, Guilian; Haginoya, Kazuhiro; Wu, Yanling; Chiba, Yoko; Nakanishi, Tohru; Onuma, Akira; Sato, Yuko; Takigawa, Masaharu; Iinuma, Kazuie; Tsuchiya, Shigeru

    2008-04-15

    The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.

  15. Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy.

    PubMed

    Koshman, Yevgeniya E; Sternlicht, Mark D; Kim, Taehoon; O'Hara, Christopher P; Koczor, Christopher A; Lewis, William; Seeley, Todd W; Lipson, Kenneth E; Samarel, Allen M

    2015-12-01

    Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective tissue growth factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic functions in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling was elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.

  16. Regulation of Connective Tissue Growth Factor Gene Expression and Fibrosis in Human Heart Failure

    PubMed Central

    Koshman, Yevgeniya E.; Patel, Nilamkumar; Chu, Miensheng; Iyengar, Rekha; Kim, Taehoon; Ersahin, Cagatay; Lewis, William; Heroux, Alain; Samarel, Allen M.

    2013-01-01

    Background Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective Tissue Growth Factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited. Methods and Results LV tissue from patients undergoing cardiac transplantation for ischemic (ICM; n=20) and dilated (DCM; n=20) cardiomyopathies, and from nonfailing (NF; n=20) donor hearts were examined. Paired samples (n=15) from patients undergoing LV assist device (LVAD) implantation as “bridge to transplant” (34-1145 days) were also analyzed. There was more interstitial fibrosis in both ICM and DCM compared to NF hearts. Hydroxyproline concentration was also significantly increased in DCM relative to NF samples. The expression of CTGF,TGFB1, COL1-A1, COL3-A1, MMP2 and MMP9 mRNAs in ICM and DCM were also significantly elevated as compared to NF controls. Although TGFB1, CTGF, COL1-A1, and COL3-A1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading. Conclusions CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete. PMID:23582094

  17. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    PubMed Central

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  18. [Connective tissue dysplasia].

    PubMed

    Piantkovskiĭ, A S

    2012-01-01

    The article presents a diagnosis of dysplasia of connective tissue in athletes, where the most important are the methods of clinical assessment using diagnostic tests and rating scales manifestation of connective tissue dysplasia. Evaluation of patients with suspected connective tissue dysplasia should include inspection of an ophthalmologist, orthopedic trauma, cardiology. Should also be carried out by criteria diagnosis degree of connective tissue dysplasia by T. Y. Smolnova (2003) (Large and small diagnostic criteria), which include: increased skin extensibility, joint hypermobility (sprain, dislocation and subluxation, flat feet), muscle hypotonia, a hereditary predisposition to the disease, evaluation of signs joint hypermobility (Beighton criteria). If during routine medical examination revealed athletes with manifestations of connective tissue dysplasia, they are subject to a more in-depth examination and observation. Early diagnosis of connective tissue dysplasia allows not only to plan the training process, but also reduces the trauma of athletes.

  19. Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts: Modulation by curcumin.

    PubMed

    Deng, Yi-Ting; Chen, Hsin-Ming; Cheng, Shih-Jung; Chiang, Chun-Pin; Kuo, Mark Yen-Ping

    2009-09-01

    Connective tissue growth factor (CTGF) is associated with the onset and progression of fibrosis in many human tissues. Areca nut (AN) chewing is the most important etiological factor in the pathogenesis of oral submucous fibrosis (OSF). We immunohistochemically examined the expression of CTGF protein in 20 cases of OSF and found positive CTGF staining in fibroblasts and endothelial cells in all cases. Western blot analysis showed that arecoline, a main alkaloid found in AN, stimulated CTGF synthesis in a dose- and time-dependent manner in buccal mucosal fibroblasts. Constitutive overexpression of CTGF during AN chewing may enhance the fibrotic activity in OSF and play a role in the pathogenesis of OSF. Pretreatment with NF-kappaB inhibitor Bay 11-7082, JNK inhibitor SP600125, p38 MAPK inhibitor SB203580 and antioxidant N-acetyl-l-cysteine, but not ERK inhibitor PD98059, significantly reduced arecoline-induced CTGF synthesis. Furthermore, curcumin completely inhibited arecoline-induced CTGF synthesis and the inhibition is dose-dependent. These results indicated that arecoline-induced CTGF synthesis was mediated by ROS, NF-kappaB, JNK, P38 MAPK pathways and curcumin could be a useful agent in controlling OSF.

  20. Conditional overexpression of connective tissue growth factor disrupts postnatal lung development.

    PubMed

    Wu, Shu; Platteau, Astrid; Chen, Shaoyi; McNamara, George; Whitsett, Jeffrey; Bancalari, Eduardo

    2010-05-01

    Connective tissue growth factor (CTGF) is a member of an emerging family of immediate-early gene products that coordinates complex biological processes during development, differentiation, and tissue repair. Overexpression of CTGF is associated with mechanical ventilation with high tidal volume and oxygen exposure in newborn lungs. However, the role of CTGF in postnatal lung development and remodeling is not well understood. In the present study, a double-transgenic mouse model was generated with doxycycline-inducible overexpression of CTGF in respiratory epithelial cells. Overexpression of CTGF from Postnatal Days 1-14 resulted in thicker alveolar septa and decreased secondary septal formation. This is correlated with increased myofibroblast differentiation and disorganized elastic fiber deposition in alveolar septa. Overexpression of CTGF also decreased alveolar capillary network formation. There were increased alpha-smooth muscle actin expression and collagen deposition, and dramatic thickening in the peribronchial/peribronchiolar and perivascular regions in the double-transgenic lungs. Furthermore, overexpression of CTGF increased integrin-linked kinase expression, activated its downstream signaling target, Akt, as well as increased mRNA expression of fibronectin. These data demonstrate that overexpression of CTGF disrupts alveologenesis and capillary formation, and induces fibrosis during the critical period of alveolar development. These histologic changes are similar to those observed in lungs of infants with bronchopulmonary dysplasia.

  1. Development of a novel gene silencer pyrrole-imidazole polyamide targeting human connective tissue growth factor.

    PubMed

    Wan, Jian-Xin; Fukuda, Noboru; Ueno, Takahiro; Watanabe, Takayoshi; Matsuda, Hiroyuki; Saito, Kosuke; Nagase, Hiroki; Matsumoto, Yoshiaki; Matsumoto, Koichi

    2011-01-01

    Pyrrole-imidazole (PI) polyamide can bind to specific sequences in the minor groove of double-helical DNA and inhibit transcription of the genes. We designed and synthesized a PI polyamide to target the human connective tissue growth factor (hCTGF) promoter region adjacent to the Smads binding site. Among coupling activators that yield PI polyamides, 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU) was most effective in total yields of PI polyamides. A gel shift assay showed that a PI polyamide designed specifically for hCTGF (PI polyamide to hCTGF) bound the appropriate double-stranded oligonucleotide. A fluorescein isothiocyanate (FITC)-conjugated PI polyamide to CTGF permeated cell membranes and accumulated in the nuclei of cultured human mesangial cells (HMCs) and remained there for 48 h. The PI polyamide to hCTGF significantly decreased phorbol 12-myristate acetate (PMA)- or transforming growth factor-β1 (TGF-β1)-stimulated luciferase activity of the hCTGF promoter in cultured HMCs. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated expression of hCTGF mRNA in a dose-dependent manner. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated levels of hCTGF protein in HMCs. These results indicate that the developed synthetic PI polyamide to hCTGF could be a novel gene silencer for fibrotic diseases.

  2. Dynamic Vibration Cooperates with Connective Tissue Growth Factor to Modulate Stem Cell Behaviors

    PubMed Central

    Tong, Zhixiang; Zerdoum, Aidan B.; Duncan, Randall L.

    2014-01-01

    Vocal fold disorders affect 3–9% of the U.S. population. Tissue engineering offers an alternative strategy for vocal fold repair. Successful engineering of vocal fold tissues requires a strategic combination of therapeutic cells, biomimetic scaffolds, and physiologically relevant mechanical and biochemical factors. Specifically, we aim to create a vocal fold-like microenvironment to coax stem cells to adopt the phenotype of vocal fold fibroblasts (VFFs). Herein, high frequency vibratory stimulations and soluble connective tissue growth factor (CTGF) were sequentially introduced to mesenchymal stem cells (MSCs) cultured on a poly(ɛ-caprolactone) (PCL)-derived microfibrous scaffold for a total of 6 days. The initial 3-day vibratory culture resulted in an increased production of hyaluronic acids (HA), tenascin-C (TNC), decorin (DCN), and matrix metalloproteinase-1 (MMP1). The subsequent 3-day CTGF treatment further enhanced the cellular production of TNC and DCN, whereas CTGF treatment alone without the vibratory preconditioning significantly promoted the synthesis of collagen I (Col 1) and sulfated glycosaminoglycans (sGAGs). The highest level of MMP1, TNC, Col III, and DCN production was found for cells being exposed to the combined vibration and CTGF treatment. Noteworthy, the vibration and CTGF elicited a differential stimulatory effect on elastin (ELN), HA synthase 1 (HAS1), and fibroblast-specific protein-1 (FSP-1). The mitogenic activity of CTGF was only elicited in naïve cells without the vibratory preconditioning. The combined treatment had profound, but opposite effects on mitogen-activated protein kinase (MAPK) pathways, Erk1/2 and p38, and the Erk1/2 pathway was critical for the observed mechano-biochemical responses. Collectively, vibratory stresses and CTGF signals cooperatively coaxed MSCs toward a VFF-like phenotype and accelerated the synthesis and remodeling of vocal fold matrices. PMID:24456068

  3. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  4. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  5. Connective Tissue Growth Factor Is Required for Normal Follicle Development and Ovulation

    PubMed Central

    Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei; Lydon, John P.; DeMayo, Francesco J.; Lyons, Karen M.

    2011-01-01

    Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-β superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-β family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-β and progesterone signaling cascades and is necessary for normal follicle development and ovulation. PMID:21868453

  6. Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis

    PubMed Central

    Charrier, Alyssa; Brigstock, David R.

    2010-01-01

    Alcoholic chronic pancreatitis (ACP) is characterized by pancreatic necrosis, inflammation, and scarring, the latter of which is due to excessive collagen deposition by activated pancreatic stellate cells (PSC). The aim of this study was to establish a model of ACP in mice, a species that is usually resistant to the toxic effects of alcohol, and to identify the cell type(s) responsible for production of connective tissue growth factor (CTGF), a pro-fibrotic molecule. C57Bl/6 male mice received intraperitoneal ethanol injections for three weeks against a background of cerulein-induced acute pancreatitis. Peak blood alcohol levels remained consistently high in ethanol-treated mice as compared to control mice. In mice receiving ethanol plus cerulein, there was increased collagen deposition as compared to other treatment groups as well as increased frequency of α-smooth muscle actin and desmin-positive PSC which also demonstrated significantly enhanced CTGF protein production. Expression of mRNA for collagen α1(I), α-smooth muscle actin or CTGF were all increased and co-localized exclusively to activated PSC in ACP. Pancreatic expression of mRNA for key profibrotic markers were all increased in ACP. In conclusion, a mouse model of ACP has been developed that mimics key pathophysiological features of the disease in humans and which shows that activated PSC are the principal producers of collagen and CTGF. PSC-derived CTGF is thus a candidate therapeutic target in anti-fibrotic strategies for ACP. PMID:20368699

  7. Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves’ Ophthalmopathy

    PubMed Central

    Chang, Pei-Chen; Wei, Yau-Huei

    2015-01-01

    Graves’ ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green-based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age-matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 μM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO. PMID:26599235

  8. Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome.

    PubMed

    Chen, Y; Segarini, P; Raoufi, F; Bradham, D; Leask, A

    2001-11-15

    Connective tissue growth factor (CTGF) is a cysteine-rich heparin-binding polypeptide that promotes proliferation, collagen synthesis, and chemotaxis in mesanchymal cells. When coinjected subcutaneously with transforming growth factor beta (TGFbeta), CTGF promotes sustained fibrosis in rats. However, little is known about the cell biology and structure/functional relationship of CTGF. In particular, no detailed characterization of the subcellular localization of CTGF has occurred, nor have sequences been identified within this protein required for this localization. In this report, using immunofluorescence and Western blot analysis, we show that CTGF is localized to the Golgi apparatus both in dermal fibroblasts and activated hepatic stellate cells. Using these methods, no CTGF was detected in endosomal, plasma membrane, cytosolic or nuclear fractions. Addition of brefeldin A, a drug that disrupts the Golgi, blocks the secretion of CTGF. We further show that the amino-terminal 37 amino acids of CTGF are sufficient to localize a heterologous protein (red fluorescent protein, RFP) to the Golgi. Although within this region of human CTGF is a N-glycosylation site, tunicamycin, which blocks N-linked glycosylation, has no significant effect on CTGF secretion. Surprisingly, mutation of a single amino acid residue, CYS-34, to alanine prevents localization of a CTGF-RFP fusion protein to the Golgi. These results are the first proof that endogenous CTGF is localized to the Golgi apparatus. Furthermore, using exogenously added (125)I-labeled CTGF, we show that CTGF is internalized and rapidly degraded in the endosome. That is, CTGF is quantitatively secreted through the golgi and is degraded in the endosome.

  9. Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

    PubMed Central

    Gao, Run-Ping; Brigstock, David R

    2009-01-01

    AIM: To determine the effect of hammerhead ribozyme targeting connective tissue growth factor (CCN2) on human hepatic stellate cell (HSC) function. METHODS: CCN2 hammerhead ribozyme cDNA plus two self-cleaving sequences were inserted into pTriEx2 to produce pTriCCN2-Rz. Each vector was individually transfected into cultured LX-2 human HSCs, which were then stimulated by addition of transforming growth factor (TGF)-β1 to the culture medium. Semi-quantitative RT-PCR was used to determine mRNA levels for CCN2 or collagen I, while protein levels of each molecule in cell lysates and conditioned medium were measured by ELISA. Cell-cycle progression of the transfected cells was assessed by flow cytometry. RESULTS: In pTriEx2-transfected LX-2 cells, TGF-β1 treatment caused an increase in the mRNA level for CCN2 or collagen I, and an increase in produced and secreted CCN2 or extracellular collagen I protein levels. pTriCCN2-Rz-transfected LX-2 cells showed decreased basal CCN2 or collagen mRNA levels, as well as produced and secreted CCN2 or collagen I protein. Furthermore, the TGF-β1-induced increase in mRNA or protein for CCN2 or collagen I was inhibited partially in pTriCCN2-Rz-transfected LX-2 cells. Inhibition of CCN2 using hammerhead ribozyme cDNA resulted in fewer of the cells transitioning into S phase. CONCLUSION: Endogenous CCN2 is a mediator of basal or TGF-β1-induced collagen I production in human HSCs and regulates entry of the cells into S phase. PMID:19673024

  10. Hammerhead Ribozyme-Mediated Knockdown of mRNA for Fibrotic Growth Factors: Transforming Growth Factor-Beta 1 and Connective Tissue Growth Factor

    PubMed Central

    Robinson, Paulette M.; Blalock, Timothy D.; Yuan, Rong; Lewin, Alfred S.; Schultz, Gregory S.

    2013-01-01

    Excessive scarring (fibrosis) is a major cause of pathologies in multiple tissues, including lung, liver, kidney, heart, cornea, and skin. The transforming growth factor- β (TGF- β) system has been shown to play a key role in regulating the formation of scar tissue throughout the body. Furthermore, connective tissue growth factor (CTGF) has been shown to mediate most of the fibrotic actions of TGF- β, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. Currently, no approved drugs selectively and specifically regulate scar formation. Thus, there is a need for a drug that selectively targets the TGF- β cascade at the molecular level and has minimal off-target side effects. This chapter focuses on the design of hammerhead ribozymes, measurement of kinetic activity, and assessment of knockdown mRNAs of TGF- β and CTGF in cell cultures. PMID:22131029

  11. Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer.

    PubMed

    Wells, Julia E; Howlett, Meegan; Cole, Catherine H; Kees, Ursula R

    2015-08-01

    Connective tissue growth factor (CTGF/CCN2) has long been associated with human cancers. The role it plays in these neoplasms is diverse and tumour specific. Recurring patterns in clinical outcome, histological desmoplasia and mechanisms of action have been found. When CTGF is overexpressed compared to low-expressing normal tissue or is underexpressed compared to high-expressing normal tissue, the functional outcome favours tumour survival and disease progression. CTGF acts by altering proliferation, drug resistance, angiogenesis, adhesion and migration contributing to metastasis. The pattern of CTGF expression and tumour response helps to clarify the role of this matricellular protein across a multitude of human cancers.

  12. Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion

    PubMed Central

    Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M

    2010-01-01

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using α6β1 and α3β1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. PMID:19382180

  13. Connective tissue growth factor and its regulation: a new element in diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Cortes, P

    2001-01-01

    Connective tissue growth factor (CTGF), a member of the closely related CCN family of cytokines appears to be fibrotic in skin. To determine whether CTGF is implicated in diabetic glomerulosclerosis we studied cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to rhCTGF significantly increased fibronectin and collagen type I secretion. Further, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36-38 kDa). However, exposure to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in glomerulosclerosis, markedly induced the expression of CTGF transcripts. With all but mechanical strain there was a concomitant stimulation of CTGF protein secretion. TGF-beta also induced abundant quantities of a small molecular weight form of CTGF (18 kDa). The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta neutralizing antibody blocked this stimulation. In vivo studies using quantitative RT-PCR demonstrated that while CTGF transcripts were low in the glomeruli of control mice, expression was increased 27-fold after approximately 3.5 months of diabetes. These changes occurred early in diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced elevation of CTGF mRNA (2-fold) observed in whole kidney cortices indicted that the primary alteration of CTGF expression was in the glomerulus. These results suggest that CTGF upregulation is an important factor in the pathogenesis of mesangial matrix accumulation in both diabetic and non-diabetic glomerulosclerosis, acting downstream of TGF-beta. PMID:11499561

  14. Mechanisms of bradykinin-induced expression of connective tissue growth factor and nephrin in podocytes.

    PubMed

    Abou Msallem, J; Chalhoub, H; Al-Hariri, M; Saad, L; Jaffa, M A; Ziyadeh, F N; Jaffa, A A

    2015-12-01

    Diabetic nephropathy (DN) is the main cause of morbidity and mortality in diabetes and is characterized by mesangial matrix deposition and podocytopathy, including podocyte loss. The risk factors and mechanisms involved in the pathogenesis of DN are still not completely defined. In the present study, we aimed to understand the cellular mechanisms through which activation of B2 kinin receptors contribute to the initiation and progression of DN. Stimulation of cultured rat podocytes with bradykinin (BK) resulted in a significant increase in ROS generation, and this was associated with a significant increase in NADPH oxidase (NOX)1 and NOX4 protein and mRNA levels. BK stimulation also resulted in a signicant increase in the phosphorylation of ERK1/2 and Akt, and this effect was inhibited in the presence of NOX1 and Nox4 small interfering (si)RNA. Furthermore, podocytes stimulated with BK resulted in a significant increase in protein and mRNA levels of connective tissue growth factor (CTGF) and, at the same time, a significant decrease in protein and mRNA levels of nephrin. siRNA targeted against NOX1 and NOX4 significantly inhibited the BK-induced increase in CTGF. Nephrin expression was increased in response to BK in the presence of NOX1 and NOX4 siRNA, thus implicating a role for NOXs in modulating the BK response in podocytes. Moreover, nephrin expression in response to BK was also significantly increased in the presence of siRNA targeted against CTGF. These findings provide novel aspects of BK signal transduction pathways in pathogenesis of DN and identify novel targets for interventional strategies.

  15. [Connective tissue and inflammation].

    PubMed

    Jakab, Lajos

    2014-03-23

    The author summarizes the structure of the connective tissues, the increasing motion of the constituents, which determine the role in establishing the structure and function of that. The structure and function of the connective tissue are related to each other in the resting as well as inflammatory states. It is emphasized that cellular events in the connective tissue are part of the defence of the organism, the localisation of the damage and, if possible, the maintenance of restitutio ad integrum. The organism responds to damage with inflammation, the non specific immune response, as well as specific, adaptive immunity. These processes are located in the connective tissue. Sterile and pathogenic inflammation are relatively similar processes, but inevitable differences are present, too. Sialic acids and glycoproteins containing sialic acids have important roles, and the role of Siglecs is also highlighted. Also, similarities and differences in damages caused by pathogens and sterile agents are briefly summarized. In addition, the roles of adhesion molecules linked to each other, and the whole event of inflammatory processes are presented. When considering practical consequences it is stressed that the structure (building up) of the organism and the defending function of inflammation both have fundamental importance. Inflammation has a crucial role in maintaining the integrity and the unimpaired somato-psychological state of the organism. Thus, inflammation serves as a tool of organism identical with the natural immune response, inseparably connected with the specific, adaptive immune response. The main events of the inflammatory processes take place in the connective tissue.

  16. Optimum scratch assay condition to evaluate connective tissue growth factor expression for anti-scar therapy.

    PubMed

    Moon, Heekyung; Yong, Hyeyoung; Lee, Ae-Ri Cho

    2012-02-01

    To evaluate a potential anti-scar therapy, we first need to have a reliable in vitro wound model to understand dermal fibroblast response upon cell injury and how cytokine levels are changed upon different wound heal phases. An in vitro wound model with different scratch assay conditions on primary human foreskin fibroblast monolayer cultures was prepared and cytokine levels and growth properties were evaluated with the aim of determining optimum injury conditions and observation time. Morphological characteristics of differently scratched fibroblasts from 0 to 36 h post injury (1 line, 2 lines and 3 lines) were investigated. The expression of connective tissue growth factor, CTGF, which is a key mediator in hyper-tropic scarring, and relative intensity of CTGF as a function of time were determined by western blot and gelatin Zymography. After injury (1 line), CTGF level was increased more than 2-fold within 1 h and continuously increased up to 3-fold at 6 h and was leveled down to reach normal value at 36 h, at which cell migration was complete. In more serious injury (2 lines), higher expression of CTGF was observed. The down regulation of CTGF expression after CTGF siRNA/lipofectamine transfection in control, 1 line and 2 lines scratch conditions were 40%, 75% and 55%, respectively. As a model anti-CTGF based therapy, CTGF siRNA with different ratios of linear polyethyleneimine (PEI) complexes (1:1, 1:5, 1:10, 1:20 and 1:30) were prepared and down-regulation efficacy of CTGF was evaluated with our optimized scratch assay, which is 1 line injury at 6 h post injury observation time. As the cationic linear PEI ratio increased, the down regulation efficacy was increased from 20% (1:20) to 55% (1:30). As CTGF level was increased to the highest at 6 h and leveled down afterwards, CTGF level at 6 h could provide the most sensitive response upon CTGF siRNA transfection. The scratch assay in the present study can be employed as a useful experimental tool to differentiate

  17. Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-{beta} responsiveness

    SciTech Connect

    Mori, Yasuji; Hinchcliff, Monique; Wu, Minghua; Warner-Blankenship, Matthew; Lyons, Karen M.

    2008-03-10

    Background: The matricellular protein connective tissue growth factor (CCN2) has been implicated in pathological fibrosis, but its physiologic role remains elusive. In vitro, transforming growth factor-{beta} (TGF-{beta}) induces CCN2 expression in mesenchymal cells. Because CCN2 can enhance profibrotic responses elicited by TGF-{beta}, it has been proposed that CCN2 functions as an essential downstream signaling mediator for TGF-{beta}. To explore this notion, we characterized TGF-{beta}-induced activation of fibroblasts from CCN2-null (CCN2{sup -/-}) mouse embryos. Methods: The regulation of CCN2 expression was examined in vivo in a model of fibrosis induced by bleomycin. Cellular TGF-{beta} signal transduction and regulation of collagen gene expression were examined in CCN2{sup -/-} MEFs by immunohistochemistry, Northern, Western and RT-PCR analysis, immunocytochemistry and transient transfection assays. Results: Bleomycin-induced skin fibrosis in the mouse was associated with substantial CCN2 up-regulation in lesional fibroblasts. Whereas in vitro proliferation rate of CCN2{sup -/-} MEFs was markedly reduced compared to wild type MEFs, TGF-{beta}-induced activation of the Smad pathways, including Smad2 phosphorylation, Smad2/3 and Smad4 nuclear accumulation and Smad-dependent transcriptional responses, were unaffected by loss of CCN2. The stimulation of COL1A2 and fibronectin mRNA expression and promoter activity, and of corresponding protein levels, showed comparable time and dose-response in wild type and CCN2{sup -/-} MEFs, whereas stimulation of alpha smooth muscle actin and myofibroblast transdifferentiation showed subtle impairment in MEFs lacking CCN2. Conclusion: Whereas endogenous CCN2 plays a role in regulation of proliferation and TGF-{beta}-induced myofibroblast transdifferentiation, it appears to be dispensable for Smad-dependent stimulation of collagen and extracellular matrix synthesis in murine embryonic fibroblasts.

  18. Chemically-defined medium for growth and differentiation of mixed epithelial and connective tissues in organ culture.

    PubMed

    Hodges, G M; Melcher, A H

    1976-06-01

    The effect on tissue differentiation and growth in vitro of certain of the factors implicated in collagen synthesis (ascorbic acid, alpha-ketoglutarate and oxygen) and the influence of hydrocortisone was studied using organ cultures of fetal mouse mandible as a mixed epithelial and connective tissue system. Using serum-free Waymouth's MB 752/1 chemically-defined medium, addition of high levels of ascorbic acid (300mug per ml), hydrocortisone (1mug per ml) and oxygen (95%) enhanced differentiation in a number of tissues, in particular skin and appendages, tooth germs and bone, while osteoid and dentine production were noticeable promoted. It is suggested that an essential aspect of media design for organ culture involves the incorporaation of collagen-promoting factors to the in vitro enviornment particularly with regard to the controlling role implicated for collagen in a variety of biological processess.

  19. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    PubMed

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury.

  20. Connective Tissue Ulcers

    PubMed Central

    Dabiri, Ganary; Falanga, Vincent

    2013-01-01

    Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren’s syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers. PMID:23756459

  1. Mixed connective tissue disease.

    PubMed

    Gunnarsson, Ragnar; Hetlevik, Siri Opsahl; Lilleby, Vibke; Molberg, Øyvind

    2016-02-01

    The concept of mixed connective tissue disease (MCTD) as a separate connective tissue disease (CTD) has persisted for more than four decades. High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD, in addition to distinct clinical features including Raynaud's phenomenon (RP), "puffy hands," arthritis, myositis, pleuritis, pericarditis, interstitial lung disease (ILD), and pulmonary hypertension (PH). Recently, population-based epidemiology data from Norway estimated the point prevalence of adult-onset MCTD to be 3.8 per 100,000 and the mean annual incidence to be 2.1 per million per year, supporting the notion that MCTD is the least common CTD. Little is known about the etiology of MCTD, but recent genetic studies have confirmed that MCTD is a strongly HLA (​human leukocyte antigen)-linked disease, as the HLA profiles of MCTD differ distinctly from the corresponding profiles of ethnically matched healthy controls and other CTDs. In the first section of this review, we provide an update on the clinical, immunological, and genetic features of MCTD and discuss the relationship between MCTD and the other CTDs. Then we proceed to discuss the recent advances in therapy and our current understanding of prognosis and prognostic factors, especially those that are associated with the more serious pulmonary and cardiovascular complications of the disease. In the final section, we discuss some of the key, unresolved questions related to anti-RNP-associated diseases and indicate how these questions may be approached in future studies. PMID:27421219

  2. Controlling the Fibroblastic Differentiation of Mesenchymal Stem Cells Via the Combination of Fibrous Scaffolds and Connective Tissue Growth Factor

    PubMed Central

    Tong, Zhixiang; Sant, Shilpa

    2011-01-01

    Controlled differentiation of multi-potent mesenchymal stem cells (MSCs) into vocal fold-specific, fibroblast-like cells in vitro is an attractive strategy for vocal fold repair and regeneration. The goal of the current study was to define experimental parameters that can be used to control the initial fibroblastic differentiation of MSCs in vitro. To this end, connective tissue growth factor (CTGF) and micro-structured, fibrous scaffolds based on poly(glycerol sebacate) (PGS) and poly(ɛ-caprolactone) (PCL) were used to create a three-dimensional, connective tissue-like microenvironment. MSCs readily attached to and elongated along the microfibers, adopting a spindle-shaped morphology during the initial 3 days of preculture in an MSC maintenance medium. The cell-laden scaffolds were subsequently cultivated in a conditioned medium containing CTGF and ascorbic acids for up to 21 days. Cell morphology, proliferation, and differentiation were analyzed collectively by quantitative PCR analyses, and biochemical and immunocytochemical assays. F-actin staining showed that MSCs maintained their fibroblastic morphology during the 3 weeks of culture. The addition of CTGF to the constructs resulted in an enhanced cell proliferation, elevated expression of fibroblast-specific protein-1, and decreased expression of mesenchymal surface epitopes without markedly triggering chondrogenesis, osteogenesis, adipogenesis, or apoptosis. At the mRNA level, CTGF supplement resulted in a decreased expression of collagen I and tissue inhibitor of metalloproteinase 1, but an increased expression of decorin and hyaluronic acid synthesase 3. At the protein level, collagen I, collagen III, sulfated glycosaminoglycan, and elastin productivity was higher in the conditioned PGS-PCL culture than in the normal culture. These findings collectively demonstrate that the fibrous mesh, when combined with defined biochemical cues, is capable of fostering MSC fibroblastic differentiation in vitro. PMID

  3. Activation of JNK signaling mediates connective tissue growth factor expression and scar formation in corneal wound healing.

    PubMed

    Shi, Long; Chang, Yuan; Yang, Yongmei; Zhang, Ying; Yu, Fu-Shin X; Wu, Xinyi

    2012-01-01

    Connective Tissue Growth Factor (CTGF) and Transforming growth factor-β1 (TGF-β1) are key growth factors in regulating corneal scarring. Although CTGF was induced by TGF-β1 and mediated many of fibroproliferative effects of TGF-β1, the signaling pathway for CTGF production in corneal scarring remains to be clarified. In the present study, we firstly investigated the effects of c-Jun N-terminal kinase (JNK) on CTGF expression induce by TGF-β1 in Telomerase-immortalized human cornea stroma fibroblasts (THSF). Then, we created penetrating corneal wound model and determined the effect of JNK in the pathogenesis of corneal scarring. TGF-β1 activated MAPK pathways in THSF cells. JNK inhibitor significantly inhibited CTGF, fibronectin and collagen I expression induced by TGF-β1 in THSF. In corneal wound healing, the JNK inhibitor significantly inhibited CTGF expression, markedly improved the architecture of corneal stroma and reduced corneal scar formation, but did not have a measurable impact on corneal wound healing in vivo. Our results indicate that JNK mediates the expression of CTGF and corneal scarring in corneal wound healing, and might be considered as specific targets of drug therapy for corneal scarring.

  4. Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

    PubMed Central

    Gravning, Jørgen; Ørn, Stein; Kaasbøll, Ole Jørgen; Martinov, Vladimir N.; Manhenke, Cord; Dickstein, Kenneth; Edvardsen, Thor; Attramadal, Håvard; Ahmed, Mohammed Shakil

    2012-01-01

    Aims Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI. Methods and Results Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15. Conclusion Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis. PMID:23284892

  5. Schwann cells but not olfactory ensheathing cells inhibit CNS myelination via the secretion of connective tissue growth factor.

    PubMed

    Lamond, Rebecca; Barnett, Susan C

    2013-11-20

    Cell transplantation is a promising strategy to promote CNS repair and has been studied for several decades with a focus on glial cells. Promising candidates include Schwann cells (SCs) and olfactory ensheathing cells (OECs). Both cell types are thought to be neural crest derived and share many properties in common, although OECs appear to be a better candidate for transplantation by evoking less astrogliosis. Using CNS mixed myelinating rat cultures plated on to a monolayer of astrocytes, we demonstrated that SCs, but not OECs, secrete a heat labile factor(s) that inhibits oligodendrocyte myelination. Comparative qRT-PCR and ELISA showed that SCs expressed higher levels of mRNA and protein for connective tissue growth factor (CTGF) than OECs. Anti-CTGF reversed the SCM-mediated effects on myelination. Both SCM and CTGF inhibited the differentiation of purified rat oligodendrocyte precursor cells (OPCs). Furthermore, pretreatment of astrocyte monolayers with SCM inhibited CNS myelination and led to transcriptional changes in the astrocyte, corresponding to upregulation of bone morphogenic protein 4 mRNA and CTGF mRNA (inhibitors of OPC differentiation) and the downregulation of insulin-like growth factor 2 mRNA (promoter of OPC differentiation). CTGF pretreatment of astrocytes increased their expression of CTGF, suggesting that this inhibitory factor can be positively regulated in astrocytes. These data provide evidence for the advantages of using OECs, and not mature SCs, for transplant-mediated repair and provide more evidence that they are a distinct and unique glial cell type.

  6. Dexamethasone Induces Connective Tissue Growth Factor Expression in Renal Tubular Epithelial Cells in a Mouse Strain-Specific Manner

    PubMed Central

    Okada, Hirokazu; Kikuta, Tomohiro; Inoue, Tsutomu; Kanno, Yoshihiko; Ban, Shinichi; Sugaya, Takeshi; Takigawa, Masaharu; Suzuki, Hiromichi

    2006-01-01

    Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-β1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 × SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the −897- to −628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the −897- to −628-bp region of the CTGF promoter. PMID:16507889

  7. Connective Tissue Growth Factor reporter mice label a subpopulation of mesenchymal progenitor cells that reside in the trabecular bone region.

    PubMed

    Wang, Wen; Strecker, Sara; Liu, Yaling; Wang, Liping; Assanah, Fayekah; Smith, Spenser; Maye, Peter

    2015-02-01

    Few gene markers selectively identify mesenchymal progenitor cells inside the bone marrow. We have investigated a cell population located in the mouse bone marrow labeled by Connective Tissue Growth Factor reporter expression (CTGF-EGFP). Bone marrow flushed from CTGF reporter mice yielded an EGFP+ stromal cell population. Interestingly, the percentage of stromal cells retaining CTGF reporter expression decreased with age in vivo and was half the frequency in females compared to males. In culture, CTGF reporter expression and endogenous CTGF expression marked the same cell types as those labeled using Twist2-Cre and Osterix-Cre fate mapping approaches, which previously had been shown to identify mesenchymal progenitors in vitro. Consistent with this past work, sorted CTGF+ cells displayed an ability to differentiate into osteoblasts, chondrocytes, and adipocytes in vitro and into osteoblast, adipocyte, and stromal cell lineages after transplantation into a parietal bone defect. In vivo examination of CTGF reporter expression in bone tissue sections revealed that it marked cells highly localized to the trabecular bone region and was not expressed in the perichondrium or periosteum. Mesenchymal cells retaining high CTGF reporter expression were adjacent to, but distinct from mature osteoblasts lining bone surfaces and endothelial cells forming the vascular sinuses. Comparison of CTGF and Osterix reporter expression in bone tissue sections indicated an inverse correlation between the strength of CTGF expression and osteoblast maturation. Down-regulation of CTGF reporter expression also occurred during in vitro osteogenic differentiation. Collectively, our studies indicate that CTGF reporter mice selectively identify a subpopulation of bone marrow mesenchymal progenitor cells that reside in the trabecular bone region.

  8. [Muscles and connective tissue: histology].

    PubMed

    Delage, J-P

    2012-10-01

    Here, we give some comments about the DVD movies "Muscle Attitudes" from Endovivo productions, the movies up lighting some loss in the attention given to studies on the connective tissue, and especially them into muscles. The main characteristics of the different components in the intra-muscular connective tissue (perimysium, endomysium, epimysium) are shown here with special references to their ordered architecture and special references to their spatial distributions. This connective tissue is abundant into the muscles and is in continuity with the muscles in vicinity, with their tendons and their sheath, sticking the whole on skin. This connective tissue has also very abundant connections on the muscles fibres. It is then assumed that the connective tissue sticks every organs or cells of the locomotion system. Considering the elastic properties of the collagen fibres which are the most abundant component of connective tissue, it is possible to up light a panel of connective tissue associated functions such as the transmission of muscle contractions or the regulation of protein and energetic muscles metabolism.

  9. Connective tissue and its growth factor CTGF distinguish the morphometric and molecular remodeling of the bladder in a model of neurogenic bladder.

    PubMed

    Altuntas, Cengiz Z; Daneshgari, Firouz; Izgi, Kenan; Bicer, Fuat; Ozer, Ahmet; Sakalar, Cagri; Grimberg, Kerry O; Sayin, Ismail; Tuohy, Vincent K

    2012-11-01

    We previously reported that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), develop profound urinary bladder dysfunction. Because neurogenic bladder in MS patients causes marked bladder remodeling, we next examined morphometric and molecular alterations of the bladder in EAE mice. EAE was created in female SJL/J mice by immunization with the p139-151 encephalitogenic peptide of myelin proteolipid protein in complete Freund's adjuvant, along with intraperitoneal injections of Bordetella pertussis toxin. Seventy days after immunization, mice were scored for the level of neurological impairment and then killed. Spinal cord sections were assessed for demyelination, inflammation, and T cell infiltration; the composition of the bladder tissue was measured quantitatively; and gene expression of markers of tissue remodeling and fibrosis was assessed. A significant increase in the bladder weight-to-body weight ratio was observed with increasing neurological impairment, and morphometric analysis showed marked bladder remodeling with increased luminal area and tissue hypertrophy. Despite increased amounts of all tissue components (urothelium, smooth muscle, and connective tissue), the ratio of connective tissue to muscle increased significantly in EAE mice compared with control mice. Marked increases in mRNA expression of collagen type I α(2), tropoelastin, transforming growth factor-β3, and connective tissue growth factor (CTGF) were observed in EAE mice, as were decreased levels of mRNAs for smooth muscle myosin heavy chain, nerve growth factors, and muscarinic and purinergic receptors. Our results suggest that bladder remodeling corresponding to EAE severity may be due to enhanced expression of CTGF and increased growth of connective tissue.

  10. Connective tissue and its growth factor CTGF distinguish the morphometric and molecular remodeling of the bladder in a model of neurogenic bladder

    PubMed Central

    Altuntas, Cengiz Z.; Izgi, Kenan; Bicer, Fuat; Ozer, Ahmet; Sakalar, Cagri; Grimberg, Kerry O.; Sayin, Ismail; Tuohy, Vincent K.

    2012-01-01

    We previously reported that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), develop profound urinary bladder dysfunction. Because neurogenic bladder in MS patients causes marked bladder remodeling, we next examined morphometric and molecular alterations of the bladder in EAE mice. EAE was created in female SJL/J mice by immunization with the p139–151 encephalitogenic peptide of myelin proteolipid protein in complete Freund's adjuvant, along with intraperitoneal injections of Bordetella pertussis toxin. Seventy days after immunization, mice were scored for the level of neurological impairment and then killed. Spinal cord sections were assessed for demyelination, inflammation, and T cell infiltration; the composition of the bladder tissue was measured quantitatively; and gene expression of markers of tissue remodeling and fibrosis was assessed. A significant increase in the bladder weight-to-body weight ratio was observed with increasing neurological impairment, and morphometric analysis showed marked bladder remodeling with increased luminal area and tissue hypertrophy. Despite increased amounts of all tissue components (urothelium, smooth muscle, and connective tissue), the ratio of connective tissue to muscle increased significantly in EAE mice compared with control mice. Marked increases in mRNA expression of collagen type I α2, tropoelastin, transforming growth factor-β3, and connective tissue growth factor (CTGF) were observed in EAE mice, as were decreased levels of mRNAs for smooth muscle myosin heavy chain, nerve growth factors, and muscarinic and purinergic receptors. Our results suggest that bladder remodeling corresponding to EAE severity may be due to enhanced expression of CTGF and increased growth of connective tissue. PMID:22993071

  11. Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy Is Caused by Local Production and Tubular Dysfunction

    PubMed Central

    Gerritsen, Karin G. F.; Leeuwis, Jan Willem; Koeners, Maarten P.; Bakker, Stephan J. L.; van Oeveren, Willem; Aten, Jan; Tarnow, Lise; Rossing, Peter; Wetzels, Jack F. M.; Joles, Jaap A.; Kok, Robbert Jan; Goldschmeding, Roel; Nguyen, Tri Q.

    2015-01-01

    Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease. PMID:26171399

  12. Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- β/Smads Signalings.

    PubMed

    Jeong, Moon Hee; Kim, Shang-Jin; Kang, Hara; Park, Kye Won; Park, Woo Jin; Yang, Seung Yul; Yang, Dong Kwon

    2015-01-01

    Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I's utility as a novel therapeutic agent for the management of heart diseases. PMID:26296085

  13. SMAD3 and SP1/SP3 Transcription Factors Collaborate to Regulate Connective Tissue Growth Factor Gene Expression in Myoblasts in Response to Transforming Growth Factor β.

    PubMed

    Córdova, Gonzalo; Rochard, Alice; Riquelme-Guzmán, Camilo; Cofré, Catalina; Scherman, Daniel; Bigey, Pascal; Brandan, Enrique

    2015-09-01

    Fibrotic disorders are characterized by an increase in extracellular matrix protein expression and deposition, Duchene Muscular Dystrophy being one of them. Among the factors that induce fibrosis are Transforming Growth Factor type β (TGF-β) and the matricellular protein Connective Tissue Growth Factor (CTGF/CCN2), the latter being a target of the TGF-β/SMAD signaling pathway and is the responsible for the profibrotic effects of TGF-β. Both CTGF and TGF are increased in tissues affected by fibrosis but little is known about the regulation of the expression of CTGF mediated by TGF-β in muscle cells. By using luciferase reporter assays, site directed mutagenesis and specific inhibitors in C2C12 cells; we described a novel SMAD Binding Element (SBE) located in the 5' UTR region of the CTGF gene important for the TGF-β-mediated expression of CTGF in myoblasts. In addition, our results suggest that additional transcription factor binding sites (TFBS) present in the 5' UTR of the CTGF gene are important for this expression and that SP1/SP3 factors are involved in TGF-β-mediated CTGF expression.

  14. Connective tissue growth factor inhibition attenuates left ventricular remodeling and dysfunction in pressure overload-induced heart failure.

    PubMed

    Szabó, Zoltán; Magga, Johanna; Alakoski, Tarja; Ulvila, Johanna; Piuhola, Jarkko; Vainio, Laura; Kivirikko, Kari I; Vuolteenaho, Olli; Ruskoaho, Heikki; Lipson, Kenneth E; Signore, Pierre; Kerkelä, Risto

    2014-06-01

    Connective tissue growth factor (CTGF) is involved in the pathogenesis of various fibrotic disorders. However, its role in the heart is not clear. To investigate the role of CTGF in regulating the development of cardiac fibrosis and heart failure, we subjected mice to thoracic aortic constriction (TAC) or angiotensin II infusion, and antagonized the function of CTGF with CTGF monoclonal antibody (mAb). After 8 weeks of TAC, mice treated with CTGF mAb had significantly better preserved left ventricular (LV) systolic function and reduced LV dilatation compared with mice treated with control immunoglobulin G. CTGF mAb-treated mice exhibited significantly smaller cardiomyocyte cross-sectional area and reduced expression of hypertrophic marker genes. CTGF mAb treatment reduced the TAC-induced production of collagen 1 but did not significantly attenuate TAC-induced accumulation of interstitial fibrosis. Analysis of genes regulating extracellular matrix proteolysis showed decreased expression of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 in mice treated with CTGF mAb. In contrast to TAC, antagonizing the function of CTGF had no effect on LV dysfunction or LV hypertrophy in mice subjected to 4-week angiotensin II infusion. Further analysis showed that angiotensin II-induced expression of hypertrophic marker genes or collagens was not affected by treatment with CTGF mAb. In conclusion, CTGF mAb protects from adverse LV remodeling and LV dysfunction in hearts subjected to pressure overload by TAC. Antagonizing the function of CTGF may offer protection from cardiac end-organ damage in patients with hypertension.

  15. Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF)

    PubMed Central

    Jadhav, Vaishnavi; Luo, Qianyi; M. Dominguez, James; Al-Sabah, Jude; Chaqour, Brahim; Grant, Maria B.; Bhatwadekar, Ashay D.

    2016-01-01

    Period 2-mutant mice (Per2m/m), which possess a circadian dysfunction, recapitulate the retinal vascular phenotype similar to diabetic retinopathy (DR). The vascular dysfunction in Per2m/m is associated with an increase in connective tissue growth factor (CTGF/CCN2). At the molecular level, CTGF gene expression is dependent on the canonical Wnt/β-catenin pathway. The nuclear binding of β-catenin to a transcription factor, lymphoid enhancer binding protein (Lef)/ T-cell factor (TCF/LEF), leads to downstream activation of CTGF. For this study, we hypothesized that the silencing of Per2 results in nuclear translocation and subsequent transactivation of the CTGF gene. To test this hypothesis, we performed immunofluorescence labeling for CTGF in retinal sections from wild-type (WT) and Per2m/m mice. Human retinal endothelial cells (HRECs) were transfected with siRNA for Per2, and the protein expression of CTGF and β-catenin was evaluated. The TCF/LEF luciferase reporter (TOPflash) assay was performed to validate the involvement of β-catenin in the activation of CTGF. Per2m/m retinas exhibited an increased CTGF immunostaining in ganglion cell layer and retinal endothelium. Silencing of Per2 using siRNA resulted in an upregulation of CTGF and β-catenin. The TOPflash assay revealed an increase in luminescence for HRECs transfected with Per2 siRNA. Our studies show that loss of Per2 results in an activation of CTGF via nuclear entry of β-catenin. Our study provides novel insight into the understanding of microvascular dysfunction in Per2m/m mice. PMID:27662578

  16. Lysophosphatidic acid upregulates connective tissue growth factor expression in osteoblasts through the GPCR/PKC and PKA pathways.

    PubMed

    Yu, Zi-Li; Li, Dian-Qi; Huang, Xiang-Yu; Xing, Xin; Yu, Ru-Qing; Li, Zhi; Li, Zu-Bing

    2016-02-01

    Lysophosphatidic acid (LPA) is an efficient, bioactive phospholipid involved in various biological processes. In this study, LPA-induced connective tissue growth factor (CTGF/CCN2) expression and the underlying mechanisms were investigated using the MC3T3-E1 cell line. The MC3T3-E1 cells were stimulated with an inhibitor of LPA receptors, an activator and inhibitor of protein kinase C (PKC) and protein kinase A (PKA) for indicated periods of time. RT-qPCR and western blot analyses were used to measure the expression levels of CCN2. Immunofluorescence staining was used to observe the translocation of PKC. The mRNA expression level of CCN2 was increased following stimulation of the cells with LPA; LPA transiently induced the mRNA expression of CCN2; maximum expression levels were observed 2 h following stimulation with LPA. This increase was accompanied by CCN2 protein synthesis. LPA receptor1/3 was inhibited by Ki16425, a specific inhibitor of LPA1/3; as a result, the LPA-induced increase in CCN2 expression was abrogated. LPA also induced the membrane translocation of PKC and enhanced PKC activity in the osteoblasts. Pre-treatment of the osteoblasts with staurosporine prevented the increase in CCN2 expression by induced by LPA, and the activation of PKC by phorbol 12-myristate 13-acetate (PMA) enhanced CCN2 expression, indicating that the PKC pathway is involved in the LPA-induced increase in CCN2 expression. The interference of PKA signaling also led to the induction of CCN2 expresion by LPA. These data indicate that LPA increases CCN2 expression through the activation of PKC and PKA. Thus, the regulatory functions of the PKC and PKA pathways are implicated in the LPA-induced increase in CCN2 expression.

  17. MicroRNA-145 Is Downregulated in Glial Tumors and Regulates Glioma Cell Migration by Targeting Connective Tissue Growth Factor

    PubMed Central

    Cazacu, Simona; Finniss, Susan; Xiang, Cunli; Twito, Hodaya; Poisson, Laila M.; Mikkelsen, Tom; Slavin, Shimon; Jacoby, Elad; Yalon, Michal; Toren, Amos; Rempel, Sandra A.; Brodie, Chaya

    2013-01-01

    Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3′-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3′-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors. PMID:23390502

  18. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Denichilo, M; Cortes, P; Baker, C; Grondin, J M; Yee, J; Narins, R G

    2000-01-01

    Connective tissue growth factor (CTGF) is a peptide secreted by cultured endothelial cells and fibroblasts when stimulated by transforming growth factor-beta (TGF-beta), and is overexpressed during fibrotic processes in coronary arteries and in skin. To determine whether CTGF is implicated in the pathogenesis of diabetic glomerulosclerosis, cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli were examined from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to recombinant human CTGF significantly increased fibronectin and collagen type I production. Furthermore, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36 to 38 kD) into the media. However, sodium heparin treatment resulted in a greater than fourfold increase in media-associated CTGF, suggesting that the majority of CTGF produced was cell- or matrix-bound. Exposure of MC to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in diabetic glomerulosclerosis, markedly induced the expression of CTGF transcripts, while recombinant human CTGF was able to autoinduce its own expression. TGF-, and high glucose, but not mechanical strain, stimulated the concomitant secretion of CTGF protein, the former also inducing abundant quantities of a small molecular weight form of CTGF (18 kD) containing the heparin-binding domain. The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta-neutralizing antibody blocked this stimulation. In vivo studies using quantitative reverse transcription-PCR demonstrated that although CTGF transcripts were low in the glomeruli of control mice, expression was increased 28-fold after approximately 3.5 mo of diabetes. This change occurred early in the course of diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced

  19. Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells

    PubMed Central

    Pi, Liya; Chung, Pei-Yu; Sriram, Sriniwas; Rahman, Masmudur M; Song, Wen-Yuan; Scott, Edward W; Petersen, Bryon E; Schultz, Gregory S

    2015-01-01

    AIM: To study the binding of connective tissue growth factor (CTGF) to cystine knot-containing ligands and how this impacts platelet-derived growth factor (PDGF)-B signaling. METHODS: The binding strengths of CTGF to cystine knot-containing growth factors including vascular endothelial growth factor (VEGF)-A, PDGF-B, bone morphogenetic protein (BMP)-4, and transforming growth factor (TGF)-β1 were compared using the LexA-based yeast two-hybrid system. EYG48 reporter strain that carried a wild-type LEU2 gene under the control of LexA operators and a lacZ reporter plasmid (p80p-lacZ) containing eight high affinity LexA binding sites were used in the yeast two-hybrid analysis. Interactions between CTGF and the tested growth factors were evaluated based on growth of transformed yeast cells on selective media and colorimetric detection in a liquid β-galactosidase activity assay. Dissociation constants of CTGF to VEGF-A isoform 165 or PDGF-BB homo-dimer were measured in surface plasma resonance (SPR) analysis. CTGF regulation in PDGF-B presentation to the PDGF receptor β (PDGFRβ) was also quantitatively assessed by the SPR analysis. Combinational effects of CTGF protein and PDGF-BB on activation of PDGFRβ and downstream signaling molecules ERK1/2 and AKT were assessed in rabbit corneal fibroblast cells by Western analysis. RESULTS: In the LexA-based yeast two-hybrid system, cystine knot motifs of tested growth factors were fused to the activation domain of the transcriptional factor GAL4 while CTGF was fused to the DNA binding domain of the bacterial repressor protein LexA. Yeast co-transformants containing corresponding fusion proteins for CTGF and all four tested cystine knot motifs survived on selective medium containing galactose and raffinose but lacking histidine, tryptophan, and uracil. In liquid β-galactosidase assays, CTGF expressing cells that were co-transformed with the cystine knot of VEGF-A had the highest activity, at 29.88 ± 0.91 fold above controls

  20. The matrix-binding domain of microfibril-associated glycoprotein-1 targets active connective tissue growth factor to a fibroblast-produced extracellular matrix.

    PubMed

    Weinbaum, Justin S; Tranquillo, Robert T; Mecham, Robert P

    2010-11-10

    It is advantageous to use biomaterials in tissue engineering that stimulate extracellular matrix (ECM) production by the cellular component. Connective tissue growth factor (CTGF) stimulates type I collagen (COL1A1) transcription, but is functionally limited as a free molecule. Using a matrix-binding domain (MBD) from microfibril-associated glycoprotein-1, the fusion protein MBD-CTGF was targeted to the ECM and tested for COL1A1 transcriptional activation. MBD-CTGF produced by the ECM-synthesizing fibroblasts, or provided exogenously, localized to the elastic fiber ECM. MBD-CTGF, but not CTGF alone, led to a two-fold enhancement of COL1A1 expression. This study introduces a targeting technology that can be used to elevate collagen transcription in engineered tissues and thereby improve tissue mechanics.

  1. Effects of transforming growth factor β2 and connective tissue growth factor on induction of epithelial mesenchymal transition and extracellular matrix synthesis in human lens epithelial cells

    PubMed Central

    Pei, Cheng; Ma, Bo; Kang, Qian-Yan; Qin, Li; Cui, Li-Jun

    2013-01-01

    AIM To investigate the effects of transforming growth factor β2 (TGF-β2) and connective tissue growth factor (CTGF) on transdifferentiation of human lens epithelial cells (HLECs) cultured in vitro and synthesis of extracellular matrix (ECM). METHODS HLECs were treated with TGF-β2 (0, 0.5, 1.0, 5, 10µg/L) and CTGF (0, 15, 30, 60, 100µg/L) for different times (0, 24, 48, 72h) in vitro and the expression of α-smooth muscle actin (α-SMA), the main component of the extracellular matrix type I collagen (Col-1) and fibronectin (Fn) were measured by using real-time polymerase chain reaction (PCR) and western-blot. RESULTS TGF-β2 and CTGF significantly increased expression of α-SMA mRNA and protein (P<0.05, P<0.001), Fn mRNA and protein (P<0.001), Col-1 mRNA and protein (P<0.001). TGF-β2 could induce HLECs expression of CTGF mRNA and protein in dose-dependent manner (P<0.05, P<0.001). TGF-β2 and CTGF could induce HLECs to express α-SMA, Fn and Col-1 in time-dependent manner. Each time of TGF-β2 and CTGF induced HELCs expression of α-SMA, Fn, Col-1 mRNA and protein was significant increase compared with control (P<0.05, P<0.001). CONCLUSION TGF-β2 and CTGF could induce HLECs epithelial mesenchymal transition and ECM synthesis. PMID:24392320

  2. Growth and maturational changes in dense fibrous connective tissue following 14 days of rhGH supplementation in the dwarf rat

    NASA Technical Reports Server (NTRS)

    Kyparos, Antonios; Orth, Michael W.; Vailas, Arthur C.; Martinez, Daniel A.

    2002-01-01

    The purpose of this study was to investigate the impact of recombinant human growth hormone (rhGH) on patella tendon (PT), medial collateral ligament (MCL), and lateral collateral ligament (LCL) on collagen growth and maturational changes in dwarf GH-deficient rats. Twenty male Lewis mutant dwarf rats, 37 days of age, were randomly assigned to Dwarf + rhGH (n = 10) and Dwarf + vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt twice daily for 14 days. rhGH administration stimulated dense fibrous connective tissue growth, as demonstrated by significant increases in hydroxyproline specific activity and significant decreases in the non-reducible hydroxylysylpyridinoline (HP) collagen cross-link contents. The increase in the accumulation of newly accreted collagen was 114, 67, and 117% for PT, MCL, and LCL, respectively, in 72 h. These findings suggest that a short course rhGH treatment can affect the rate of new collagen production. However, the maturation of the tendon and ligament tissues decreased 18-25% during the rapid accumulation of de novo collagen. We conclude that acute rhGH administration in a dwarf rat can up-regulate new collagen accretion in dense fibrous connective tissues, while causing a reduction in collagen maturation. Copyright 2002 Elsevier Science Ltd.

  3. Transforming growth factor-β (TGF-β) expression is increased in the subsynovial connective tissues of patients with idiopathic carpal tunnel syndrome.

    PubMed

    Chikenji, Takako; Gingery, Anne; Zhao, Chunfeng; Passe, Sandra M; Ozasa, Yasuhiro; Larson, Dirk; An, Kai-Nan; Amadio, Peter C

    2014-01-01

    Non-inflammatory fibrosis of the subsynovial connective tissue (SSCT) is a hallmark of carpal tunnel syndrome (CTS). The etiology of this finding and its relationship to the development of CTS remain poorly understood. Recent studies have found that transforming growth factor-β (TGF-β) plays a central role in fibrosis. The purpose of this study was to investigate the expression of TGF-β and connective tissue growth factor (CTGF), a downstream mediator of TGF-β, in the pathogenesis of CTS. We compared SSCT specimens from 26 idiopathic CTS patients with specimens from 10 human cadaver controls with no previous diagnosis of CTS. Immunohistochemistry was performed to determine levels TGF-β1, CTGF, collagen 1(Col1) and collagen 3 (Col3) expression. TGF-β1 (p < 0.01), CTGF (p < 0.01), and Col3 (p < 0.01) were increased in SSCT of CTS patients compared with control tissue. In addition, a strong positive correlation was found between TGF-β1 and CTGF, (R(2) = 0.80, p < 0.01) and a moderate positive correlation between Col3 and TGF-β1 (R(2) = 0.49, p < 0.01). These finding suggest that there is an increased expression of TGF-β and CTGF, a TGF-β regulated protein, and that this TGF-β activation may be responsible for SSCT fibrosis in CTS patients.

  4. Hematopoietic stem cell origin of connective tissues.

    PubMed

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications.

  5. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties.

    PubMed

    Carroll, Chad C

    2016-01-01

    Exercising individuals commonly consume analgesics, but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling.

  6. Werner's syndrome: a review of recent research with an analysis of connective tissue metabolism, growth control of cultured cells, and chromosomal aberrations.

    PubMed

    Salk, D

    1982-01-01

    Werner's syndrome is a rare, autosomal recessive condition with multiple progeroid features, but it is an imitation of aging rather than accelerated or premature senescence. Somatic chromosome aberrations occur in multiple tissues in vivo and in vitro, and there is an increased incidence of neoplasia. Thus. Werner's syndrome can be classified in the group of chromosome instability syndromes. Recent findings provide additional support for the concept that there is an aberration of connective tissue metabolism in Werner's syndrome, but it is unclear whether this is a primary or secondary manifestation of the underlying genetic defect. Abnormal growth characteristics are observed in cultured skin fibroblast-like cells and this provides another avenue for current research. Identification of the basic genetic defect in Werner's syndrome might clarify our understanding of the normal aging process in general, or might elucidate specific aspects such as the development of neoplasia, atherosclerosis, diabetes, or osteoporosis.

  7. Transforming growth factor-β (TGF-β) expression is increased in the subsynovial connective tissue in a rabbit model of carpal tunnel syndrome.

    PubMed

    Chikenji, Takako; Gingery, Anne; Zhao, Chunfeng; Vanhees, Matthias; Moriya, Tamami; Reisdorf, Ramona; An, Kai-Nan; Amadio, Peter C

    2014-01-01

    Carpal tunnel syndrome (CTS) is an idiopathic disease that results from increased fibrosis of the subsynovial connective tissue (SSCT). A recent study found overexpression of both transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) in the SSCT of CTS patients. This study investigated TGF-β and CTGF expression in a rabbit model of CTS, in which SSCT fibrosis is induced by a surgical injury. Levels of TGF-β1 and CTGF at 6, 12, 24 weeks after injury were determined by immunohistochemistry A significant increase in TGF-β1 and a concomitant significant increase in CTGF were found at 6 weeks, in addition to higher cell density compared to normal (all p<0.05), Interestingly, CTGF expression was reduced at 12 and 24 weeks, suggesting that an initial insult results in a time limited response. We conclude that this rabbit model mimics the fibrosis found in human CTS, and may be useful to study pathogenetic mechanisms of CTS in vivo.

  8. Radiotherapy in patients with connective tissue diseases.

    PubMed

    Giaj-Levra, Niccolò; Sciascia, Savino; Fiorentino, Alba; Fersino, Sergio; Mazzola, Rosario; Ricchetti, Francesco; Roccatello, Dario; Alongi, Filippo

    2016-03-01

    The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy.

  9. Inhibition of connective tissue growth factor (CTGF/CCN2) expression decreases the survival and myogenic differentiation of human rhabdomyosarcoma cells.

    PubMed

    Croci, Stefania; Landuzzi, Lorena; Astolfi, Annalisa; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Follo, Matilde Y; Oliver, Noelynn; De Giovanni, Carla; Nanni, Patrizia; Lollini, Pier-Luigi

    2004-03-01

    Connective tissue growth factor (CTGF/CCN2), a cysteine-rich protein of the CCN (Cyr61, CTGF, Nov) family of genes, emerged from a microarray screen of genes expressed by human rhabdomyosarcoma cells. Rhabdomyosarcoma is a soft tissue sarcoma of childhood deriving from skeletal muscle cells. In this study, we investigated the role of CTGF in rhabdomyosarcoma. Human rhabdomyosarcoma cells of the embryonal (RD/12, RD/18, CCA) and the alveolar histotype (RMZ-RC2, SJ-RH4, SJ-RH30), rhabdomyosarcoma tumor specimens, and normal skeletal muscle cells expressed CTGF. To determine the function of CTGF, we treated rhabdomyosarcoma cells with a CTGF antisense oligonucleotide or with a CTGF small interfering RNA (siRNA). Both treatments inhibited rhabdomyosarcoma cell growth, suggesting the existence of a new autocrine loop based on CTGF. CTGF antisense oligonucleotide-mediated growth inhibition was specifically due to a significant increase in apoptosis, whereas cell proliferation was unchanged. CTGF antisense oligonucleotide induced a strong decrease in the level of myogenic differentiation of rhabdomyosarcoma cells, whereas the addition of recombinant CTGF significantly increased the proportion of myosin-positive cells. CTGF emerges as a survival and differentiation factor and could be a new therapeutic target in human rhabdomyosarcoma.

  10. A virus-like particle-based connective tissue growth factor vaccine suppresses carbon tetrachloride-induced hepatic fibrosis in mice.

    PubMed

    Li, Shuang; Lv, Yi-Fei; Su, Hou-Qiang; Zhang, Qian-Nan; Wang, Li-Rong; Hao, Zhi-Ming

    2016-01-01

    Connective tissue growth factor (CTGF) has been recognized as a central mediator and promising therapeutic target in hepatic fibrosis. In this study, we generated a novel virus-like particle (VLP) CTGF vaccine by inserting the 138-159 amino acid (aa) fragment of CTGF into the central c/e1 epitope of C-terminus truncated hepatitis B virus core antigen (HBc, aa 1-149) using a prokaryotic expression system. Immunization of BALB/c mice with the VLP vaccine efficiently elicited the production of anti-CTGF neutralizing antibodies. Vaccination with this CTGF vaccine significantly protected BALB/c mice from carbon tetrachloride (CCl4)-induced hepatic fibrosis, as indicated by decreased hepatic hydroxyproline content and lower fibrotic score. CCl4 intoxication-induced hepatic stellate cell activation was inhibited by the vaccination, as indicated by decreased α-smooth muscle actin expression and Smad2 phosphorylation. Vaccination against CTGF also attenuated the over-expression of some profibrogenic factors, such as CTGF, transforming growth factor-β1, platelet-derived growth factor-B and tissue inhibitor of metalloproteinase-1 in the fibrotic mouse livers, decreased hepatocyte apoptosis and accelerated hepatocyte proliferation in the fibrotic mouse livers. Our results clearly indicate that vaccination against CTGF inhibits fibrogenesis, alleviates hepatocyte apoptosis and facilitate hepatic regeneration. We suggest that the vaccine should be developed into an effective therapeutic measure for hepatic fibrosis. PMID:27562139

  11. A virus-like particle-based connective tissue growth factor vaccine suppresses carbon tetrachloride-induced hepatic fibrosis in mice

    PubMed Central

    Li, Shuang; Lv, Yi-Fei; Su, Hou-Qiang; Zhang, Qian-Nan; Wang, Li-Rong; Hao, Zhi-Ming

    2016-01-01

    Connective tissue growth factor (CTGF) has been recognized as a central mediator and promising therapeutic target in hepatic fibrosis. In this study, we generated a novel virus-like particle (VLP) CTGF vaccine by inserting the 138–159 amino acid (aa) fragment of CTGF into the central c/e1 epitope of C-terminus truncated hepatitis B virus core antigen (HBc, aa 1–149) using a prokaryotic expression system. Immunization of BALB/c mice with the VLP vaccine efficiently elicited the production of anti-CTGF neutralizing antibodies. Vaccination with this CTGF vaccine significantly protected BALB/c mice from carbon tetrachloride (CCl4)-induced hepatic fibrosis, as indicated by decreased hepatic hydroxyproline content and lower fibrotic score. CCl4 intoxication-induced hepatic stellate cell activation was inhibited by the vaccination, as indicated by decreased α-smooth muscle actin expression and Smad2 phosphorylation. Vaccination against CTGF also attenuated the over-expression of some profibrogenic factors, such as CTGF, transforming growth factor-β1, platelet-derived growth factor-B and tissue inhibitor of metalloproteinase-1 in the fibrotic mouse livers, decreased hepatocyte apoptosis and accelerated hepatocyte proliferation in the fibrotic mouse livers. Our results clearly indicate that vaccination against CTGF inhibits fibrogenesis, alleviates hepatocyte apoptosis and facilitate hepatic regeneration. We suggest that the vaccine should be developed into an effective therapeutic measure for hepatic fibrosis. PMID:27562139

  12. [Connective tissue and prolapse genesis].

    PubMed

    Tremollieres, F

    2010-06-01

    The pathophysiology of pelvic floor disorders still remains not well understood. Increasing age as well as vaginal multiparity are the main commonly accepted factors. The hypothesis of a defect of connective tissues of the pelvic floor with aging due to collagen deficiency and/or elastic fiber degradation is often highlighted. The issue of a potential protective role of HRT is also discussed although the recent results from the WHI would suggest a negative impact of HRT on urinary incontinence, especially when HRT is initiated in elderly women, far from the menopause. Nevertheless, environmental factors cannot explain the full pathogenesis of pelvic organ prolapse (POP) and the contribution of genetic factors to the development of pelvic floor disorders is widely recognized. Support for a genetic influence on POP derives from reports suggesting that heritability is a strong contributing factor and a familial history of POP is considered as a classical risk factor. However, the characterization of the underlying molecular mechanisms remains limited, since POP may be considered the end result of a multifactorial process leading to destruction of vaginal wall connective tissue. Experimental studies in mice with null mutations in the genes encoding different putative factors involved in elastic fibers remodeling and homeostasis are crucial in the understanding of the pathogenesis of POP. Mice with null mutation in the gene encoding lysyl oxidase-like 1 (LOXL1) or fibulin-5, demonstrate signs of elastinopathy including the development of a POP in the postpartum. Likewise, homeobox genes such as HOXA11, which are essential in the embryonic development of the urogenital tract might also be involved in the pathogenesis of POP. The better understanding of the underlying determinants of pelvic floor disorders with a special focus on genetic factors may offer new therapeutic strategies, in addition to or replacement of surgical procedures.

  13. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G; Gibbs, Allison M; Smith, Cassandra P; Taylor-Howell, Cheryl; Kearney, Sean R; MacVittie, Thomas J

    2015-11-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

  14. Patients with Encapsulating Peritoneal Sclerosis Have Increased Peritoneal Expression of Connective Tissue Growth Factor (CCN2), Transforming Growth Factor-β1, and Vascular Endothelial Growth Factor

    PubMed Central

    Abrahams, Alferso C.; Habib, Sayed M.; Dendooven, Amélie; Riser, Bruce L.; van der Veer, Jan Willem; Toorop, Raechel J.; Betjes, Michiel G. H.; Verhaar, Marianne C.; Watson, Christopher J. E.; Nguyen, Tri Q.; Boer, Walther H.

    2014-01-01

    Introduction Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD). The pathogenesis is not exactly known and no preventive strategy or targeted medical therapy is available. CCN2 has both pro-fibrotic and pro-angiogenic actions and appears an attractive target. Therefore, we studied peritoneal expression of CCN2, as well as TGFβ1 and VEGF, in different stages of peritoneal fibrosis. Materials and methods Sixteen PD patients were investigated and compared to 12 hemodialysis patients and four pre-emptively transplanted patients. Furthermore, expression was investigated in 12 EPS patients in comparison with 13 PD and 12 non-PD patients without EPS. Peritoneal tissue was taken during kidney transplantation procedure or during EPS surgery. In a subset of patients, CCN2 protein levels in peritoneal effluent and plasma were determined. Samples were examined by qPCR, histology, immunohistochemistry, and ELISA. Results Peritoneal CCN2 expression was 5-fold higher in PD patients compared to pre-emptively transplanted patients (P<0.05), but did not differ from hemodialysis patients. Peritoneal expression of TGFβ1 and VEGF were not different between the three groups; neither was peritoneal thickness. Peritoneum of EPS patients exhibited increased expression of CCN2 (35-fold, P<0.001), TGFβ1 (24-fold, P<0.05), and VEGF (77-fold, P<0.001) compared to PD patients without EPS. In EPS patients, CCN2 protein was mainly localized in peritoneal endothelial cells and fibroblasts. CCN2 protein levels were significantly higher in peritoneal effluent of EPS patients compared to levels in dialysate of PD patients (12.0±4.5 vs. 0.91±0.92 ng/ml, P<0.01), while plasma CCN2 levels were not increased. Conclusions Peritoneal expression of CCN2, TGFβ1, and VEGF are significantly increased in EPS patients. In early stages of peritoneal fibrosis, only CCN2 expression is slightly increased. Peritoneal CCN2 overexpression in EPS patients is a

  15. Requirement for active glycogen synthase kinase-3β in TGF-β1 upregulation of connective tissue growth factor (CCN2/CTGF) levels in human gingival fibroblasts

    PubMed Central

    Bahammam, Maha; Black, Samuel A.; Sume, Siddika Selva; Assaggaf, Mohammad A.; Faibish, Michael

    2013-01-01

    Connective tissue growth factor (CCN2/CTGF) mediates transforming growth factor-β (TGF-β)-induced fibrosis. Drug-induced gingival overgrowth is tissue specific. Here the role of the phosphoinositol 3-kinase (PI3K) pathway in mediating TGF-β1-stimulated CCN2/CTGF expression in primary human adult gingival fibroblasts and human adult lung fibroblasts was compared. Data indicate that PI3K inhibitors attenuate upregulation of TGF-β1-induced CCN2/CTGF expression in human gingival fibroblasts independent of reducing JNK MAP kinase activation. Pharmacologic inhibitors and small interfering (si)RNA-mediated knockdown studies indicate that calcium-dependent isoforms and an atypical isoform of protein kinase C (PKC-δ) do not mediate TGF-β1-stimulated CCN2/CTGF expression in gingival fibroblasts. As glycogen synthase kinase-3β (GSK-3β) can undergo phosphorylation by the PI3K/pathway, the effects of GSK-3β inhibitor kenpaullone and siRNA knockdown were investigated. Data in gingival fibroblasts indicate that kenpaullone attenuates TGF-β1-mediated CCN2/CTGF expression. Activation of the Wnt canonical pathways with Wnt3a, which inhibits GSK-3β, similarly inhibits TGF-β1-stimulated CCN2/CTGF expression. In contrast, inhibition of GSK-3β by Wnt3a does not inhibit, but modestly stimulates, CCN2/CTGF levels in primary human adult lung fibroblasts and is β-catenin dependent, consistent with previous studies performed in other cell models. These data identify a novel pathway in gingival fibroblasts in which inhibition of GSK-3β attenuates CCN2/CTGF expression. In adult lung fibroblasts inhibition of GSK-3β modestly stimulates TGF-β1-regulated CCN2/CTGF expression. These studies have potential clinical relevance to the tissue specificity of drug-induced gingival overgrowth. PMID:23824844

  16. TGF-β1, in association with the increased expression of connective tissue growth factor, induce the hypertrophy of the ligamentum flavum through the p38 MAPK pathway

    PubMed Central

    Cao, Yan-Lin; Duan, Yang; Zhu, Li-Xin; Zhan, Ye-Nan; Min, Shao-Xiong; Jin, An-Min

    2016-01-01

    Hypertrophy of the ligamentum flavum (LF) is one of the key pathomechanisms of lumbar spinal stenosis (LSS). Transforming growth factor (TGF)-β1 is abundantly expressed in hypertrophied degenerative LF tissues from LSS. However, the molecular mechanisms underling the association between TGF-β1 and LF hypertrophy have not yet been fully elucidated. In this study, we investigated the important role of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of LSS by analyzing the expression of connective tissue growth factor (CTGF) and extracellular matrix (ECM) components (collagen I and collagen III) in TGF-β1-treated LF cells. Cell growth assay revealed that TGF-β1, in association with CTGF, enhanced the the proliferation of LF cells, and we found that TGF-β1 also elevated CTGF expression and subsequently enhanced the mRNA expression of collagen I and collagen III. The increased mRNA expression levels of CTGF, collagen I and collagen III were abolished by p38 inhibitors. Both immunofluorescence imaging and western blot analysis of p38 and p-p38 revealed the increased expression and phosphorylation of p38. Silencing the expression of p38 by siRNA in LF cells decreased the protein expression of p38, p-p38 and CTGF, as well as the mRNA expression of CTGF, collagen I and collagen III. Taken together, our findings indicate that TGF-β1, in association with the increased expression of CTGF, contribute to the homeostasis of the ECM and to the hypertrophy of LF through the p38 MAPK pathway. PMID:27279555

  17. MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway.

    PubMed

    Mu, Shengzhi; Kang, Bei; Zeng, Weihui; Sun, Yaowen; Yang, Fan

    2016-05-01

    Post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production, which is a response to tissue injury by fibroblasts. Although emerging evidence has indicated that miRNA contributes to hypertrophic scarring, the role of miRNA in HS formation remains unclear. In this study, we found that miR-143-3p was markedly downregulated in HS tissues and fibroblasts (HSFs) using qRT-PCR. The expression of connective tissue growth factor (CTGF/CCN2) was upregulated both in HS tissues and HSFs, which is proposed to play a key role in ECM deposition in HS. The protein expression of collagen I (Col I), collagen III (Col III), and α-smooth muscle actin (α-SMA) was obviously inhibited after treatment with miR-143-3p in HSFs. The CCK-8 assay showed that miR-143-3p transfection reduced the proliferation ability of HSFs, and flow cytometry showed that either early or late apoptosis of HSFs was upregulated by miR-143-3p. In addition, the activity of caspase 3 and caspase 9 was increased after miR-143-3p transfection. On the contrary, the miR-143-3p inhibitor was demonstrated to increase cell proliferation and inhibit apoptosis of HSFs. Moreover, miR-143-3p targeted the 3'-UTR of CTGF and caused a significant decrease of CTGF. Western blot demonstrated that Akt/mTOR phosphorylation and the expression of CTGF, Col I, Col III, and α-SMA were inhibited by miR-143-3p, but increased by CTGF overexpression. In conclusion, we found that miR-143-3p inhibits hypertrophic scarring by regulating the proliferation and apoptosis of human HSFs, inhibiting ECM production-associated protein expression by targeting CTGF, and restraining the Akt/mTOR pathway.

  18. MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway.

    PubMed

    Mu, Shengzhi; Kang, Bei; Zeng, Weihui; Sun, Yaowen; Yang, Fan

    2016-05-01

    Post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production, which is a response to tissue injury by fibroblasts. Although emerging evidence has indicated that miRNA contributes to hypertrophic scarring, the role of miRNA in HS formation remains unclear. In this study, we found that miR-143-3p was markedly downregulated in HS tissues and fibroblasts (HSFs) using qRT-PCR. The expression of connective tissue growth factor (CTGF/CCN2) was upregulated both in HS tissues and HSFs, which is proposed to play a key role in ECM deposition in HS. The protein expression of collagen I (Col I), collagen III (Col III), and α-smooth muscle actin (α-SMA) was obviously inhibited after treatment with miR-143-3p in HSFs. The CCK-8 assay showed that miR-143-3p transfection reduced the proliferation ability of HSFs, and flow cytometry showed that either early or late apoptosis of HSFs was upregulated by miR-143-3p. In addition, the activity of caspase 3 and caspase 9 was increased after miR-143-3p transfection. On the contrary, the miR-143-3p inhibitor was demonstrated to increase cell proliferation and inhibit apoptosis of HSFs. Moreover, miR-143-3p targeted the 3'-UTR of CTGF and caused a significant decrease of CTGF. Western blot demonstrated that Akt/mTOR phosphorylation and the expression of CTGF, Col I, Col III, and α-SMA were inhibited by miR-143-3p, but increased by CTGF overexpression. In conclusion, we found that miR-143-3p inhibits hypertrophic scarring by regulating the proliferation and apoptosis of human HSFs, inhibiting ECM production-associated protein expression by targeting CTGF, and restraining the Akt/mTOR pathway. PMID:27075467

  19. Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy.

    PubMed

    Tam, Frederick W K; Riser, Bruce L; Meeran, Karim; Rambow, JoAnn; Pusey, Charles D; Frankel, Andrew H

    2009-07-01

    Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p<0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p<0.01 and p<0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R=0.49, p<0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R=0.61, p<0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease. PMID:19409809

  20. The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor.

    PubMed

    Segarini, P R; Nesbitt, J E; Li, D; Hays, L G; Yates, J R; Carmichael, D F

    2001-11-01

    Connective tissue growth factor (CTGF) expression is regulated by transforming growth factor-beta (TGF-beta) and strong up-regulation occurs during wound healing; in situ hybridization data indicate that there are high levels of CTGF expression in fibrotic lesions. Recently the binding parameters of CTGF to both high and lower affinity cell surface binding components have been characterized. Affinity cross-linking and SDS-polyacrylamide gel electrophoresis analysis demonstrated the binding of CTGF to a cell surface protein with a mass of approximately 620 kDa. We report here the purification of this protein by affinity chromatography on CTGF coupled to Sepharose and sequence information obtained by mass spectroscopy. The binding protein was identified as the multiligand receptor, low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor (LRP). The identification of LRP as a receptor for CTGF was validated by several studies: 1) binding competition with many ligands that bind to LRP, including receptor-associated protein; 2) immunoprecipitation of CTGF-receptor complex with LRP antibodies; and 3) cells that are genetically deficient for LRP were unable to bind CTGF. Last, CTGF is rapidly internalized and degraded and this process is LRP-dependent. In summary, our data indicate that LRP is a receptor for CTGF, and may play an important role in mediating CTGF biology.

  1. The Genetics of Soft Connective Tissue Disorders.

    PubMed

    Vanakker, Olivier; Callewaert, Bert; Malfait, Fransiska; Coucke, Paul

    2015-01-01

    Over the last few years, the field of hereditary connective tissue disorders has changed tremendously. This review highlights exciting insights into three prototypic disorders affecting the soft connective tissue: Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and cutis laxa. For each of these disorders, the identification and characterization of several novel but related conditions or subtypes have widened the phenotypic spectrum. In parallel, the vast underlying molecular network connecting these phenotypes is progressively being uncovered. Identification and characterization (both clinical and molecular) of new phenotypes within the connective tissue disorder spectrum are often key to further unraveling the pathways involved in connective tissue biology and delineating the clinical spectrum and pathophysiology of the disorders. Although difficult challenges remain, recent findings have expanded our pathophysiological understanding and may lead to targeted therapies in the near future. PMID:26002060

  2. FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis.

    PubMed

    Raghu, Ganesh; Scholand, Mary Beth; de Andrade, João; Lancaster, Lisa; Mageto, Yolanda; Goldin, Jonathan; Brown, Kevin K; Flaherty, Kevin R; Wencel, Mark; Wanger, Jack; Neff, Thomas; Valone, Frank; Stauffer, John; Porter, Seth

    2016-05-01

    FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway.

  3. TGF-β1 Up-Regulates Connective Tissue Growth Factor Expression in Human Granulosa Cells through Smad and ERK1/2 Signaling Pathways

    PubMed Central

    Cheng, Jung-Chien; Chang, Hsun-Ming; Fang, Lanlan; Sun, Ying-Pu; Leung, Peter C. K.

    2015-01-01

    Connective tissue growth factor (CTGF), which is also called CCN2, is a secreted matricellular protein. CTGF regulates various important cellular functions by interacting with multiple molecules in the microenvironment. In the ovary, CTGF is mainly expressed in granulosa cells and involved in the regulation of follicular development, ovulation and luteinization. TGF-β1 has been shown to up-regulate CTGF expression in rat and hen granulosa cells. However, the underlying molecular mechanisms of this up-regulation remain undefined. More importantly, whether the stimulatory effect of TGF-β1 on CTGF expression can be observed in human granulosa cells remains unknown. In the present study, our results demonstrated that TGF-β1 treatment up-regulates CTGF expression in both immortalized human granulosa cells and primary human granulosa cells. Using a siRNA-mediated knockdown approach and a pharmacological inhibitor, we demonstrated that the inhibition of Smad2, Smad3 or ERK1/2 attenuates the TGF-β1-induced up-regulation of CTGF. This study provides important insights into the molecular mechanisms that mediate TGF-β1-up-regulated CTGF expression in human granulosa cells. PMID:25955392

  4. Connective tissue growth factor is critical for proper β-cell function and pregnancy-induced β-cell hyperplasia in adult mice.

    PubMed

    Pasek, Raymond C; Dunn, Jennifer C; Elsakr, Joseph M; Aramandla, Mounika; Matta, Anveetha R; Gannon, Maureen

    2016-09-01

    During pregnancy, maternal β-cells undergo compensatory changes, including increased β-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and β-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf(LacZ/+)) have an impairment in maternal β-cell proliferation; no difference was observed in virgin Ctgf(LacZ/+) females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (Ctgf(ΔEndo)) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal β-cell proliferation. Moreover, virgin Ctgf(ΔEndo) females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in β-cell function has been reported. PMID:27460898

  5. TGF-β1 Up-Regulates Connective Tissue Growth Factor Expression in Human Granulosa Cells through Smad and ERK1/2 Signaling Pathways.

    PubMed

    Cheng, Jung-Chien; Chang, Hsun-Ming; Fang, Lanlan; Sun, Ying-Pu; Leung, Peter C K

    2015-01-01

    Connective tissue growth factor (CTGF), which is also called CCN2, is a secreted matricellular protein. CTGF regulates various important cellular functions by interacting with multiple molecules in the microenvironment. In the ovary, CTGF is mainly expressed in granulosa cells and involved in the regulation of follicular development, ovulation and luteinization. TGF-β1 has been shown to up-regulate CTGF expression in rat and hen granulosa cells. However, the underlying molecular mechanisms of this up-regulation remain undefined. More importantly, whether the stimulatory effect of TGF-β1 on CTGF expression can be observed in human granulosa cells remains unknown. In the present study, our results demonstrated that TGF-β1 treatment up-regulates CTGF expression in both immortalized human granulosa cells and primary human granulosa cells. Using a siRNA-mediated knockdown approach and a pharmacological inhibitor, we demonstrated that the inhibition of Smad2, Smad3 or ERK1/2 attenuates the TGF-β1-induced up-regulation of CTGF. This study provides important insights into the molecular mechanisms that mediate TGF-β1-up-regulated CTGF expression in human granulosa cells.

  6. The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover.

    PubMed

    Jugdaohsingh, Ravin; Watson, Abigail I E; Pedro, Liliana D; Powell, Jonathan J

    2015-06-01

    previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues.

  7. The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover☆

    PubMed Central

    Jugdaohsingh, Ravin; Watson, Abigail I.E.; Pedro, Liliana D.; Powell, Jonathan J.

    2015-01-01

    lower than previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues. PMID:25687224

  8. Undifferentiated connective tissue disease with pulmonary involvement.

    PubMed

    Arjun, P; Ameer, K A; Sasikumar, S; Rajalakshmi, A; Hari, T A; Thomas, Mathew

    2011-03-01

    Pulmonary involvement in collagen vascular diseases is extremely common. It is usually seen in the well described dyscollagenoses and in mixed connective tissue diseases (MCTD). However, there is a lesser known entity called Undifferentiated Connective Tissue Disease (UCTD) which can also involve the lung. We herein present a case of a young man who was detected to have lung involvement secondary to UCTD. PMID:21751630

  9. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

    SciTech Connect

    Matsuzaki, Shinichi; Ishizuka, Tamotsu; Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo; Komachi, Mayumi; Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko; Dobashi, Kunio; Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki; Mori, Masatomo; Okajima, Fumikazu

    2011-10-07

    Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.

  10. HBX Protein-Induced Downregulation of microRNA-18a is Responsible for Upregulation of Connective Tissue Growth Factor in HBV Infection-Associated Hepatocarcinoma

    PubMed Central

    Liu, Xiaomin; Zhang, Yingjian; Wang, Ping; Wang, Hongyun; Su, Huanhuan; Zhou, Xin; Zhang, Lamei

    2016-01-01

    Background This study was designed to improve our understanding of the role of miR-18a and its target (connective tissue growth factor (CTGF), which are mediators in HBX-induced hepatocellular carcinoma (HCC). Material/Methods We first investigated the expression of several candidate microRNAs (miRNAs) reported to have been aberrantly expressed between HepG2 and HepG2.2.15, which is characterized by stable HBV infection, while the CTGF is identified as a target of miR-18a. Furthermore, the expression of CTGF evaluated in HepG2 was transfected with HBX, while the HepG2.2.15 was transfected with miR-18a and CTGF siRNA. We examined the cell cycle at the same time. Results We found that the expression of miR-18a was abnormally reduced in the HBV-positive HCC tissue samples compared with HBV-negative HCC samples. Through the use of a luciferase reporter system, we also identified CTGF 3′UTR (1046–1052 bp) as the exact binding site for miR-18a. We also observed a clear increase in CTGF mRNA and protein expression levels in HBV-positive HCC human tissue samples in comparison with the HBV-negative controls, indicating a possible negatively associated relationship between miR-18a and CTGF. Furthermore, we investigated the effect of HBX overexpression on miR-18a and CTGF, as well as the viability and cell cycle status of HepG2 cells. In addition, we found that HBX introduction downregulated miR-18a, upregulated CTGF, elevated the viability, and promoted cell cycle progression. We transfected HepG2.2.15 with miR-18a mimics and CTGF siRNA, finding that upregulated miR-18a and downregulated CTGF suppress the viability and cause cell cycle arrest. Conclusions Our study shows the role of the CTGF gene as a target of miR-18a, and identifies the function of HBV/HBX/miR-18a/CTGF as a key signaling pathway mediating HBV infection-induced HCC. PMID:27421245

  11. Comparison of prostaglandin F2alpha, bimatoprost (prostamide), and butaprost (EP2 agonist) on Cyr61 and connective tissue growth factor gene expression.

    PubMed

    Liang, Yanbin; Li, Chen; Guzman, Victor M; Evinger, Albert J; Protzman, Charles E; Krauss, Achim H-P; Woodward, David F

    2003-07-18

    Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F2alpha (PGF2alpha) (FP receptor agonist), Butaprost (EP2 receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF2alpha dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF2alpha-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF2alpha and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF2alpha up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF2alpha and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP2 receptors (Gs-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog

  12. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.

    PubMed

    Pennica, D; Swanson, T A; Welsh, J W; Roy, M A; Lawrence, D A; Lee, J; Brush, J; Taneyhill, L A; Deuel, B; Lew, M; Watanabe, C; Cohen, R L; Melhem, M F; Finley, G G; Quirke, P; Goddard, A D; Hillan, K J; Gurney, A L; Botstein, D; Levine, A J

    1998-12-01

    Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.

  13. Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features.

    PubMed

    Xie, D; Nakachi, K; Wang, H; Elashoff, R; Koeffler, H P

    2001-12-15

    To gain insight into the role of the CCN genes in human breast carcinomas, we quantified connective tissue growth factor (CTGF), WISP-1, CYR61, and human NOV (NOVH) mRNA expression levels in samples from 44 primary breast tumors and seven normal breasts using quantitative real-time PCR assay. Overexpression of CTGF, WISP-1, CYR61, and NOVH was found in 55 (24 of 44), 46 (20 of 44), 39 (17 of 44), and 11% (5 of 44) primary breast tumors, respectively. Statistical univariate analysis was performed to explore the links between expression of the CCN genes and clinical and pathological parameters. Interestingly, significant associations were found between CTGF expression versus stage, tumor size, lymph node status, and age at diagnosis; WISP-1 mRNA levels versus stage, tumor size, lymph node, and HER-2/neu overexpression; and CYR61 expression with stage, tumor size, lymph node, age, and estrogen receptor expression. In contrast to CTGF, WISP-1, and CYR61, no significant correlation was found between NOVH expression and any of the clinical and pathological factors. Furthermore, multivariate classification tree model analysis showed that stage and lymph node involvement were important for predicting CTGF expression in breast cancers; the stage, age, and HER-2/neu status were key factors for WISP-1 expression; and the stage, age, and estrogen receptor were valuable predictors for CYR61 expression. In summary, these results suggest that CTGF, WISP-1, and CYR61 may play a role in the progression of breast cancer and might serve as a valuable tool for monitoring tumor status of breast cancer patients.

  14. The matri-cellular proteins 'cysteine-rich, angiogenic-inducer, 61' and 'connective tissue growth factor' are regulated in experimentally-induced sepsis with multiple organ dysfunction.

    PubMed

    Hviid, Claus V B; Erdem, Johanna Samulin; Kunke, David; Ahmed, Shakil M; Kjeldsen, Signe F; Wang, Yun Yong; Attramadal, Håvard; Aasen, Ansgar O

    2012-10-01

    Organ failure is a severe complication in sepsis for which the pathophysiology remains incompletely understood. Recently, the matri-cellular cysteine-rich, angiogenic induced, 61 (Cyr61/CCN1); connective tissue growth factor (Ctgf/CCN2); and nephroblastoma overexpressed gene (Nov/CCN3) (CCN)-protein family have been attributed organ-protective properties. Their expression is sensitive to mediators of sepsis pathophysiology but a potential role in sepsis remains elusive. To provide an initial assessment, 50 rats were subjected to 18 h of cecal-ligation and puncture or sham operation. Hepatic and pulmonary CCN1 mRNA displayed an average 7.4- and 3.3-fold induction, while its cardiac expression was unchanged. The changes coincided with excessive hepatic and pulmonary inflammatory gene activation and a restricted cardiac inflammation. Furthermore, hepatocytes displayed a dosage-dependent CCN1 mRNA response in vitro, supporting a cytokine-mediated CCN1 regulation in sepsis. CCN2 mRNA was 2.2-fold induced in the liver, while 2.0-fold and 1.4-fold repressed in the heart and lung. Meanwhile, it did not respond to TNF-α exposure in vitro, which indicates different means of regulation than for CCN1. Taken together, this study provides the first evidence for multi-organ regulation of CCN1 and CCN2 in early stages of sepsis, and implies the eruption of inflammatory mediators as a potential mechanism behind the observed CCN1 regulation.

  15. Involvement of Connective Tissue Growth Factor (CTGF) in Insulin-like Growth Factor-I (IGF1) Stimulation of Proliferation of a Bovine Mammary Epithelial Cell Line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin-like growth factor I (IGF1) plays an important role in mammary gland development and lactation in part by stimulating proliferation of the milk-producing epithelial cells. In this study, we used the bovine mammary epithelial cell line MAC-T cells as a model to understand the mechanism by whi...

  16. CXCL12 induces connective tissue growth factor expression in human lung fibroblasts through the Rac1/ERK, JNK, and AP-1 pathways.

    PubMed

    Lin, Chien-Huang; Shih, Chung-Huang; Tseng, Chih-Chieh; Yu, Chung-Chi; Tsai, Yuan-Jhih; Bien, Mauo-Ying; Chen, Bing-Chang

    2014-01-01

    CXCL12 (stromal cell-derived factor-1, SDF-1) is a potent chemokine for homing of CXCR4+ fibrocytes to injury sites of lung tissue, which contributes to pulmonary fibrosis. Overexpression of connective tissue growth factor (CTGF) plays a critical role in pulmonary fibrosis. In this study, we investigated the roles of Rac1, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CXCL12-induced CTGF expression in human lung fibroblasts. CXCL12 caused concentration- and time-dependent increases in CTGF expression and CTGF-luciferase activity. CXCL12-induced CTGF expression was inhibited by a CXCR4 antagonist (AMD3100), small interfering RNA of CXCR4 (CXCR4 siRNA), a dominant negative mutant of Rac1 (RacN17), a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor (PD98059), a JNK inhibitor (SP600125), a p21-activated kinase inhibitor (PAK18), c-Jun siRNA, and an AP-1 inhibitor (curcumin). Treatment of cells with CXCL12 caused activations of Rac1, Rho, ERK, and c-Jun. The CXCL12-induced increase in ERK phosphorylation was inhibited by RacN17. Treatment of cells with PD98059 and SP600125 both inhibited CXCL12-induced c-Jun phosphorylation. CXCL12 caused the recruitment of c-Jun and c-Fos binding to the CTGF promoter. Furthermore, CXCL12 induced an increase in α-smooth muscle actin (α-SMA) expression, a myofibroblastic phenotype, and actin stress fiber formation. CXCL12-induced actin stress fiber formation and α-SMA expression were respectively inhibited by AMD3100 and CTGF siRNA. Taken together, our results suggest that CXCL12, acting through CXCR4, activates the Rac/ERK and JNK signaling pathways, which in turn initiates c-Jun phosphorylation, and recruits c-Jun and c-Fos to the CTGF promoter and ultimately induces CTGF expression in human lung fibroblasts. Moreover, overexpression of CTGF mediates CXCL12-induced α-SMA expression. PMID:25121739

  17. Invited review: mesenchymal progenitor cells in intramuscular connective tissue development.

    PubMed

    Miao, Z G; Zhang, L P; Fu, X; Yang, Q Y; Zhu, M J; Dodson, M V; Du, M

    2016-01-01

    The abundance and cross-linking of intramuscular connective tissue contributes to the background toughness of meat, and is thus undesirable. Connective tissue is mainly synthesized by intramuscular fibroblasts. Myocytes, adipocytes and fibroblasts are derived from a common pool of progenitor cells during the early embryonic development. It appears that multipotent mesenchymal stem cells first diverge into either myogenic or non-myogenic lineages; non-myogenic mesenchymal progenitors then develop into the stromal-vascular fraction of skeletal muscle wherein adipocytes, fibroblasts and derived mesenchymal progenitors reside. Because non-myogenic mesenchymal progenitors mainly undergo adipogenic or fibrogenic differentiation during muscle development, strengthening progenitor proliferation enhances the potential for both intramuscular adipogenesis and fibrogenesis, leading to the elevation of both marbling and connective tissue content in the resulting meat product. Furthermore, given the bipotent developmental potential of progenitor cells, enhancing their conversion to adipogenesis reduces fibrogenesis, which likely results in the overall improvement of marbling (more intramuscular adipocytes) and tenderness (less connective tissue) of meat. Fibrogenesis is mainly regulated by the transforming growth factor (TGF) β signaling pathway and its regulatory cascade. In addition, extracellular matrix, a part of the intramuscular connective tissue, provides a niche environment for regulating myogenic differentiation of satellite cells and muscle growth. Despite rapid progress, many questions remain in the role of extracellular matrix on muscle development, and factors determining the early differentiation of myogenic, adipogenic and fibrogenic cells, which warrant further studies.

  18. Microgravity Stress: Bone and Connective Tissue.

    PubMed

    Bloomfield, Susan A; Martinez, Daniel A; Boudreaux, Ramon D; Mantri, Anita V

    2016-03-15

    The major alterations in bone and the dense connective tissues in humans and animals exposed to microgravity illustrate the dependency of these tissues' function on normal gravitational loading. Whether these alterations depend solely on the reduced mechanical loading of zero g or are compounded by fluid shifts, altered tissue blood flow, radiation exposure, and altered nutritional status is not yet well defined. Changes in the dense connective tissues and intervertebral disks are generally smaller in magnitude but occur more rapidly than those in mineralized bone with transitions to 0 g and during recovery once back to the loading provided by 1 g conditions. However, joint injuries are projected to occur much more often than the more catastrophic bone fracture during exploration class missions, so protecting the integrity of both tissues is important. This review focuses on the research performed over the last 20 years in humans and animals exposed to actual spaceflight, as well as on knowledge gained from pertinent ground-based models such as bed rest in humans and hindlimb unloading in rodents. Significant progress has been made in our understanding of the mechanisms for alterations in bone and connective tissues with exposure to microgravity, but intriguing questions remain to be solved, particularly with reference to biomedical risks associated with prolonged exploration missions.

  19. Microgravity Stress: Bone and Connective Tissue.

    PubMed

    Bloomfield, Susan A; Martinez, Daniel A; Boudreaux, Ramon D; Mantri, Anita V

    2016-04-01

    The major alterations in bone and the dense connective tissues in humans and animals exposed to microgravity illustrate the dependency of these tissues' function on normal gravitational loading. Whether these alterations depend solely on the reduced mechanical loading of zero g or are compounded by fluid shifts, altered tissue blood flow, radiation exposure, and altered nutritional status is not yet well defined. Changes in the dense connective tissues and intervertebral disks are generally smaller in magnitude but occur more rapidly than those in mineralized bone with transitions to 0 g and during recovery once back to the loading provided by 1 g conditions. However, joint injuries are projected to occur much more often than the more catastrophic bone fracture during exploration class missions, so protecting the integrity of both tissues is important. This review focuses on the research performed over the last 20 years in humans and animals exposed to actual spaceflight, as well as on knowledge gained from pertinent ground-based models such as bed rest in humans and hindlimb unloading in rodents. Significant progress has been made in our understanding of the mechanisms for alterations in bone and connective tissues with exposure to microgravity, but intriguing questions remain to be solved, particularly with reference to biomedical risks associated with prolonged exploration missions. PMID:27065165

  20. Bioreactors for connective tissue engineering: design and monitoring innovations.

    PubMed

    El Haj, A J; Hampson, K; Gogniat, G

    2009-01-01

    The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropriate mechanical integrity necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally occur ring cell phenotypes. Part of the development of more recent models is to create growth environments or bioreactors which enable three-dimensional culture. Evidence suggests that in order to grow functional load-bearing tissues in a bioreactor, the cells must experience mechanical loading stimuli similar to that experienced in vivo which sets out the requirements for mechanical loading bioreactors. An essential part of developing new bioreactors for tissue growth is identifying ways of routinely and continuously measuring neo-tissue formation and in order to fully identify the successful generation of a tissue implant, the appropriate on-line monitoring must be developed. New technologies are being developed to advance our efforts to grow tissue ex vivo. The bioreactor is a critical part of these developments in supporting growth of biological implants and combining this with new advances in the detection of tissue formation allows us to refine our protocols and move nearer to off-the-shelf implants for clinical applications. PMID:19290498

  1. Bioreactors for Connective Tissue Engineering: Design and Monitoring Innovations

    NASA Astrophysics Data System (ADS)

    Haj, A. J. El; Hampson, K.; Gogniat, G.

    The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropri ate mechanical integrity necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally occur ring cell phenotypes. Part of the development of more recent models is to create growth environments or bioreactors which enable three-dimensional culture. Evidence suggests that in order to grow functional load-bearing tissues in a bioreactor, the cells must experience mechanical loading stimuli similar to that experienced in vivo which sets out the requirements for mechanical loading bioreactors. An essential part of developing new bioreactors for tissue growth is identifying ways of routinely and continuously measuring neo-tissue formation and in order to fully identify the successful generation of a tissue implant, the appropriate on-line monitoring must be developed. New technologies are being developed to advance our efforts to grow tissue ex vivo. The bioreactor is a critical part of these develop ments in supporting growth of biological implants and combining this with new advances in the detection of tissue formation allows us to refine our protocols and move nearer to off-the-shelf implants for clinical applications.

  2. Expression of the Elm1 Gene, a Novel Gene of the CCN (Connective Tissue Growth Factor, Cyr61/Cef10, and Neuroblastoma Overexpressed Gene) Family, Suppresses In Vivo Tumor Growth and Metastasis of K-1735 Murine Melanoma Cells

    PubMed Central

    Hashimoto, Yasunobu; Shindo-Okada, Nobuko; Tani, Masachika; Nagamachi, Yasuhiro; Takeuchi, Kaori; Shiroishi, Toshihiko; Toma, Hiroshi; Yokota, Jun

    1998-01-01

    We previously isolated a partial cDNA fragment of a novel gene, Elm1 (expressed in low-metastatic cells), that is expressed in low-metastatic but not in high-metastatic K-1735 mouse melanoma cells. Here we determined the full-length cDNA structure of Elm1 and investigated the effect of Elm1 expression on growth and metastatic potential of K-1735 cells. The Elm1 gene encodes a predicted protein of 367 amino acids showing ∼40% amino acid identity with the CCN (connective tissue growth factor [CTGF], Cyr61/Cef10, neuroblastoma overexpressed gene [Nov]) family proteins, which consist of secreted cysteine-rich proteins with growth regulatory functions. Elm1 is also a cysteine-rich protein and contains a signal peptide and four domains conserved in the CCN family proteins. Elm1 was highly conserved, expressed ubiquitously in diverse organs, and mapped to mouse chromosome 15. High-metastatic K-1735 M-2 cells, which did not express Elm1, were transfected with an Elm1 expression vector, and several stable clones with Elm1 expression were established. The in vivo growth rates of cells expressing a high level of Elm1 were remarkably slower than those of cells expressing a low level of Elm1. Metastatic potential of transfectants was reduced in proportion to the level of Elm1 expression. Thus, Elm1 is a novel gene of CCN family that can suppress the in vivo growth and metastatic potential of K-1735 mouse melanoma cells. PMID:9449709

  3. [Pulmonary involvement in connective tissue disease].

    PubMed

    Bartosiewicz, Małgorzata

    2016-01-01

    The connective tissue diseases are a variable group of autoimmune mediated disorders characterized by multiorgan damage. Pulmonary complications are common, usually occur after the onset of joint symptoms, but can also be initially presenting complaint. The respiratory system may be involved in all its component: airways, vessels, parenchyma, pleura and respiratory muscles. Lung involvement is an increasing cause of morbidity and mortality in the connective tissue diseases. Clinical course is highly variable - can range from mild to rapidly progressive, some processes are reversible, while others are irreversible. Thus, the identification of reversible disease , and separately progressive disease, are important clinical issues. The frequency, clinical presentation, prognosis and responce to therapy are different, depending on the pattern of involvement as well as on specyfic diagnostic method used to identify it. High- resolution computed tompography plays an important role in identifying patients with respiratory involvement. Pulmonary function tests are a sensitive tool detecting interstitial lung disease. In this article, pulmonary lung involvement accompanying most frequently apperaing connective tissue diseases - rheumatoid arthritis, systemic sclerosis, lupus erythematosus, polymyositis/dermatomyositis, Sjögrens syndrome and mixed connective tissue disaese are reviewed.

  4. [Pulmonary involvement in connective tissue disease].

    PubMed

    Bartosiewicz, Małgorzata

    2016-01-01

    The connective tissue diseases are a variable group of autoimmune mediated disorders characterized by multiorgan damage. Pulmonary complications are common, usually occur after the onset of joint symptoms, but can also be initially presenting complaint. The respiratory system may be involved in all its component: airways, vessels, parenchyma, pleura and respiratory muscles. Lung involvement is an increasing cause of morbidity and mortality in the connective tissue diseases. Clinical course is highly variable - can range from mild to rapidly progressive, some processes are reversible, while others are irreversible. Thus, the identification of reversible disease , and separately progressive disease, are important clinical issues. The frequency, clinical presentation, prognosis and responce to therapy are different, depending on the pattern of involvement as well as on specyfic diagnostic method used to identify it. High- resolution computed tompography plays an important role in identifying patients with respiratory involvement. Pulmonary function tests are a sensitive tool detecting interstitial lung disease. In this article, pulmonary lung involvement accompanying most frequently apperaing connective tissue diseases - rheumatoid arthritis, systemic sclerosis, lupus erythematosus, polymyositis/dermatomyositis, Sjögrens syndrome and mixed connective tissue disaese are reviewed. PMID:27421127

  5. Epigenetic regulation of connective tissue growth factor by microRNA-214 delivery in exosomes from mouse or human hepatic stellate cells

    PubMed Central

    Chen, Li; Charrier, Alyssa; Zhou, Yu; Chen, Ruju; Yu, Bo; Agarwal, Kitty; Tsukamoto, Hidekazu; Lee, L. James; Paulaitis, Michael E; Brigstock, David R

    2013-01-01

    Connective tissue growth factor (CCN2) drives fibrogenesis in hepatic stellate cells (HSC). Here we show that CCN2 up-regulation in fibrotic or steatotic livers, or in culture-activated or ethanol-treated primary mouse HSC is associated with a reciprocal down-regulation of microRNA-214 (miR-214). By using protector or reporter assays to investigate the 3′-untranslated region (UTR) of CCN2 mRNA, we found that induction of CCN2 expression in HSC by fibrosis-inducing stimuli was due to reduced expression of miR-214 which otherwise inhibited CCN2 expression by directly binding to the CCN2 3′-UTR. Additionally, miR-214 was present in HSC exosomes, which were bi-membrane vesicles, 50–150nm in diameter, negatively charged (−26mV), and positive for CD9. MiR-214 levels in exosomes but not in cell lysates were reduced by pre-treatment of the cells with the exosome inhibitor, GW4869. Co-culture of miR-214-transfected donor HSC with CCN2 3′-UTR luciferase reporter-transfected recipient HSC resulted in miR-214- and exosome-dependent regulation of a wild type CCN2 3′-UTR reporter but not of a mutant CCN2 3′-UTR reporter lacking the miR-214 binding site. Exosomes from HSC were a conduit for uptake of miR-214 by primary mouse hepatocytes. Down-regulation of CCN2 expression by miR-214 also occurred in human LX-2 HSC, consistent with a conserved miR-214 binding site in the human CCN2 3′-UTR. MiR-214 in LX-2 cells was shuttled via exosomes to recipient LX-2 cells or human HepG2 hepatocytes, resulting in suppression of CCN2 3′-UTR activity or expression of CCN2 downstream targets, including αSMA or collagen. Experimental fibrosis in mice was associated with reduced circulating miR-214 levels. Conclusion Exosomal transfer of miR-214 is a paradigm for the regulation of CCN2-dependent fibrogenesis and identifies fibrotic pathways as targets of epigenetic regulation by exosomal miRs. PMID:24122827

  6. Stretching Impacts Inflammation Resolution in Connective Tissue.

    PubMed

    Berrueta, Lisbeth; Muskaj, Igla; Olenich, Sara; Butler, Taylor; Badger, Gary J; Colas, Romain A; Spite, Matthew; Serhan, Charles N; Langevin, Helene M

    2016-07-01

    Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 min twice daily reduced inflammation and improved pain, 2 weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch versus no stretch for 48 h, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue.

  7. Stretching Impacts Inflammation Resolution in Connective Tissue.

    PubMed

    Berrueta, Lisbeth; Muskaj, Igla; Olenich, Sara; Butler, Taylor; Badger, Gary J; Colas, Romain A; Spite, Matthew; Serhan, Charles N; Langevin, Helene M

    2016-07-01

    Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 min twice daily reduced inflammation and improved pain, 2 weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch versus no stretch for 48 h, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue. PMID:26588184

  8. Connective tissue abnormalities in MRL/1 mice.

    PubMed Central

    Edwards, J C; Cooke, A; Moore, A R; Collins, C; Hay, F; Willoughby, D A

    1986-01-01

    Pathological changes in the connective tissue of the limbs of MRL/1 mice are described. Focal infiltrates of polymorphs or large mononuclear cells, or both, were seen both in synovial lining and subcutaneous tissue. Infiltrates were associated with vasculitis in some cases. Deposits of amorphous material were seen in and around joints and in foot pads. The material was more particulate and refractile than typical 'fibrinoid' and showed a positive Feulgen reaction. It was not surrounded by palisading cells and when seen in synovial tissue was not usually associated with changes in synovial lining cells. No obvious difference was seen between intra-articular and extra-articular lesions. Lesions in subcutaneous tissue occurred exclusively in the foot pads. Lymphocyte infiltration was not prominent at any site and no follicle formation was seen. Of two colonies studied, only one showed a significant increase in lining cell numbers in synovial tissue. Exercised animals had a similar distribution and severity of disease to those of matched controls. All lesions described were distinguishable from non-specific inflammatory lesions in normal control mice and MRL/++ mice on assessment of unmarked sections. The relation between these connective tissue lesions and the changes found in human chronic synovitis is discussed. Images PMID:3729576

  9. Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells.

    PubMed

    Wünsche, Christin; Koch, Alexander; Goldschmeding, Roel; Schwalm, Stephanie; Meyer Zu Heringdorf, Dagmar; Huwiler, Andrea; Pfeilschifter, Josef

    2015-05-01

    Transforming growth factor β2 (TGF-β2) is well known to stimulate the expression of pro-fibrotic connective tissue growth factor (CTGF) in several cell types including human mesangial cells. The present study demonstrates that TGF-β2 enhances sphingosine 1-phosphate receptor 5 (S1P5) mRNA and protein expression in a time and concentration dependent manner. Pharmacological and siRNA approaches reveal that this upregulation is mediated via activation of classical TGF-β downstream effectors, Smad and mitogen-activated protein kinases. Most notably, inhibition of Gi with pertussis toxin and downregulation of S1P5 by siRNA block TGF-β2-stimulated upregulation of CTGF, demonstrating that Gi coupled S1P5 is necessary for TGF-β2-triggered expression of CTGF in human mesangial cells. Overall, these findings indicate that TGF-β2 dependent upregulation of S1P5 is required for the induction of pro-fibrotic CTGF by TGF-β. Targeting S1P5 might be an attractive novel approach to treat renal fibrotic diseases.

  10. PDGFRα plays a crucial role in connective tissue remodeling.

    PubMed

    Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

    2015-12-07

    Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

  11. Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology.

    PubMed

    Pepmueller, Peri Hickman

    2016-01-01

    Autoimmune diseases often have overlapping symptoms and laboratory somewhat unfamiliar to the non-rheumatologist. Characteristic signs, symptoms, and autoantibodies define specific connective tissue diseases. Some patients have some characteristic symptoms, but cannot be definitively classified. Still other patients meet criteria for more than one specific connective tissue disease. These patients can be confusing with regard to diagnosis and prognosis. Clarification of each patient's condition can lead to improved patient care.

  12. Connective tissue: Vascular and hematological (blood) support

    PubMed Central

    Calvino, Nick

    2003-01-01

    Abstract Connective Tissue (CT) is a ubiquitous component of all major tissues and structures of the body (50% of all body protein is CT), including that of the blood, vascular, muscle, tendon, ligament, fascia, bone, joint, IVD's (intervertebral discs) and skin. Because of its ubiquitous nature, CT is an often overlooked component of any essential nutritional program that may address the structure, and/or function of these tissues. The central role of CT in the health of a virtually all cells, tissues, organs, and organ systems, is discussed. General nutritional CT support strategies, as well as specific CT support strategies that focus on blood, vascular, structural system (eg, muscles, tendons, ligaments, fascia, bone, and joints), integument (skin) and inflammatory and immune mediation will be discussed here and will deal with connective tissue dynamics and dysfunction. An overview of the current scientific understanding and possible options for naturally enhancing the structure and function of CT through the application of these concepts will be discussed in this article, with specific attention on the vascular and hematological systems. PMID:19674592

  13. Pregnancy and autoimmune connective tissue diseases.

    PubMed

    Marder, Wendy; Littlejohn, Emily A; Somers, Emily C

    2016-02-01

    Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy.

  14. Pregnancy and autoimmune connective tissue diseases.

    PubMed

    Marder, Wendy; Littlejohn, Emily A; Somers, Emily C

    2016-02-01

    Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy. PMID:27421217

  15. The growth of tissue engineering.

    PubMed

    Lysaght, M J; Reyes, J

    2001-10-01

    This report draws upon data from a variety of sources to estimate the size, scope, and growth rate of the contemporary tissue engineering enterprise. At the beginning of 2001, tissue engineering research and development was being pursued by 3,300 scientists and support staff in more than 70 startup companies or business units with a combined annual expenditure of over $600 million. Spending by tissue engineering firms has been growing at a compound annual rate of 16%, and the aggregate investment since 1990 now exceeds $3.5 billion. At the beginning of 2001, the net capital value of the 16 publicly traded tissue engineering startups had reached $2.6 billion. Firms focusing on structural applications (skin, cartilage, bone, cardiac prosthesis, and the like) comprise the fastest growing segment. In contrast, efforts in biohybrid organs and other metabolic applications have contracted over the past few years. The number of companies involved in stem cells and regenerative medicine is rapidly increasing, and this area represents the most likely nidus of future growth for tissue engineering. A notable recent trend has been the emergence of a strong commercial activity in tissue engineering outside the United States, with at least 16 European or Australian companies (22% of total) now active.

  16. [Eye connective tissues: cornea and vitreous body].

    PubMed

    Labat-Robert, Jacqueline; Pouliquen, Yves; Robert, Ladislas

    2012-01-01

    The authors, ophtalmologist (Y.P.) and basic scientists (J.L.-R and L.R.), collaborated on eye-research since 1962 on normal and pathological aspects of eye tissues, considered as specialized forms of connective tissues, and on specific aspects of the physiology and pathology of the eye. This date coincides with the foundation of the French Society of Connective Tissues, which celebrates the 50th anniversary of its creation. We shall present here some of our work on the ontogenetic and phylogenetic aspects of the cornea, on its structure, function and regulation in normal and pathological states, taken from a large number of publications of our laboratories. Our work on cornea started with the study of the morphogenesis of its lamellar structure, made of collagen fibers and proteoglycans. This led us to the isolation and characterization of structural (or matrix) glycoproteins, a new class of matrix components, present also in all other connective tissues, and to the study of their biosynthesis by keratocytes. Corneal wounds and regeneration were also studied, as well as some corneal pathologies such as keratoconus. The confrontation of quantitative morphological methods with biochemical procedures were to yield important results on the mechanisms of the maintenance of corneal structure and function. Another series of studies concerned the vitreous where we detected, besides previously characterized components, such as hyaluronan and collagens, fibronectin which plays an important role in the adhesion of hyaluronan to the collagen network. Its age-dependent modifications were also studied, with a special focus on the role of reactive oxygen species (ROS)-mediated degradation of hyaluronan, especially important for the aging of the vitreous.

  17. Connective tissue response to periodontal dressing.

    PubMed

    Nezwek, R A; Caffesse, R G; Bergenholtz, A; Nasjleti, C E

    1980-09-01

    The effects of three periodontal dressings (Coe-Pak, PPC, Perio Putty) upon subcutaneous tissues in 26 Sprague-Dawley rats were investigated. The three dressings, and a control (Teflon), were placed into polyethylene tubes. Two tubes per animal were implanted on either side of the dorsal midline area. After 14 days the specimens were retrieved and prepared for histological examination. Three methods of scoring were utilized for evaluation. First, a system evaluating the overall number of inflammatory cells, connective tissue capsule thickness, and the vascular changes produced; second, an inflammatory cell count, the Inflammatory Index (I.I), computing the inflammatory cells in a particular field of view for each material; and third, a Reaction Spread Index (R.S.I.) comparing the distance of the spread of the inflammatory reaction into the connective tissues. Statistical analysis of the data was carried out utilizing the Chi-square test and analysis of variance. While the three scoring systems utilized did result in some comparative variation in reactions, the overall order of decreasing severity was always PPC, Coe-Pak, Perio Putty, and Teflon.

  18. Muscle and tendon connective tissue adaptation to unloading, exercise and NSAID.

    PubMed

    Dideriksen, Kasper

    2014-04-01

    The extracellular matrix network of skeletal muscle and tendon connective tissue is primarily composed of collagen and connects the muscle contractile protein to the bones in the human body. The mechanical properties of the connective tissue are important for the effectiveness of which the muscle force is transformed into movement. Periods of unloading and exercise affect the synthesis rate of connective tissue collagen protein, whereas only sparse information exits regarding collagen protein degradation. It is likely, though, that changes in both collagen protein synthesis and degradation are required for remodeling of the connective tissue internal structure that ultimately results in altered mechanical properties of the connective tissue. Both unloading and exercise lead to increased production of growth factors and inflammatory mediators that are involved in connective tissue remodeling. Despite the fact that non-steroidal anti-inflammatory drugs seem to inhibit the healing process of connective tissue and the stimulating effect of exercise on connective tissue protein synthesis, these drugs are often consumed in relation to connective tissue injury and soreness. However, the potential effect of non-steroidal anti-inflammatory drugs on connective tissue needs further investigation.

  19. Effect of growth hormone on aging connective tissue in muscle and tendon: gene expression, morphology, and function following immobilization and rehabilitation.

    PubMed

    Boesen, A P; Dideriksen, K; Couppé, C; Magnusson, S P; Schjerling, P; Boesen, M; Aagaard, P; Kjaer, M; Langberg, H

    2014-01-15

    It is unknown whether loss in musculotendinous tissue during inactivity can be counteracted by growth hormone (GH), and whether GH accelerate rehabilitation in aging individuals. Elderly men (65-75 yr; n = 12) had one leg immobilized 2 wk followed by 6 wk of retraining and were randomly assigned to daily injections of recombinant GH (rhGH; n = 6) or placebo (Plc; n = 6). Cross-sectional area (CSA), muscle strength (MVC), and biomechanical properties of m. quadriceps and patellar tendon were determined. Muscle and tendon biopsies were analyzed for gene expressions (mRNA) of collagen (COL1A1/3A1) and insulin-like growth factors (IGF-1Ea/Ec). Fibril morphology was analyzed by transmission electron microscope (TEM). In tendon, CSA and biomechanical properties did not change following immobilization, but an increase in CSA was found after 6 wk of rehabilitation in both groups. The changes were more pronounced when GH was injected. Furthermore, tendon stiffness increased in the GH group. Muscle CSA declined after immobilization in the Plc but not in the GH group. Muscle CSA increased during retraining, with a significantly larger increase in the GH group compared with the Plc group. Both a time and a group effect were seen for IGF-1Ea/Ec and COL1A1/3A1 mRNA expression in muscle, with a difference between GH and Plc. IGF-1Ea/Ec and COL-1A1/3A1 mRNA expression increased in muscle following immobilization and retraining in subjects receiving GH, whereas an increase in IGF-1Ec mRNA expression was seen in the Plc group only after retraining. In conclusion, in elderly humans, GH seems to have a matrix stabilizing effect during inactivity and rehabilitation by stimulating collagen expression in the musculotendinous tissue and increasing tendon CSA and stiffness. PMID:24235105

  20. Comparative Glycomics of Connective Tissue Glycosaminoglycans

    PubMed Central

    Hitchcock, Alicia M.; Yates, Karen E.; Costello, Catherine E.; Zaia, Joseph

    2008-01-01

    Homeostasis of connective joint tissues depends on the maintenance of an extracellular matrix, consisting of an integrated assembly of collagens, glycoproteins, proteoglycans and glycosaminoglycans (GAGs). Isomeric chondroitin sulfate (CS) glycoforms differing in position and degree of sulfation and uronic acid epimerization play specific and distinct functional roles during development and disease onset. This work profiles the CS epitopes expressed by different joint tissues as a function of age and osteoarthritis. Glycosaminoglycans were extracted from joint tissues (cartilage, tendon, ligment, muscle and synovium) and partially depolymerized using chondroitinase enzymes. The oligosaccharide products were differentially stable isotope labeled by reductive amination using 2-anthranilic acid- d0 or -d4 and subjected to amide-HILIC on-line liquid chromatography-tandem mass spectrometry. The analysis presented herein enables simultaneous profiling of the expression of non-reducing end, linker region, and Δ-unsaturated interior oligosaccharide domains of the CS chains among the different joint tissues. The results provide important new information on the changes to the expression of CS GAG chains during disease and development. PMID:18318007

  1. A Novel Esthetic Approach using Connective Tissue Graft for Soft Tissue Defect Following Surgical Excision of Gingival Fibrolipoma.

    PubMed

    Balasundaram, Aruna; Parthasarathy, Harinath; Kumar, Praveenkrishna; Gajendran, Priyalochana; Appukuttan, Devapriya

    2014-11-01

    The aim of the present case report is to evaluate the adjunctive use of a connective tissue graft to overcome soft tissue defects following excision of a gingival fibrolipoma in the aesthetic region. Connective tissue graft has been well documented for treating defects of esthetic concern. However, the literature does not contain many reports on the esthetic clinical outcome following the use of connective tissue graft secondary to excision of soft tissue tumours. A 28-year-old male patient reported with a complaint of a recurrent growth in relation to his lower front tooth region. The lesion which was provisionally diagnosed as fibroma was treated with a complete surgical excision, following which a modified coronally advanced flap and connective tissue graft was adopted to overcome the soft tissue defect. The excised growth was diagnosed histologically as fibrolipoma. One year follow up showed no recurrence of the lesion and good esthetics.The adjunctive use of the connective tissue graft and modified coronally advanced flap predictably yields optimal soft tissue fill and excellent esthetics. Hence, routine use of this procedure may be recommended for surgical excision of soft tissue growths in esthetically sensitive areas.

  2. EDTA separation and recombination of epithelium and connective tissue of human oral mucosa. Studies of tissue transplants in nude mice.

    PubMed

    Holmstrup, P; Dabelsteen, E; Harder, F

    1985-01-01

    A possible epithelial-mesenchymal interaction in determining epithelial histologic features of human oral mucosa was examined. The study comprised 74 biopsies of normal buccal mucosa and 54 biopsies of normal palatal mucosa. Epithelium was separated from connective tissue by the use of 1 mM ethylenediamine tetraacetate dihydrate. Self-recombined and cross-recombined epithelial and connective tissues and connective tissue sheets alone were transplanted to subcutaneous sites of nude mice. Histologic examination of cross-recombined palatal epithelium/buccal connective tissue transplants showed a change in keratinization pattern but no major change in number of epithelial cell layers as the result of connective tissue influence. Transplanted sheets of connective tissue after growth for 14 days showed that complete separation of biopsies from buccal mucosa had been obtained. However, palatal mucosa had been incompletely separated as evidenced by re-epithelialization of most of the connective tissue transplants. The consequences of the incomplete palatal epithelium-connective tissue separation are discussed.

  3. Vasculitis associated with connective tissue diseases.

    PubMed

    Cozzani, E; Gasparini, G; Papini, M; Burlando, M; Drago, F; Parodi, A

    2015-04-01

    Vasculitis in connective tissue disease (CTD) is quite rare, it is reported in approximately 10% of patients with CTD; systemic lupus erythematosus (SLE) shows the highest association rate. Vessels of any size may be involved, but mainly small vessels vasculitis is reported. At present the classification of these vasculitis is unsatisfactory. According to the 2012 revised International Chapel Hill Consensus Conference, vasculitides secondary to CTD are a well identified entity and are classified under the category of "vasculitis associated with systemic disease". However only lupus vasculitis and rheumatoid vasculitis are explicitly listed, while the remaining are generically included under the heading "others". Petechiae, purpura, gangrene and ulcers are the most frequent cutaneous manifestations that should investigated in order to rule out potentially dangerous systemic involvement, especially if cryoglobulinemic or necrotizing vasculitis are suspected. This review will focus on the cutaneous involvement in CTD associated vasculitis. PMID:25732106

  4. Chondroitin sulphate inhibits connective tissue mast cells

    PubMed Central

    Theoharides, T C; Patra, P; Boucher, W; Letourneau, R; Kempuraj, D; Chiang, G; Jeudy, S; Hesse, Leah; Athanasiou, A

    2000-01-01

    Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes.Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell ‘stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis.Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides.Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes.Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications. PMID:11082109

  5. Connective tissue disorders in domestic animals.

    PubMed

    Halper, Jaroslava

    2014-01-01

    Though soft tissue disorders have been recognized and described to some detail in several types of domestic animals and small mammals for some years, not much progress has been made in our understanding of the biochemical basis and pathogenesis of these diseases in animals. Ehlers-Danlos syndrome described in dogs already in 1943 and later in cats affects mainly skin in these animals. The involved skin is thin and hyperextensible with easily inflicted injuries resulting in hemorrhagic wounds and atrophic scars. Joint laxity and dislocation common in people are less frequently found in dogs. No systemic complications, such as organ rupture or cardiovascular problems which have devastating consequences in people have been described in cats and dogs. The diagnosis is based on clinical presentation and on light or electron microscopic features of disorganized and fragmented collagen fibrils. Several cases of bovine and ovine dermatosparaxis analogous to human Ehlers-Danlos syndrome type VIIC were found to be caused by mutations in the procollagen I N-proteinase (pnPI) or ADAMTS2 gene, though mutations in other sites are likely responsible for other types of dermatosparaxis. Cattle suffering from a form of Marfan syndrome were described to have aortic dilatation and aneurysm together with ocular abnormalities and skeletal involvement. As in people mutations at different sites of bovine FBN1 may be responsible for Marfan phenotype. Hereditary equine regional dermal asthenia (HERDA), or hyperelastosis cutis, has been recognized in several horse breeds as affecting primarily skin, and, occasionally, tendons. A mutation in cyclophilin B, a chaperon involved in proper folding of collagens, has been identified in some cases. Degenerative suspensory ligament desmitis (DSLD) affects primarily tendons and ligaments of certain horse breeds. New data from our laboratory showed excessive accumulation of proteoglycans in organs with high content of connective tissues. We have

  6. Liver abnormalities in connective tissue diseases.

    PubMed

    De Santis, Maria; Crotti, Chiara; Selmi, Carlo

    2013-08-01

    The liver is a lymphoid organ involved in the immune response and in the maintenance of tolerance to self molecules, but it is also a target of autoimmune reactions, as observed in primary liver autoimmune diseases (AILD) such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Further, the liver is frequently involved in connective tissue diseases (CTD), most commonly in the form of liver function test biochemical changes with predominant cholestatic or hepatocellular patterns. CTD commonly affecting the liver include systemic lupus erythematosus, antiphospholypid syndrome, primary Sjögren's syndrome, systemic sclerosis, dermatomyositis, polimyositis, and anti-synthetase syndrome, while overlap syndromes between AILD and CTD may also be diagnosed. Although liver cirrhosis and failure are extremely rare in patients with CTD, unusual liver conditions such as nodular regenerative hyperplasia or Budd-Chiari syndrome have been reported with increasing frequency in patients with CTD. Acute or progressing liver involvement is generally related to viral hepatitis reactivation or to a concomitant AILD, so it appears to be fundamental to screen patients for HBV and HCV infection, in order to provide the ideal therapeutic regimen and avoid life-threatening reactivations. Finally, it is important to remember that the main cause of biochemical liver abnormalities in patients with CTD is a drug-induced alteration or coexisting viral hepatitis. The present article will provide a general overview of the liver involvement in CTD to allow rheumatologists to discriminate the most common clinical scenarios.

  7. [Autoimmune connective tissue diseases and vaccination].

    PubMed

    Więsik-Szewczyk, Ewa; Jahnz-Różyk, Karina

    2015-12-31

    The idea that infectious agents can induce autoimmune diseases in genetically susceptible subjects has been a matter of discussion for years. Moreover, increased incidence of autoimmune diseases and introduction of prophylactic vaccinations from early childhood suggest that these two trends are linked. In the medical literature and even non-professional media, case reports or events temporally related to vaccination are reported. It raises the issue of vaccination safety. In everyday practice medical professionals, physicians, rheumatologists and other specialists will be asked their opinion of vaccination safety. The decision should be made according to evidence-based medicine and the current state of knowledge. The purpose of this paper is to discuss a potential mechanism which links infections, vaccinations and autoimmunity. We present an overview of published case reports, especially of systemic connective tissue diseases temporally related to vaccination and results from case-nested studies. As yet, no conclusive evidence supports a causal relationship between vaccination and autoimmune diseases. It has to be determined whether the performed studies are sufficiently sensitive to detect the link. The debate is ongoing, and new data may be required to explain the pathogenesis of autoimmunity. We would like to underscore the need for prophylactic vaccination in patients with autoimmune rheumatic diseases and to break down the myth that the vaccines are contraindicated in this target group.

  8. Electrospun nanofibrous scaffolds for engineering soft connective tissues.

    PubMed

    James, Roshan; Toti, Udaya S; Laurencin, Cato T; Kumbar, Sangamesh G

    2011-01-01

    Tissue-engineered medical implants, such as polymeric nanofiber scaffolds, are potential alternatives to autografts and allografts, which are short in supply and carry risks of disease transmission. These scaffolds have been used to engineer various soft connective tissues such as skin, ligament, muscle, and tendon, as well as vascular and neural tissue. Bioactive versions of these materials have been produced by encapsulating molecules such as drugs and growth factors during fabrication. The fibers comprising these scaffolds can be designed to match the structure of the native extracellular matrix (ECM) closely by mimicking the dimensions of the collagen fiber bundles evident in soft connective tissues. These nanostructured implants show improved biological performance over the bulk materials in aspects of cellular infiltration and in vivo integration, and the topography of such scaffolds has been shown to dictate cellular attachment, migration, proliferation, and differentiation, which are critical steps in engineering complex functional tissues and crucial to improved biocompatibility and functional performance. Nanofiber matrices can be fabricated using a variety of techniques, including drawing, molecular self-assembly, freeze-drying, phase separation, and electrospinning. Among these processes, electrospinning has emerged as a simple, elegant, scalable, continuous, and reproducible technique to produce polymeric nanofiber matrices from solutions and their melts. We have shown the ability of this technique to be used to fabricate matrices composed of fibers from a few hundred nanometers to several microns in diameter by simply altering the polymer solution concentration. This chapter will discuss the use of the electrospinning technique in the fabrication of ECM-mimicking scaffolds. Furthermore, selected scaffolds will be seeded with primary adipose-derived stromal cells, imaged using scanning electron microscopy and confocal microscopy, and evaluated in terms

  9. Pectus Excavatum and Heritable Disorders of the Connective Tissue

    PubMed Central

    Tocchioni, Francesca; Ghionzoli, Marco; Messineo, Antonio; Romagnoli, Paolo

    2013-01-01

    Pectus excavatum, the most frequent congenital chest wall deformity, may be rarely observed as a sole deformity or as a sign of an underlying connective tissue disorder. To date, only few studies have described correlations between this deformity and heritable connective tissue disorders such as Marfan, Ehlers-Danlos, Poland, MASS (Mitral valve prolapse, not progressive Aortic enlargement, Skeletal and Skin alterations) phenotype among others. When concurring with connective tissue disorder, cardiopulmonary and vascular involvement may be associated to the thoracic defect. Ruling out the concomitance of pectus excavatum and connective tissue disorders, therefore, may have a direct implication both on surgical outcome and long term prognosis. In this review we focused on biological bases of connective tissue disorders which may be relevant to the pathogenesis of pectus excavatum, portraying surgical and clinical implication of their concurrence. PMID:24198927

  10. Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma

    PubMed Central

    Sun, Dawei; Han, Shen; Liu, Chao; Zhou, Rui; Sun, Weihai; Zhang, Zhijun; Qu, Jianjun

    2016-01-01

    Background The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. Material/Methods We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. Results We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. Conclusions Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma. PMID:27062921

  11. Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing

    PubMed Central

    Henshaw, F. R.; Boughton, P.; Lo, L.; McLennan, S. V.; Twigg, S. M.

    2015-01-01

    Aims/Hypothesis. Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. Methods. Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 μg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. Results. CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound α-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (r = 0.406; P < 0.001). Conclusions/Interpretation. These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers. PMID:25789327

  12. Comment on "Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing".

    PubMed

    Li, Hongling; Cao, Cong; Huang, Ai; Man, Yi

    2015-01-01

    A recent paper in this journal, presented a novel method by topical application of growth factors in stimulating diabetic cutaneous wound healing that caught our attention. We believe that the experimental method in the article is efficient and creative, but it also has some controversies and shortcomings to be discussed. We noted that the authors used "Tegaderm" as a semiocclusive dressing film and stated that it exerted a "splinting effect" on the wound margins and controlled contraction. Indeed, the "Tegaderm" itself can serve as a dressing film to isolate the wound bed with outside environments while the "splinting effect" is mainly achieved by adding silicone splints around the wound. Considering the unique properties of silicone splints and "Tegaderm," our experimental group propose an alternative method named "combined-suturing" technique that is not only suturing the silicone splints but also securing the "Tegaderm" around the wound. The specific reasons and operative procedures are explained in detail in this letter. PMID:26457307

  13. Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2).

    PubMed

    Morales, María Gabriela; Cabrera, Daniel; Céspedes, Carlos; Vio, Carlos P; Vazquez, Yaneisi; Brandan, Enrique; Cabello-Verrugio, Claudio

    2013-07-01

    The renin-angiotensin system (RAS), through angiotensin II and the angiotensin-converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-β), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-β1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-β1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases.

  14. Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2).

    PubMed

    Morales, María Gabriela; Cabrera, Daniel; Céspedes, Carlos; Vio, Carlos P; Vazquez, Yaneisi; Brandan, Enrique; Cabello-Verrugio, Claudio

    2013-07-01

    The renin-angiotensin system (RAS), through angiotensin II and the angiotensin-converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-β), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-β1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-β1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases. PMID:23673415

  15. Effects of integrin ανβ3 on differentiation and collagen synthesis induced by connective tissue growth factor in human hypertrophic scar fibroblasts.

    PubMed

    Hu, Xiaolong; Li, Na; Tao, Ke; Fang, Xiaobing; Liu, Jiaqi; Wang, Yaojun; Wang, Hongtao; Shi, Jihong; Wang, Yunchuan; Ji, Peng; Cai, Weixia; Bai, Xiaozhi; Zhu, Xiongxiang; Han, Juntao; Hu, Dahai

    2014-11-01

    CCN2 is a matricellular protein that appears to be important in scar formation. CCN2 mediates the pro-fibrotic effects in hypertrophic scars (HTSs) through an unknown mechanism. However, many activities of CCN2 protein are known to be mediated by direct binding to integrin receptors. In this study, we investigated the role of integrin α(ν)β(3) in the differentiation of hypertrophic scar fibroblasts (HTSFs) induced by CCN2. The levels of integrin α(ν)β(3) between normal skin and hypertrophic scar (HTS) tissues were compared, and integrin α(ν)β(3) was found to be upregulated in HTS. CCN2 was shown to induce HTSF differentiation and collagen (COL) synthesis at the mRNA and protein levels. Based on these results, the expression of integrin α(ν)β(3) was upregulated by CCN2 stimulation during HTSF differentiation. Blockade of integrin α(ν)β(3) prevented CCN2-induced HTSF differentiation and COL synthesis. Furthermore, the CCN2-induced increase in contractility of the HTSF in COL lattices was inhibited by integrin α(ν)β(3) blocking antibodies. HTSs were established in a rabbit ear model, and the inhibitor of integrin α(ν)β(3) significantly improved the architecture of the rabbit ear scar. Results of the present study showed that integrin α(ν)β(3) contributes to pro-fibrotic CCN2 signaling. Blocking this pathway may therefore be beneficial for the treatment of HTS.

  16. Imaging of connective tissue diseases of the head and neck.

    PubMed

    Abdel Razek, Ahmed Abdel Khalek

    2016-06-01

    We review the imaging appearance of connective tissue diseases of the head and neck. Bilateral sialadenitis and dacryoadenitis are seen in Sjögren's syndrome; ankylosis of the temporo-mandibular joint with sclerosis of the crico-arytenoid joint are reported in rheumatoid arthritis and lupus panniculitis with atypical infection are reported in patients with systemic lupus erythematosus. Relapsing polychondritis shows subglottic stenosis, prominent ear and saddle nose; progressive systemic sclerosis shows osteolysis of the mandible, fibrosis of the masseter muscle with calcinosis of the subcutaneous tissue and dermatomyositis/polymyositis shows condylar erosions and autoimmune thyroiditis. Vascular thrombosis is reported in antiphospholipid antibodies syndrome; cervical lymphadenopathy is seen in adult-onset Still's disease, and neuropathy with thyroiditis reported in mixed connective tissue disorder. Imaging is important to detect associated malignancy with connective tissue disorders. Correlation of the imaging findings with demographic data and clinical findings are important for the diagnosis of connective tissue disorders.

  17. [Protein-energy malnutrition in patients with connective tissue dysplasia].

    PubMed

    Lialiukova, E A

    2013-01-01

    In the conditions of the specialized Center of a dysplasia of a connecting tissue the assessment of an protein--energy malnutrition at 121 patients with signs of a dysplasia of a connecting tissue is carried out. High frequency of an oligotrophy at patients with a dysplasia of a connecting tissue is registered. The I degree of a gipotorofiya is taped at 26.21% of the patients, II degree--at 18.44%, the III degree--at 3.88% of patients.

  18. Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

    SciTech Connect

    Lim, Taekyu; Lee, Inkyoung; Kim, Jungmin; Kang, Won Ki

    2015-10-01

    Purpose: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Methods and Materials: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. Results: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. Conclusion: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

  19. Connective tissue diseases, multimorbidity and the ageing lung.

    PubMed

    Spagnolo, Paolo; Cordier, Jean-François; Cottin, Vincent

    2016-05-01

    Connective tissue diseases encompass a wide range of heterogeneous disorders characterised by immune-mediated chronic inflammation often leading to tissue damage, collagen deposition and possible loss of function of the target organ. Lung involvement is a common complication of connective tissue diseases. Depending on the underlying disease, various thoracic compartments can be involved but interstitial lung disease is a major contributor to morbidity and mortality. Interstitial lung disease, pulmonary hypertension or both are found most commonly in systemic sclerosis. In the elderly, the prevalence of connective tissue diseases continues to rise due to both longer life expectancy and more effective and better-tolerated treatments. In the geriatric population, connective tissue diseases are almost invariably accompanied by age-related comorbidities, and disease- and treatment-related complications, which contribute to the significant morbidity and mortality associated with these conditions, and complicate treatment decision-making. Connective tissue diseases in the elderly represent a growing concern for healthcare providers and an increasing burden of global health resources worldwide. A better understanding of the mechanisms involved in the regulation of the immune functions in the elderly and evidence-based guidelines specifically designed for this patient population are instrumental to improving the management of connective tissue diseases in elderly patients.

  20. Micromechanics and constitutive modeling of connective soft tissues.

    PubMed

    Fallah, A; Ahmadian, M T; Firozbakhsh, K; Aghdam, M M

    2016-07-01

    In this paper, a micromechanical model for connective soft tissues based on the available histological evidences is developed. The proposed model constituents i.e. collagen fibers and ground matrix are considered as hyperelastic materials. The matrix material is assumed to be isotropic Neo-Hookean while the collagen fibers are considered to be transversely isotropic hyperelastic. In order to take into account the effects of tissue structure in lower scales on the macroscopic behavior of tissue, a strain energy density function (SEDF) is developed for collagen fibers based on tissue hierarchical structure. Macroscopic response and properties of tissue are obtained using the numerical homogenization method with the help of ABAQUS software. The periodic boundary conditions and the proposed constitutive models are implemented into ABAQUS using the DISP and the UMAT subroutines, respectively. The existence of the solution and stable material behavior of proposed constitutive model for collagen fibers are investigated based on the poly-convexity condition. Results of the presented micromechanics model for connective tissues are compared and validated with available experimental data. Effects of geometrical and material parameters variation at microscale on macroscopic mechanical behavior of tissues are investigated. The results show that decrease in collagen content of the connective tissues like the tendon due to diseases leads 20% more stretch than healthy tissue under the same load which can results in connective tissue malfunction and hypermobility in joints. PMID:26807767

  1. Micromechanics and constitutive modeling of connective soft tissues.

    PubMed

    Fallah, A; Ahmadian, M T; Firozbakhsh, K; Aghdam, M M

    2016-07-01

    In this paper, a micromechanical model for connective soft tissues based on the available histological evidences is developed. The proposed model constituents i.e. collagen fibers and ground matrix are considered as hyperelastic materials. The matrix material is assumed to be isotropic Neo-Hookean while the collagen fibers are considered to be transversely isotropic hyperelastic. In order to take into account the effects of tissue structure in lower scales on the macroscopic behavior of tissue, a strain energy density function (SEDF) is developed for collagen fibers based on tissue hierarchical structure. Macroscopic response and properties of tissue are obtained using the numerical homogenization method with the help of ABAQUS software. The periodic boundary conditions and the proposed constitutive models are implemented into ABAQUS using the DISP and the UMAT subroutines, respectively. The existence of the solution and stable material behavior of proposed constitutive model for collagen fibers are investigated based on the poly-convexity condition. Results of the presented micromechanics model for connective tissues are compared and validated with available experimental data. Effects of geometrical and material parameters variation at microscale on macroscopic mechanical behavior of tissues are investigated. The results show that decrease in collagen content of the connective tissues like the tendon due to diseases leads 20% more stretch than healthy tissue under the same load which can results in connective tissue malfunction and hypermobility in joints.

  2. Epidemiology of organic solvents and connective tissue disease

    PubMed Central

    Garabrant, David H; Dumas, Constantine

    2000-01-01

    Case reports suggest that solvents are associated with various connective tissue diseases (systemic sclerosis, scleroderma, undifferentiated connective tissue disease, systemic lupus erythematosis, and rheumatoid arthritis), particularly systemic sclerosis. A small number of epidemiological studies have shown statistically significant but weak associations between solvent exposure, systemic sclerosis, and undifferentiated connective tissue disease. However, the interpretation of these positive findings is tempered by a lack of replication, an inability to specify which solvents convey risk, and an absence of increasing risk with increasing exposure. Existing studies, on aggregate, do not show conclusively that solvents (either as a group of chemicals or individual chemicals) are causally associated with any connective tissue disease. Further investigations should be carried out to replicate the positive existing findings and to specify the solvents and circumstances of exposure that carry risk. PMID:11094414

  3. [CT imaging features of pulmonary involvement in connective tissue disorders].

    PubMed

    Brillet, P Y; Mama, N; Nunes, H; Uzunhan, Y; Abbad, S; Brauner, M W

    2009-11-01

    Connective tissue disorders correspond to a heterogeneous group of inflammatory diseases characterized by abnormal immune system activity leading to connective tissue alterations in multiple parts of the body. In adults, connective tissue disorders include rheumatoid arthritis, progressive systemic sclerosis, Sjögren syndrome, systemic lupus erythematosus, dermatomyositis and polymyositis, ankylosing spondylitis, and mixed connective tissue disease. Broncho-pulmonary involvement may be variable with involvement of all anatomical components of the lung. Involvement of other intrathoracic structures (pleura, respiratory muscles, heart, rib cage) is frequent. The most specific manifestations include interstitial lung diseases and pulmonary hypertension. During follow-up, progressive respiratory diseases may occur due to the treatment, infections, pulmonary embolism or neoplasms.

  4. Combined effects of connective tissue growth factor-modified bone marrow-derived mesenchymal stem cells and NaOH-treated PLGA scaffolds on the repair of articular cartilage defect in rabbits.

    PubMed

    Zhu, Songsong; Zhang, Bi; Man, Cheng; Ma, Yongqing; Liu, Xianwen; Hu, Jing

    2014-04-01

    In cartilage tissue engineering using stem cells, it is important to stimulate proliferation and control the differentiation of stem cells to specific lineages. Here we reported a combined technique for articular cartilage repair, consisting of bone marrow mesenchymal stem cells (BMMSCs) transfected with connective tissue growth factor (CTGF) gene and NaOH-treated poly(lactic-co-glycolic) acid (PLGA) scaffolds. In the present study, BMMSCs or CTGF-modified BMMSCs seeded on PLGA or NaOH-treated PLGA scaffolds were incubated in vitro and NaOH-treated PLGA significantly stimulated proliferation of BMMSCs, while CTGF gene transfer promoted chondrogenic differentiation. The effects of the composite on the repair of cartilage defects were evaluated in rabbit knee joints in vivo. Full-thickness cartilage defects (diameter: 5 mm; depth: 3 mm) were created unilaterally in the patellar groove. Defects were either left empty (n = 18) or implanted with BMMSCs/PLGA (n = 18), BMMSCs/NaOH-treated PLGA (n = 18), or CTGF-modified BMMSCs/NaOH-treated PLGA (n = 18). The defect area was examined grossly, histologically, and mechanically at 6, 12, and 24 weeks postoperatively. Implanted cells were tracked using adeno-LacZ labeling at 6 weeks after implantation. Overall, the CTGF-modified BMMSCs/NaOH-treated PLGA group showed successful hyaline-like cartilage regeneration similar to normal cartilage, which was superior to the other groups using gross examination, qualitative and quantitative histology, and mechanical assessment. The in vivo viability of the implanted cells was demonstrated by their retention for 6 weeks after implantation. These findings suggested that a combination of CTGF-modified BMMSCs and NaOH-treated PLGA may be an alternative treatment for large osteochondral defects in high-loading sites.

  5. Fibroblast cytoskeletal remodeling contributes to connective tissue tension.

    PubMed

    Langevin, Helene M; Bouffard, Nicole A; Fox, James R; Palmer, Bradley M; Wu, Junru; Iatridis, James C; Barnes, William D; Badger, Gary J; Howe, Alan K

    2011-05-01

    The visco-elastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the visco-elastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast's processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the visco-elastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular, and immune cell populations residing within connective tissue.

  6. FIBROBLAST CYTOSKELETAL REMODELING CONTRIBUTES TO CONNECTIVE TISSUE TENSION

    PubMed Central

    Langevin, Helene M.; Bouffard, Nicole A.; Fox, James R.; Palmer, Bradley M.; Wu, Junru; Iatridis, James C.; Barnes, William D.; Badger, Gary J.; Howe, Alan K.

    2011-01-01

    The viscoelastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the viscoelastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast’s processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the viscoelastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular and immune cell populations residing within connective tissue. PMID:20945345

  7. Hypericin-mediated selective photomodification of connective tissues

    SciTech Connect

    Hovhannisyan, V. Guo, H. W.; Chen, Y. F.; Hovhannisyan, A.; Ghukasyan, V.; Dong, C. Y.

    2014-12-29

    Controllable modification of biological molecules and supramolecular components of connective tissue are important for biophysical and biomedical applications. Through the use of second harmonic generation imaging, two-photon fluorescence microscopy, and spectrofluorimetry, we found that hypericin, a natural pigment, induces photosensitized destruction of collagen fibers but does not affect elastic fibers and lipids in chicken tendon, skin, and blood vessels. We demonstrated the dynamics and efficiency of collagen photomodification and investigated mechanisms of this processes. Our results suggest that hypericin–mediated photoprocesses in biological tissues may be useful in biomedical applications that require selective modification of connective tissues.

  8. Hypericin-mediated selective photomodification of connective tissues

    NASA Astrophysics Data System (ADS)

    Hovhannisyan, V.; Hovhannisyan, A.; Ghukasyan, V.; Guo, H. W.; Chen, Y. F.; Dong, C. Y.

    2014-12-01

    Controllable modification of biological molecules and supramolecular components of connective tissue are important for biophysical and biomedical applications. Through the use of second harmonic generation imaging, two-photon fluorescence microscopy, and spectrofluorimetry, we found that hypericin, a natural pigment, induces photosensitized destruction of collagen fibers but does not affect elastic fibers and lipids in chicken tendon, skin, and blood vessels. We demonstrated the dynamics and efficiency of collagen photomodification and investigated mechanisms of this processes. Our results suggest that hypericin-mediated photoprocesses in biological tissues may be useful in biomedical applications that require selective modification of connective tissues.

  9. Oral manifestations of connective tissue disease and novel therapeutic approaches.

    PubMed

    Heath, Kenisha R; Rogers, Roy S; Fazel, Nasim

    2015-10-16

    Connective tissue diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren syndrome (SS) have presented many difficulties both in their diagnosis and treatment. Known causes for this difficulty include uncertainty of disease etiology, the multitude of clinical presentations, the unpredictable disease course, and the variable cell types, soluble mediators, and tissue factors that are believed to play a role in the pathogenesis of connective tissue diseases. The characteristic oral findings seen with these specific connective tissue diseases may assist with more swift diagnostic capability. Additionally, the recent use of biologics may redefine the success rate in the treatment and management of the disease. In this review we describe the oral manifestations associated with SLE, SSc, and SS and review the novel biologic drugs used to treat these conditions.

  10. [Progress of Autoantibody Examinations for Connective Tissue Diseases].

    PubMed

    Akashi, Kengo; Saegusa, Jun; Morinobu, Akio

    2015-05-01

    Connective tissue diseases are chronic inflammatory diseases that can affect multiple organs and, thus, have a broad spectrum of clinical presentations. Various autoantibodies are detected in patients with connective tissue diseases, represented by anti-nuclear antibody for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Sjögren's syndrome, and mixed connective tissue disease. Assessment of the autoantibody profile is fundamental for the clinical management of patients with connective tissue diseases, providing important data for the diagnosis, clinical characterization, and disease activity evaluation. Anti-ribosomal P antibody and anti-NMDA receptor antibody are associated with neuropsychiatric SLE. Anti-synthetase syndrome comprises the association of myositis (PM/DM), interstitial lung disease, fever, Raynaud's phenomenon, mechanic's hands, and anti-aminoacyl tRNA synthetase antibodies. Anti-MDA5 antibody is detected in patients with clinically amyopathic DM, often complicated by rapidly progressive interstitial lung disease. Between 50 and 75% of malignancy-associated DM patients are positive for anti-TIF1-γ antibody. Anti-RNA polymerase III antibody is associated with diffuse cutaneous SSc and renal crisis. This review focuses on the importance and usefulness of these autoantibodies for the diagnosis and management of patients with connective tissue diseases in clinical practice.

  11. Tissue Engineering Using Transfected Growth-Factor Genes

    NASA Technical Reports Server (NTRS)

    Madry, Henning; Langer, Robert S.; Freed, Lisa E.; Trippel, Stephen; Vunjak-Novakovic, Gordana

    2005-01-01

    A method of growing bioengineered tissues includes, as a major component, the use of mammalian cells that have been transfected with genes for secretion of regulator and growth-factor substances. In a typical application, one either seeds the cells onto an artificial matrix made of a synthetic or natural biocompatible material, or else one cultures the cells until they secrete a desired amount of an extracellular matrix. If such a bioengineered tissue construct is to be used for surgical replacement of injured tissue, then the cells should preferably be the patient s own cells or, if not, at least cells matched to the patient s cells according to a human-leucocyteantigen (HLA) test. The bioengineered tissue construct is typically implanted in the patient's injured natural tissue, wherein the growth-factor genes enhance metabolic functions that promote the in vitro development of functional tissue constructs and their integration with native tissues. If the matrix is biodegradable, then one of the results of metabolism could be absorption of the matrix and replacement of the matrix with tissue formed at least partly by the transfected cells. The method was developed for articular chondrocytes but can (at least in principle) be extended to a variety of cell types and biocompatible matrix materials, including ones that have been exploited in prior tissue-engineering methods. Examples of cell types include chondrocytes, hepatocytes, islet cells, nerve cells, muscle cells, other organ cells, bone- and cartilage-forming cells, epithelial and endothelial cells, connective- tissue stem cells, mesodermal stem cells, and cells of the liver and the pancreas. Cells can be obtained from cell-line cultures, biopsies, and tissue banks. Genes, molecules, or nucleic acids that secrete factors that influence the growth of cells, the production of extracellular matrix material, and other cell functions can be inserted in cells by any of a variety of standard transfection techniques.

  12. Aldosterone stimulates nuclear factor-kappa B activity and transcription of intercellular adhesion molecule-1 and connective tissue growth factor in rat mesangial cells via serum- and glucocorticoid-inducible protein kinase-1.

    PubMed

    Terada, Yoshio; Ueda, Satoko; Hamada, Kazu; Shimamura, Yoshiko; Ogata, Koji; Inoue, Kosuke; Taniguchi, Yoshinori; Kagawa, Toru; Horino, Taro; Takao, Toshihiro

    2012-02-01

    Several clinical and experimental data support the hypothesis that aldosterone contributes to the progression of renal injury. To determine the signaling pathway of aldosterone in relation to fibrosis and inflammation in mesangial cells, we investigated the effects of aldosterone on expression and activation of serum- and glucocorticoid-inducible protein kinase-1 (SGK1), the activation of nuclear factor-kappa B (NF-κB activation, and the expressions of intercellular adhesion molecule-1 (ICAM-1) and connective tissue growth factor (CTGF). Aldosterone stimulated SGK1 expression, phosphorylation (Ser-256), and kinase activity. The increments of phosphorylation and expression of SGK1 induced by aldosterone were inhibited by mineralocorticoid receptor (MR) inhibitor (eplerenone). Aldosterone stimulated NF-κB activity measured by NF-κB responsive elements, luciferase assay, and the levels of inhibitor of kappa B (IκB) phosphorylation. This aldosterone-induced activation of NF-κB was inhibited by the transfection of dominant-negative SGK1. Furthermore, aldosterone augmented the promoter activities and protein expressions of ICAM-1 and CTGF. The effects of aldosterone on ICAM-1 and CTGF promoter activities and protein expressions were inhibited by the transfection of dominant-negative SGK1 and dominant-negative IκBα. We also found that the MR antagonist significantly ameliorated the glomerular injury and enhancements in SGK1, ICAM-1, and CTGF expressions induced by 1% sodium chloride and aldosterone in vivo. In conclusion, our findings suggest that aldosterone stimulates ICAM-1 and CTGF transcription via activation of SGK1 and NF-κB, which may be involved in the progression of aldosterone-induced mesangial fibrosis and inflammation. MR antagonists may serve as useful therapeutic targets for the treatment of glomerular inflammatory disease.

  13. Growth Hormone and Craniofacial Tissues. An update

    PubMed Central

    Litsas, George

    2015-01-01

    Growth hormone is an important regulator of bone homeostasis. In childhood, it determines the longitudinal bone growth, skeletal maturation, and acquisition of bone mass. In adulthood, it is necessary to maintain bone mass throughout life. Although an association between craniofacial and somatic development has been clearly established, craniofacial growth involves complex interactions of genes, hormones and environment. Moreover, as an anabolic hormone seems to have an important role in the regulation of bone remodeling, muscle enhancement and tooth development. In this paper the influence of growth hormone on oral tissues is reviewed. PMID:25674165

  14. [50 years of connective tissue research: from the French Connective Tissue Club to the French Society of Extracellular Matrix Biology].

    PubMed

    Maquart, François-Xavier; Borel, Jacques-Paul

    2012-01-01

    The history of connective tissue research began in the late 18th century. However, it is only 50 years later that the concept of connective tissue was shaped. It took another fifty years before biochemical knowledge of extracellular matrix macromolecules began to emerge in the first half of the 20th century. In 1962, thanks to Ladislas and Barbara Robert, back from the US, the first society called "French Connective Tissue Club" was created in Paris. The first board was constituted of Albert Delaunay, Suzanne Bazin and Ladislas Robert. Very quickly, under the influence of these pioneers, national and international meetings were organized and, in 1967, a "Federation of the European Connective Tissue Clubs" was created at the initiative of Ladislas Robert (Paris) and John Scott (Manchester). It spread rapidly to the major European nations. In 1982 the transformation of "Clubs" in "Societies" occurred, a name more in line with the requirements of the time. In 2008, the "French Connective Tissue Society" became the "French Society of Extracellular Matrix Biology" ("Société Française de Biologie de la Matrice Extracellulaire", SFBMEc), to better highlight the importance of the extracellular matrix in the biology of living organisms. The SFBMEc's mission today is to promote and develop scientific exchanges between academic, industrial, and hospital laboratories involved in research on the extracellular matrix. SFBMEc organizes or subsidizes scientific meetings and awards scholarships to Ph.D. students or post-docs to participate in international conferences. It includes 200 to 250 members from different disciplines, developing strong interactions between scientists, clinicians and pathologists. It is present all around the French territory in many research laboratories. During these last 50 years, the extraordinary advances made possible by the development of new investigation techniques, in particular molecular biology, cell and tissue imaging, molecular modeling

  15. [Connective tissue: big unifying element of the organism].

    PubMed

    Kapandji, A-I

    2012-10-01

    The anatomical unity of the organism is realized by the connective tissue, which assumes five functions: the filling of the spaces between organs; the connexion between these organs; the driving of the vascular and nervous pedicles to these organs; the stocking of nutritive reserves in fat pads; an aesthetic role with hollows and bumps erasing. The space filling is done with jointed polyedric volumes, which are constituted, according to the theories of J.-C. Guimberteau, with microvacuoles, filled with under pressure fundamental substance. This is a status of preconstraint resulting in a form memory. So, the connective tissue under constraint get back its initial status after this constraint is over, according to the laws of a new science, the tensegrity. The explorations of the connective tissue with a 25× magnifying micro endoscopes are showing micro fibrillar structures, evoluting under constraint. Its arrangement, that seems chaotic, is in fractal disposition, in reality, and follows the "universal parcimony law" established by Williams of Ockham. The structure of the connective tissue can be integrated in a holistic conception of the organism. Many characteristics of this tissue have still to be discovered.

  16. [Connective tissue: big unifying element of the organism].

    PubMed

    Kapandji, A-I

    2012-10-01

    The anatomical unity of the organism is realized by the connective tissue, which assumes five functions: the filling of the spaces between organs; the connexion between these organs; the driving of the vascular and nervous pedicles to these organs; the stocking of nutritive reserves in fat pads; an aesthetic role with hollows and bumps erasing. The space filling is done with jointed polyedric volumes, which are constituted, according to the theories of J.-C. Guimberteau, with microvacuoles, filled with under pressure fundamental substance. This is a status of preconstraint resulting in a form memory. So, the connective tissue under constraint get back its initial status after this constraint is over, according to the laws of a new science, the tensegrity. The explorations of the connective tissue with a 25× magnifying micro endoscopes are showing micro fibrillar structures, evoluting under constraint. Its arrangement, that seems chaotic, is in fractal disposition, in reality, and follows the "universal parcimony law" established by Williams of Ockham. The structure of the connective tissue can be integrated in a holistic conception of the organism. Many characteristics of this tissue have still to be discovered. PMID:22884219

  17. Electrical impedance along connective tissue planes associated with acupuncture meridians

    PubMed Central

    Ahn, Andrew C; Wu, Junru; Badger, Gary J; Hammerschlag, Richard; Langevin, Helene M

    2005-01-01

    Background Acupuncture points and meridians are commonly believed to possess unique electrical properties. The experimental support for this claim is limited given the technical and methodological shortcomings of prior studies. Recent studies indicate a correspondence between acupuncture meridians and connective tissue planes. We hypothesized that segments of acupuncture meridians that are associated with loose connective tissue planes (between muscles or between muscle and bone) visible by ultrasound have greater electrical conductance (less electrical impedance) than non-meridian, parallel control segments. Methods We used a four-electrode method to measure the electrical impedance along segments of the Pericardium and Spleen meridians and corresponding parallel control segments in 23 human subjects. Meridian segments were determined by palpation and proportional measurements. Connective tissue planes underlying those segments were imaged with an ultrasound scanner. Along each meridian segment, four gold-plated needles were inserted along a straight line and used as electrodes. A parallel series of four control needles were placed 0.8 cm medial to the meridian needles. For each set of four needles, a 3.3 kHz alternating (AC) constant amplitude current was introduced at three different amplitudes (20, 40, and 80 μAmps) to the outer two needles, while the voltage was measured between the inner two needles. Tissue impedance between the two inner needles was calculated based on Ohm's law (ratio of voltage to current intensity). Results At the Pericardium location, mean tissue impedance was significantly lower at meridian segments (70.4 ± 5.7 Ω) compared with control segments (75.0 ± 5.9 Ω) (p = 0.0003). At the Spleen location, mean impedance for meridian (67.8 ± 6.8 Ω) and control segments (68.5 ± 7.5 Ω) were not significantly different (p = 0.70). Conclusion Tissue impedance was on average lower along the Pericardium meridian, but not along the Spleen

  18. Epidermal growth factor (urogastrone) in human tissues.

    PubMed

    Hirata, Y; Orth, D N

    1979-04-01

    Human epidermal growth factor (hEGF), which stimulates the growth of a variety of tissues, was first isolated from mouse submandibular glands, but is also excreted in large amounts (about 50 micrograms/day) in human urine and is probably identical to human beta-urogastrone (hUG), a potent inhibitor of stimulated gastric acid secretion. However, the primary tissue source of hEGF/hUG is as yet unknown. The hEGF/hUG in homogenates of human salivary glands and a wide variety of other endocrine and nonendocrine tissues was extracted by Amberlite CG-50 cation exchange chromatography and immune affinity chromatography using the immunoglobulin fraction of rabbit anti-hEGF serum covalently bound to agarose. The extracts were subjected to homologous hEGF RIA. Immunoreactive hEGF was found in extracts of adult submandibular gland, thyroid gland, duodenum, jejunum, and kidney, but not in several fetal tissues. The tissue immunoreactive hEGF was similar to standard hEGF in terms of immunoreactivity and elution from Sephadex G-50 Fine resin, but its concentrations were very low (1.3-5.5 ng/g wet tissue). Thus, it is not certain that these tissues represent the only source of the large amounts of hEGF/hUG that appear to be filtered by the kidneys each day.

  19. Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.

    PubMed

    Ashworth, J L; Murphy, G; Rock, M J; Sherratt, M J; Shapiro, S D; Shuttleworth, C A; Kielty, C M

    1999-05-15

    Fibrillin is the principal structural component of the 10-12 nm diameter elastic microfibrils of the extracellular matrix. We have previously shown that both fibrillin molecules and assembled microfibrils are susceptible to degradation by serine proteases. In this study, we have investigated the potential catabolic effects of six matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 and MMP-14) on fibrillin molecules and on intact fibrillin-rich microfibrils isolated from ciliary zonules. Using newly synthesized recombinant fibrillin molecules, major cleavage sites within fibrillin-1 were identified. In particular, the six different MMPs generated a major degradation product of approximately 45 kDa from the N-terminal region of the molecule, whereas treatment of truncated, unprocessed and furin-processed C-termini also generated large degradation products. Introduction of a single ectopia lentis-causing amino acid substitution (E2447K; one-letter symbols for amino acids) in a calcium-binding epidermal growth factor-like domain, predicted to disrupt calcium binding, markedly altered the pattern of C-terminal fibrillin-1 degradation. However, the fragmentation pattern of a mutant fibrillin-1 with a comparable E-->K substitution in an upstream calcium-binding epidermal growth factor-like domain was indistinguishable from wild-type molecules. Ultrastructural examination highlighted that fibrillin-rich microfibrils isolated from ciliary zonules were grossly disrupted by MMPs. This is the first demonstration that fibrillin molecules and fibrillin-rich microfibrils are degraded by MMPs and that certain amino acid substitutions change the fragmentation patterns. These studies have important implications for physiological and pathological fibrillin catabolism and for loss of connective tissue elasticity in ageing and disease.

  20. Epidermal growth factor receptor signaling in tissue

    SciTech Connect

    Shvartsman, Stanislav; Wiley, H. S.; Lauffenburger, Douglas A.

    2004-08-01

    Abstract: A peptide purified from the salivary gland of a mouse was shown few years ago to accelerate incisor eruption and eyelid opening in newborn mice, and was named epidermal growth factor (EGF). The members of this family of peptide growth factors had been identified in numerous physiological and pathological contexts. EGF binds to a cell surface EGF receptor, which induces a biochemical modification (phosphorylation) of the receptor's cytoplasmic tail. There is a growing consensus in the research community that, in addition to cellular and molecular studies, the dynamics of the EGFR network and its operation must be examined in tissues. A key challenge is to integrate the existing molecular and cellular information into a system-level description of the EGFR network at the tissue and organism level. In this paper, the two examples of EGFR signaling in tissues are described, and the recent efforts to model EGFR autocrine loops, which is a predominant mode of EGFR activation in vivo, are summarized.

  1. Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways

    PubMed Central

    Cheng, Yi; Lin, Chien-huang; Chen, Jing-Yun; Li, Chien-Hua; Liu, Yu-Tin; Chen, Bing-Chang

    2016-01-01

    Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and

  2. Multigenerational interstitial growth of biological tissues

    PubMed Central

    Ricken, Tim

    2010-01-01

    This study formulates a theory for multigenerational interstitial growth of biological tissues whereby each generation has a distinct reference configuration determined at the time of its deposition. In this model, the solid matrix of a growing tissue consists of a multiplicity of intermingled porous permeable bodies, each of which represents a generation, all of which are constrained to move together in the current configuration. Each generation’s reference configuration has a one-to-one mapping with the master reference configuration, which is typically that of the first generation. This mapping is postulated based on a constitutive assumption with regard to that generations’ state of stress at the time of its deposition. For example, the newly deposited generation may be assumed to be in a stress-free state, even though the underlying tissue is in a loaded configuration. The mass content of each generation may vary over time as a result of growth or degradation, thereby altering the material properties of the tissue. A finite element implementation of this framework is used to provide several illustrative examples, including interstitial growth by cell division followed by matrix turnover. PMID:20238138

  3. Systemic connective tissue features in women with fibromuscular dysplasia.

    PubMed

    O'Connor, Sarah; Kim, Esther Sh; Brinza, Ellen; Moran, Rocio; Fendrikova-Mahlay, Natalia; Wolski, Kathy; Gornik, Heather L

    2015-10-01

    Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease associated with hypertension, headache, dissection, stroke, and aneurysm. The etiology is unknown but hypothesized to involve genetic and environmental components. Previous studies suggest a possible overlap of FMD with other connective tissue diseases that present with dissections and aneurysms. The aim of this study was to investigate the prevalence of connective tissue physical features in FMD. A total of 142 FMD patients were consecutively enrolled at a single referral center (97.9% female, 92.1% of whom had multifocal FMD). Data are reported for 139 female patients. Moderately severe myopia (29.1%), high palate (33.1%), dental crowding (29.7%), and early-onset arthritis (15.6%) were prevalent features. Classic connective features such as hypertelorism, cleft palate, and hypermobility were uncommon. The frequency of systemic connective tissue features was compared between FMD patients with a high vascular risk profile (having had ⩾1 dissection and/or ⩾2 aneurysms) and those with a standard vascular risk profile. A history of spontaneous pneumothorax (5.9% high risk vs 0% standard risk) and atrophic scarring (17.6% high risk vs 6.8% standard risk) were significantly more prevalent in the high risk group, p<0.05. High palate was observed in 43.1% of the high risk group versus 27.3% in the standard risk group, p=0.055. In conclusion, in a cohort of women with FMD, there was a prevalence of moderately severe myopia, high palate, dental crowding, and early-onset osteoarthritis. However, a characteristic phenotype was not discovered. Several connective tissue features such as high palate and pneumothorax were more prominent among FMD patients with a high vascular risk profile.

  4. Role of PTPα in the destruction of periodontal connective tissues.

    PubMed

    Rajshankar, Dhaarmini; Sima, Corneliu; Wang, Qin; Goldberg, Stephanie R; Kazembe, Mwayi; Wang, Yongqiang; Glogauer, Michael; Downey, Gregory P; McCulloch, Christopher A

    2013-01-01

    IL-1β contributes to connective tissue destruction in part by up-regulating stromelysin-1 (MMP-3), which in fibroblasts is a focal adhesion-dependent process. Protein tyrosine phosphatase-α (PTPα) is enriched in and regulates the formation of focal adhesions, but the role of PTPα in connective tissue destruction is not defined. We first examined destruction of periodontal connective tissues in adult PTPα(+/+) and PTPα(-/-) mice subjected to ligature-induced periodontitis, which increases the levels of multiple cytokines, including IL-1β. Three weeks after ligation, maxillae were processed for morphometry, micro-computed tomography and histomorphometry. Compared with unligated controls, there was ∼1.5-3 times greater bone loss as well as 3-fold reduction of the thickness of the gingival lamina propria and 20-fold reduction of the amount of collagen fibers in WT than PTPα(-/-) mice. Immunohistochemical staining of periodontal tissue showed elevated expression of MMP-3 at ligated sites. Second, to examine mechanisms by which PTPα may regulate matrix degradation, human MMP arrays were used to screen conditioned media from human gingival fibroblasts treated with vehicle, IL-1β or TNFα. Although MMP-3 was upregulated by both cytokines, only IL-1β stimulated ERK activation in human gingival fibroblasts plated on fibronectin. TIRF microscopy and immunoblotting analyses of cells depleted of PTPα activity with the use of various mutated constructs or with siRNA or PTPα(KO) and matched wild type fibroblasts were plated on fibronectin to enable focal adhesion formation and stimulated with IL-1β. These data showed that the catalytic and adaptor functions of PTPα were required for IL-1β-induced focal adhesion formation, ERK activation and MMP-3 release. We conclude that inflammation-induced connective tissue degradation involving fibroblasts requires functionally active PTPα and in part is mediated by IL-1β signaling through focal adhesions.

  5. Extracellular matrix of connective tissues in the heads of teleosts.

    PubMed Central

    Benjamin, M; Ralphs, J R

    1991-01-01

    The distribution of extracellular matrix molecules (chondroitin and keratan sulphates, type II collagen) is described in cranial connective tissues of teleosts. Hyaline cartilage was similar to that in mammals and usually contained all 3 molecules. The more cellular cartilages that are not normally present in mammals were more variable in composition. Scleral cartilage closely resembled hyaline cartilage, Zellknorpel in the gill filaments resembled it in some species but not in others, and elastic/cell-rich and hyaline-cell cartilages were unlike hyaline cartilage. These variations may be related to functional or developmental differences between the tissues. Bone and chondroid bone also varied in composition between species. Whilst both tissues contained chondroitin sulphate, bone contained type II collagen in 5 of the 12 species examined. This suggests that cartilage components are more widespread in teleost bone than has previously been shown. Type II collagen also occurred in dense connective tissues of some species. Notably, where this molecule was present in one of these tissues, it was present in all. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:1817131

  6. A Framework for Modelling Connective Tissue Changes in VIIP Syndrome

    NASA Technical Reports Server (NTRS)

    Ethier, C. R.; Best, L.; Gleason, R.; Mulugeta, L.; Myers, J. G.; Nelson, E. S.; Samuels, B. C.

    2014-01-01

    Insertion of astronauts into microgravity induces a cascade of physiological adaptations, notably including a cephalad fluid shift. Longer-duration flights carry an increased risk of developing Visual Impairment and Intracranial Pressure (VIIP) syndrome, a spectrum of ophthalmic changes including posterior globe flattening, choroidal folds, distension of the optic nerve sheath, kinking of the optic nerve and potentially permanent degradation of visual function. The slow onset of changes in VIIP, their chronic nature, and the similarity of certain clinical features of VIIP to ophthalmic findings in patients with raised intracranial pressure strongly suggest that: (i) biomechanical factors play a role in VIIP, and (ii) connective tissue remodeling must be accounted for if we wish to understand the pathology of VIIP. Our goal is to elucidate the pathophysiology of VIIP and suggest countermeasures based on biomechanical modeling of ocular tissues, suitably informed by experimental data, and followed by validation and verification. We specifically seek to understand the quasi-homeostatic state that evolves over weeks to months in space, during which ocular tissue remodeling occurs. This effort is informed by three bodies of work: (i) modeling of cephalad fluid shifts; (ii) modeling of ophthalmic tissue biomechanics in glaucoma; and (iii) modeling of connective tissue changes in response to biomechanical loading.

  7. The diagnosis and classification of undifferentiated connective tissue diseases.

    PubMed

    Mosca, Marta; Tani, Chiara; Vagnani, Sabrina; Carli, Linda; Bombardieri, Stefano

    2014-01-01

    The term undifferentiated connective tissue disease (UCTD) refers to unclassifiable systemic autoimmune diseases which share clinical and serological manifestations with definite connective tissue diseases (CTDs) but not fulfilling any of the existing classification criteria. In this review we will go through the more recent evidence on UCTD and we will discuss in what extent the availability of new criteria for the CTDs could interfere with the "UCTD concept". The development of criteria able to identify early phases of defined CTD, may help in the differentiation of stable UCTD form their early stages and may offer a valuable guide to the treating physician to set up appropriate follow up schedules as well as therapeutic protocols. This simplified subset of CTD could offer a model to study clinic pathological correlations as well as the role of possible environmental factors in the development of autoimmunity.

  8. Connective tissue disease-related pulmonary arterial hypertension.

    PubMed

    Thakkar, Vivek; Lau, Edmund M T

    2016-02-01

    Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH.

  9. Connective tissue disease-related pulmonary arterial hypertension.

    PubMed

    Thakkar, Vivek; Lau, Edmund M T

    2016-02-01

    Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH. PMID:27421214

  10. [A case report of undifferentiated connective tissue disease associated myelodysplastic].

    PubMed

    Zhang, Xiao-ying; Wen, Hong-yan; Chen, Jun-wei; Li, Xiao-feng; Wang, Li-xing

    2012-04-18

    A 58-year-old man exhibited polyarthritis, fever, thrombocytopenia and progressive anemia. Undifferentiated connective tissue diseases(UCTD) was diagnosed based on laboratory and radiographic findings. After diagnosis, the patient received glucocorticoid and blood-transfusion. The symptoms were improved notablely. However,the level of hemoglobin was lower than normal(between 57 g/L and 75 g/L). Thrombocytes were 19 000/microl to 32 000/microl. Bone marrow aspiration revealed highly abnormal cell morphology, indicating myelodysplastic syndrome(MDS). A diagnosis of UCTD with MDS was made. The patient was successfully treated by decitabine and thalidomide(an immunosuppressive regimen). It is necessary to promptly examine bone marrow cell morphology and chromosomal aberration in cases with connective tissue diseases complicated by sudden cytopenia and thrombocytopenia.

  11. Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis▿ †

    PubMed Central

    Dean, Richard A.; Butler, Georgina S.; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R.; Courty, José; Overall, Christopher M.

    2007-01-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2−/− mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2−/− cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis. PMID:17908800

  12. Synaptic activity and connective tissue remodeling in denervated frog muscle

    PubMed Central

    1994-01-01

    Denervation of skeletal muscle results in dramatic remodeling of the cellular and molecular composition of the muscle connective tissue. This remodeling is concentrated in muscle near neuromuscular junctions and involves the accumulation of interstitial cells and several extracellular matrix molecules. Given the role of extracellular matrix in neurite outgrowth and synaptogenesis, we predict that this remodeling of the junctional connective tissue directly influences the regeneration of the neuromuscular junction. As one step toward understanding the role of this denervation-induced remodeling in synapse formation, we have begun to look for the signals that are involved in initiating the junctional accumulations of interstitial cells and matrix molecules. Here, the role of muscle inactivity as a signal was examined. The distributions of interstitial cells, fibronectin, and tenascin were determined in muscles inactivated by presynaptic blockade of muscle activity with tetrodotoxin. We found that blockade of muscle activity for up to 4 wk produced neither the junctional accumulation of interstitial cells nor the junctional concentrations of tenascin and fibronectin normally present in denervated frog muscle. In contrast, the muscle inactivity induced the extrajunctional appearance of two synapse-specific molecules, the acetylcholine receptor and a muscle fiber antigen, mAb 3B6. These results demonstrate that the remodeling of the junctional connective tissue in response to nerve injury is a unique response of muscle to denervation in that it is initiated by a mechanism that is independent of muscle activity. Thus connective tissue remodeling in denervated skeletal muscle may be induced by signals released from or associated with the nerve other than the evoked release of neurotransmitter. PMID:7525607

  13. Pauci-Immune Crescentic Glomerulonephritis in Connective Tissue Disease

    PubMed Central

    Cronin, Mary; Robin, Adam; Lorna, Campbell; Rosenthal, Ann K.

    2016-01-01

    Pauci-immune crescentic glomerulonephritis is commonly seen in ANCA-associated vasculitis but it is rarely seen during the course of other connective tissue diseases like lupus or Sjogren's syndrome or MCTD. We report 3 cases of pauci-immune crescentic glomerulonephritis in patients with connective tissue disease other than vasculitis. We reviewed literature and made summary of previously reported cases of this rare entity. Clinical and laboratory features of these patients varied widely, but most of patients have met criteria for lupus. In this small population of patients there is no correlation with ANCAs. Most of the patients were treated with aggressive immunosuppression and did well if they were treated early in the course of their disease. One of our patients required renal transplant, but she presented late in the course of her disease, as evidenced by chronicity on her renal biopsy. Whether these patients are overlap of vasculitis and other connective tissue diseases or to be considered as a separate entity is yet to be described. Clinicians must be aware of these presentations because initial presentation can be severe. PMID:27504208

  14. Growth, homeostatic regulation and stem cell dynamics in tissues

    PubMed Central

    Hannezo, E.; Prost, J.; Joanny, J.-F.

    2014-01-01

    The regulation of cell growth in animal tissues is a question of critical importance: most tissues contain different types of cells in interconversion and the fraction of each type has to be controlled in a precise way, by mechanisms that remain unclear. Here, we provide a theoretical framework for the homeostasis of stem-cell-containing epithelial tissues using mechanical equations, which describe the size of the tissue and kinetic equations, which describe the interconversions of the cell populations. We show that several features, such as the evolution of stem cell fractions during intestinal development, the shape of a developing intestinal wall, as well as the increase in the proliferative compartment in cancer initiation, can be studied and understood from generic modelling which does not rely on a particular regulatory mechanism. Finally, inspired by recent experiments, we propose a model where cell division rates are regulated by the mechanical stresses in the epithelial sheet. We show that pressure-controlled growth can, in addition to the previous features, also explain with few parameters the formation of stem cell compartments as well as the morphologies observed when a colonic crypt becomes cancerous. We also discuss optimal strategies of wound healing, in connection with experiments on the cornea. PMID:24478279

  15. Mechanisms of lamellar collagen formation in connective tissues.

    PubMed

    Ghazanfari, Samaneh; Khademhosseini, Ali; Smit, Theodoor H

    2016-08-01

    The objective of tissue engineering is to regenerate functional tissues. Engineering functional tissues requires an understanding of the mechanisms that guide the formation and evolution of structure in the extracellular matrix (ECM). In particular, the three-dimensional (3D) collagen fiber arrangement is important as it is the key structural determinant that provides mechanical integrity and biological function. In this review, we survey the current knowledge on collagen organization mechanisms that can be applied to create well-structured functional lamellar tissues and in particular intervertebral disc and cornea. Thus far, the mechanisms behind the formation of cross-aligned collagen fibers in the lamellar structures is not fully understood. We start with cell-induced collagen alignment and strain-stabilization behavior mechanisms which can explain a single anisotropically aligned collagen fiber layer. These mechanisms may explain why there is anisotropy in a single layer in the first place. However, they cannot explain why a consecutive collagen layer is laid down with an alternating alignment. Therefore, we explored another mechanism, called liquid crystal phasing. While dense concentrations of collagen show such behavior, there is little evidence that the conditions for liquid crystal phasing are actually met in vivo. Instead, lysyl aldehyde-derived collagen cross-links have been found essential for correct lamellar matrix deposition. Furthermore, we suggest that supra-cellular (tissue-level) shear stress may be instrumental in the alignment of collagen fibers. Understanding the potential mechanisms behind the lamellar collagen structure in connective tissues will lead to further improvement of the regeneration strategies of functional complex lamellar tissues.

  16. [Peculiarities of the connective tissue metabolism in patients with hydronephrosis].

    PubMed

    Savenkov, V I; Pavlov, S B

    2014-10-01

    The connective tissue metabolism was investigated in patients, suffering hydronephrosis, caused by obstruction of various etiology of pelvio-ureteric segment (PUS) and ureter, which has a recurrent course. On the 21th day postoperatively the blood indices enhancement was revealed, what characterizes the disorder of collagen synthesis and degradation, including, free (FOP), proteinbinded (PRBOP) and peptidebinded (PEBOP) oxyproline. The changes noted are more pronounced in patients with the inborn obstruction of PUS and recurrent course of the disease. A new marker--the PRBOP to FOP levels ratio--was proposed for prognostication of stricture recurrence.

  17. Interstitial lung disease in the connective tissue diseases.

    PubMed

    Antin-Ozerkis, Danielle; Rubinowitz, Ami; Evans, Janine; Homer, Robert J; Matthay, Richard A

    2012-03-01

    The connective tissue diseases (CTDs) are inflammatory, immune-mediated disorders in which interstitial lung disease (ILD) is common and clinically important. Interstitial lung disease may be the first manifestation of a CTD in a previously healthy patient. CTD-associated ILD frequently presents with the gradual onset of cough and dyspnea, although rarely may present with fulminant respiratory failure. Infection and drug reaction should always be ruled out. A diagnosis of idiopathic ILD should never be made without a careful search for subtle evidence of underlying CTD. Treatment of CTD-ILD typically includes corticosteroids and immunosuppressive agents.

  18. [Ultrasonography in chronic inflammatory rheumatic and connective tissue disorders].

    PubMed

    Mérot, O; Le Goff, B

    2014-08-01

    Musculoskeletal ultrasonography is now widely used by almost all rheumatologists thanks to an improvement in the quality of ultrasound unit and probe and to the systematic teaching of this imaging technique to the rheumatology fellows. Applications have broadened from the study of degenerative and mechanical diseases to inflammatory rheumatic diseases. Ultrasound is more sensitive than clinical examination. Power Doppler allows the direct visualisation of inflammation within the tissues. Finally, it is a prognostic tool helping the physician in the management of the disease. This review will focus on the value and applications of ultrasonography in the 2 most frequent rheumatic diseases: rheumatoid arthritis and spondyloarthritis. We will also give some recent data on the usefulness of this imaging technique in the study of musculoskeletal manifestations associated with connective tissue disease.

  19. [Fiftieth anniversary of the French Society for Connective Tissue Research].

    PubMed

    Robert, Ladislas; Labat-Robert, Jacqueline; Michel Robert, Alexandre

    2012-01-01

    The Society was founded in 1962, at an international meeting organized at the Biomedical Institute rue des Saints-Pères, in Paris in the Department of Biochemistry headed at that time by Pr. Max F. Jayle, and published in the "Exposés Annuels de Biochimie Médicale" in 1963. At its beginnings a "Club", with a limited number of participants, it expanded rapidly into a Society, renamed recently "French Society of the Biology of Extracellular Matrix", with approximately 200 members working on a variety of subjects. Only six of these teams could present an oral report at the meeting of the Biological Society on January 18, 2012, celebrating this anniversary at the Curie Institute. A few more could send written contributions for this special issue of "Biologie Aujourd'hui". In this short introduction we shall recall some important stages of the developing connective tissue science. Besides such classical subjects, as the macromolecular components of connective tissue matrix, this discipline incorporated progressively receptors, integrins and other molecules, that mediate cell-matrix interactions.

  20. Connective tissue disease-associated pulmonary arterial hypertension

    PubMed Central

    Howard, Luke S.

    2015-01-01

    Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression. PMID:25705389

  1. [Relation between autoimmune thyroid diseases and connective tissue diseases].

    PubMed

    Barragán-Garfias, Jorge Alberto; Zárate, Arturo

    2013-01-01

    The main physiological function of the immune system consists in the defense against infectious micro-organisms. Sometimes there is a loss of immunological tolerance with the consequence of ignorance of self-antibodies. Some thyroid diseases are related to autoimmune diseases associated with the most common exocrine glands between them. There are also the autoimmune thyroid organ specific diseases, such as Graves-Basedow and the Hashimoto thyroiditis. It has been shown that there is a higher prevalence of autoimmune thyroid diseases in patients with connective tissue diseases (systemic autoimmune) such as Sjögren syndrome, rheumatoid arthritis, systemic lupus erithmatosis and systemic myopathic diseases. In the same way a higher prevalence of antinuclear antibodies against antigens extracted from the nucleus in patients with a thyroid autoimmune disease has been identified. There is a high percentage of patients with subclinical thyroid diseases, and it is recommended for patients with connective tissue diseases with hypo- or hyperthyroidism to have thyroid globulin and peroxide antibodies measured.

  2. Myoarchitecture and connective tissue in hearts with tricuspid atresia

    PubMed Central

    Sanchez-Quintana, D; Climent, V; Ho, S; Anderson, R

    1999-01-01

    Objective—To compare the atrial and ventricular myoarchitecture in the normal heart and the heart with tricuspid atresia, and to investigate changes in the three dimensional arrangement of collagen fibrils.
Methods—Blunt dissection and cell maceration with scanning electron microscopy were used to study the architecture of the atrial and ventricular musculature and the arrangement of collagen fibrils in three specimens with tricuspid atresia and six normal human hearts.
Results—There were significant modifications in the myoarchitecture of the right atrium and the left ventricle, both being noticeably hypertrophied. The middle layer of the ventricle in the abnormal hearts was thicker than in the normal hearts. The orientation of the superficial layer in the left ventricle in hearts with tricuspid atresia was irregular compared with the normal hearts. Scanning electron microscopy showed coarser endomysial sheaths and denser perimysial septa in hearts with tricuspid atresia than in normal hearts.
Conclusions—The overall architecture of the muscle fibres and its connective tissue matrix in hearts with tricuspid atresia differed from normal, probably reflecting modelling of the myocardium that is inherent to the malformation. This is in concordance with clinical observations showing deterioration in pump function of the dominant left ventricle from very early in life.

 Keywords: tricuspid atresia; congenital heart defects; connective tissue; fibrosis PMID:9922357

  3. Connective tissue photodamage in the hairless mouse is partially reversible

    SciTech Connect

    Kligman, L.H.

    1987-03-01

    Photodamaged connective tissue in animal and human skin is characterized by excessive accumulations of elastic fibers, loss of mature collagen, concomitant overproduction of new collagen, and greatly increased levels of glycosaminoglycans. Formerly considered irreversible changes, we recently showed in hairless mice, post irradiation, that a band of normal connective tissue was laid down subepidermally. The present studies focused on 2 aspects of this repair: whether repair would occur if animals were protected by sunscreens after dermal damage was induced and irradiation continued; whether retinoic acid could enhance the repair process. To examine the first aspect, albino hairless mice were irradiated with Westinghouse FS 20 sunlamps thrice weekly for 30 weeks. Sunscreens of high sun-protection factors were applied after 10 and 20 weeks. Not only was further damage prevented, but the damage incurred before sunscreen application was repaired. This appeared as subepidermal reconstruction zones containing normal, mature collagen and a network of fine elastic fibers. The second aspect was examined by applying 0.05% retinoic acid, topically, to animals preirradiated for 10 weeks. In contrast to controls treated with vehicle, the reconstruction zone was significantly wider in retinoic acid-treated mice. The enhanced repair was dose-related.

  4. Cell-based and biomaterial approaches to connective tissue repair

    NASA Astrophysics Data System (ADS)

    Stalling, Simone Suzette

    Connective tissue injuries of skin, tendon and ligament, heal by a reparative process in adults, filling the wound site with fibrotic, disorganized scar tissue that poorly reflects normal tissue architecture or function. Conversely, fetal skin and tendon have been shown to heal scarlessly. Complete regeneration is not intrinsically ubiquitous to all fetal tissues; fetal diaphragmatic and gastrointestinal injuries form scars. In vivo studies suggest that the presence of fetal fibroblasts is essential for scarless healing. In the orthopaedic setting, adult anterior cruciate ligament (ACL) heals poorly; however, little is known about the regenerative capacity of fetal ACL or fetal ACL fibroblasts. We characterized in vitro wound healing properties of fetal and adult ACL fibroblasts demonstrating that fetal ACL fibroblasts migrate faster and elaborate greater quantities of type I collagen, suggesting the healing potential of the fetal ACL may not be intrinsically poor. Similar to fetal ACL fibroblasts, fetal dermal fibroblasts also exhibit robust cellular properties. We investigated the age-dependent effects of dermal fibroblasts on tendon-to-bone healing in rat supraspinatus tendon injuries, a reparative injury model. We hypothesized delivery of fetal dermal fibroblasts would increase tissue organization and mechanical properties in comparison to adult dermal fibroblasts. However, at 1 and 8 weeks, the presence of dermal fibroblasts, either adult or fetal, had no significant effect on tissue histology or mechanical properties. There was a decreasing trend in cross-sectional area of repaired tendons treated with fetal dermal fibroblasts in comparison to adult, but this finding was not significant in comparison to controls. Finally, we synthesized a novel polysaccharide, methacrylated methylcellulose (MA-MC), and fabricated hydrogels using a well-established photopolymerization technique. We characterized the physical and mechanical properties of MA-MC hydrogels in

  5. Identification of human connective tissue in transplant of human oral mucosa in nude mice.

    PubMed

    Holmstrup, P; Hansen, I L; Harder, F; Dabelsteen, E

    1984-01-01

    The present study describes a method for identification of connective tissue of human oral mucosal transplants in nude mice. The method was based on the development of a murine antiserum to human fibroblasts. After absorption with murine fibroblasts the antiserum in an immunofluorescence method appeared to react specifically with human connective tissue of frozen sections, whereas the antiserum did not react with murine connective tissue. The antiserum, applied to frozen sections of human oral mucosal transplants in nude mice, could distinguish between human and murine connective tissue in the sections. The ability to distinguish between the two types of tissue was utilized to elucidate a possible relation between epithelial morphology and underlying type of connective tissue. It was found that the formation of rete ridges of transplanted human oral epithelium was dependent on the presence of subepithelial human connective tissue. The method described may be useful for the recognition of human tissue in experimental studies of human transplants to other species.

  6. [Oral rehabilitation with metalloceramic restorations in patients with non-differentiated systemic connective tissue dysplasia].

    PubMed

    Stafeev, A A

    2015-01-01

    False formation of connective tissues have a great influence on structure and function of organs and tissues of the human body. In prosthodontics, the changes in connective tissues greatly occur during clinical stages of preparing metal ceramic dentures. The algorithm of treatment patients with connective tissue dysplasia during metal ceramic dentures was developed and introduced into practical dentistry based on studying the morphology and functionality of dentition and clinical experience.

  7. Cutaneous Connective Tissue Diseases: Epidemiology, Diagnosis, and Treatment

    PubMed Central

    Reddy, Bobby Y.; Hantash, Basil M.

    2010-01-01

    Connective tissue diseases (CTDs) are a group of clinical disorders that have an underlying autoimmune pathogenesis. These include a diverse set of diseases such as relapsing polychondritis, rheumatoid arthritis, and eosinophilic fasciitis, along with more common entities like Sjogren’s syndrome, dermatomyositis, scleroderma, and lupus erythematosus. The latter three will be the focus of this review, as they constitute the most significant and common CTD with cutaneous manifestations. The cutaneous signs often represent the preliminary stages of disease and the presenting clinical symptoms. Therefore, comprehensive knowledge of CTD manifestations is essential for accurate diagnosis, better assessment of prognosis, and effective management. Although the precise etiologies of CTDs remain obscure, recent advances have allowed for further understanding of their pathogenesis and improved disease classifications. In addition, there have been developments in therapeutic options for CTDs. This review provides an overview of the epidemiology, clinical presentations, and current treatment options of cutaneous lupus erythematous, dermatomyositis and scleroderma. PMID:21218179

  8. Connective tissue disease-related interstitial lung disease.

    PubMed

    Demoruelle, M Kristen; Mittoo, Shikha; Solomon, Joshua J

    2016-02-01

    Interstitial lung disease (ILD) is commonly present in patients with an underlying connective tissue disease (CTD), particularly those with systemic sclerosis, rheumatoid arthritis, and inflammatory myositis. The clinical spectrum can range from asymptomatic findings on imaging to respiratory failure and death. Distinguishing features in the clinical, radiographic, and histopathologic characteristics of CTD-ILD subsets can predict prognosis and treatment response. Treatment often consists of combinations of immunosuppressive medications, but there is a paucity of guidance in the literature to help clinicians determine appropriate screening and management of CTD-ILD. As such, there is a critical need for studies that can elucidate the natural history of the CTD-ILD, as well as clarify optimal therapies for CTD patients with ILD. PMID:27421215

  9. Connective tissue representation for detection of microcalcifications in digital mammograms

    NASA Astrophysics Data System (ADS)

    McLoughlin, Kristin J.; Bones, Philip J.; Kovesi, Peter

    2002-05-01

    Microcalcification clusters appear as an early sign of breast cancer and play an important role in interpreting mammograms. Progress is reported towards an automated computer aided detection system for clustered microcalcifications utilizing two image feature parameters: local contrast and shape. The use of a shape parameter is necessary to distinguish thin patches of connective tissue from microcalcifications. Two shape parameter techniques are compared in the segmentation of 15 digital mammogram images. The first technique implements the linear Hough transform, while the second uses image phase information in the Fourier domain. In both cases labeling of the image is performed by a deterministic relaxation scheme, in which both image data dn prior beliefs are weighted simultaneously. Similar segmentation results are obtained for each shape parameter technique however the execution time for the phase method is approximately one quarter that for the Hough method. Both techniques offer an improvement over segmentation results obtained without the shape parameter.

  10. Effects of microgravity on rat bone, cartlage and connective tissues

    NASA Technical Reports Server (NTRS)

    Doty, S.

    1990-01-01

    The response to hypogravity by the skeletal system was originally thought to be the result of a reduction in weight bearing. Thus a reduced rate of new bone formation in the weight-bearing bones was accepted, when found, as an obvious result of hypogravity. However, data on non-weight-bearing tissues have begun to show that other physiological changes can be expected to occur to animals during spaceflight. This overview of the Cosmos 1887 data discusses these results as they pertain to individual bones or tissues because the response seems to depend on the architecture and metabolism of each tissue under study. Various effects were seen in different tissues from the rats flown on Cosmos 1887. The femur showed a reduced bone mineral content but only in the central region of the diaphysis. This same region in the tibia showed changes in the vascularity of bone as well as some osteocytic cell death. The humerus demonstrated reduced morphometric characteristics plus a decrease in mechanical stiffness. Bone mineral crystals did not mature normally as a result of flight, suggesting a defect in the matrix mineralization process. Note that these changes relate directly to the matrix portion of the bone or some function of bone which slowly responds to changes in the environment. However, most cellular functions of bone are rapid responders. The stimulation of osteoblast precursor cells, the osteoblast function in collagen synthesis, a change in the proliferation rate of cells in the epiphyseal growth plate, the synthesis and secretion of osteocalcin, and the movement of water into or out of tissues, are all processes which respond to environmental change. These rapidly responding events produced results from Cosmos 1887 which were frequently quite different from previous space flight data.

  11. Pulmonary arterial hypertension among Filipino patients with connective tissue diseases.

    PubMed

    Santos Estrella, Paul V; Lin, Yih Chang; Navarra, Sandra V

    2007-01-01

    We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25 mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 +/- 14 years (mean +/- SD), and the mean duration of illness from CTD to PAH diagnosis was 53 +/- 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1-57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.

  12. Electric utility growth: The small business connection

    SciTech Connect

    Stafford, J.R. )

    1990-08-02

    In today's competitive environment utilities must seek new strategies to insure future growth. Economic development is but one of many utility strategies being implemented today. Traditionally, most utility economic development efforts involve the recruitment of targeted industries. This recruitment strategy involves the identification of attractive industries and companies, and subsequent marketing efforts to encourage company relocation or expansion in the utility's service territory. This strategy is the most practiced by utilities, yet ironically it has been judged as relatively ineffective. The purpose of this study is to evaluate the merits of utilities refocusing their economic development efforts on a new strategy currently employed by state and local growth organizations and oriented toward business retention and expansion rather than industrial targeting and recruitment. Many utilities have retention/expansion strategies, but target them at their largest industrial customers. The focus of this article is on the value of small business retention/expansion activities and the feasibility of implementing a successful plan.

  13. [Age changes of the connective tissue structures of human penis].

    PubMed

    Klimachev, V V; Neĭmark, A I; Gerval'd, V Ia; Bobrov, I P; Avdalian, A M; Muzalevskaia, N I; Gerval'd, I V; Aliev, R T; Cherdantseva, T M

    2011-01-01

    This investigation was aimed at the study of age changes of penis connective tissue structures. Tissue fragments of penis were obtained from 20 cadavers of men at the age of 20-38 years in group I, and from 20 cadavers of men at the age of 41-59 years in group II. The criteria for the exclusion of material from the research were arterial hypertension, diabetes mellitus, atherosclerosis of internal iliac arteries, Peyronie's disease, and anomalies of genital organ development. It was shown that in the cavernous body of penis, aging was associated with the increased amount and thickening of collagen and argyrophilic fibers, decreased content and thinning of elastic fibers, and the reduced amount of smooth muscle cells (SMC). The average area of fibroblast and SMC nucleolus was not different in both groups studied. The average area of endotheliocyte nucleolus was equal to 1.9+/-0.9 microm2 in group II, being lower than that one in group I, in which this index was equal to 2.1+/-0.9 microm2. No differences in the content of type III and IV collagen were found between the study groups. Age-associated decrease in the average area of endothelial cell nucleolus in the cavernous bodies may reflect the reduction of the activity of these cells and may indicate the development of endothelial dysfunction, which is one of the most important steps in the morphogenesis of age-related male erectile dysfunction.

  14. Epithelial-connective tissue boundary in the oral part of the human soft palate

    PubMed Central

    PAULSEN, FRIEDRICH; THALE, ANDREAS

    1998-01-01

    The papillary layer of the oral part of the human soft palate was studied in 31 subjects of different age by means of histological, immunohistochemical and scanning electron microscopical methods. For scanning electron microscopy a new maceration method was introduced. Results determine epithelial thickness, height and density of connective tissue papillae and their 3-dimensional architecture inside the lining epithelium as well as the collagenous arrangement of the openings of the glandular ducts. The individual connective tissue papillae of the soft palate are compared with the connective tissue boundary on the other side of the oral cavity. The connective tissue plateaux carrying a variable number of connective tissue papillae were found to be the basic structural units of the papillary body. The function of the epithelial-connective tissue interface and the extracellular matrix arrangement in the lamina propria are discussed in order to promote the comparability of normal with pathologically altered human soft palates. PMID:9877301

  15. Viscoelastic properties of bovine orbital connective tissue and fat: constitutive models.

    PubMed

    Yoo, Lawrence; Gupta, Vijay; Lee, Choongyeop; Kavehpore, Pirouz; Demer, Joseph L

    2011-12-01

    Reported mechanical properties of orbital connective tissue and fat have been too sparse to model strain-stress relationships underlying biomechanical interactions in strabismus. We performed rheological tests to develop a multi-mode upper convected Maxwell (UCM) model of these tissues under shear loading. From 20 fresh bovine orbits, 30 samples of connective tissue were taken from rectus pulley regions and 30 samples of fatty tissues from the posterior orbit. Additional samples were defatted to determine connective tissue weight proportion, which was verified histologically. Mechanical testing in shear employed a triborheometer to perform: strain sweeps at 0.5-2.0 Hz; shear stress relaxation with 1% strain; viscometry at 0.01-0.5 s(-1) strain rate; and shear oscillation at 1% strain. Average connective tissue weight proportion was 98% for predominantly connective tissue and 76% for fatty tissue. Connective tissue specimens reached a long-term relaxation modulus of 668 Pa after 1,500 s, while corresponding values for fatty tissue specimens were 290 Pa and 1,100 s. Shear stress magnitude for connective tissue exceeded that of fatty tissue by five-fold. Based on these data, we developed a multi-mode UCM model with variable viscosities and time constants, and a damped hyperelastic response that accurately described measured properties of both connective and fatty tissues. Model parameters differed significantly between the two tissues. Viscoelastic properties of predominantly connective orbital tissues under shear loading differ markedly from properties of orbital fat, but both are accurately reflected using UCM models. These viscoelastic models will facilitate realistic global modeling of EOM behavior in binocular alignment and strabismus.

  16. Viscoelastic properties of bovine orbital connective tissue and fat: constitutive models

    PubMed Central

    Yoo, Lawrence; Gupta, Vijay; Lee, Choongyeop; Kavehpore, Pirouz

    2012-01-01

    Reported mechanical properties of orbital connective tissue and fat have been too sparse to model strain–stress relationships underlying biomechanical interactions in strabismus. We performed rheological tests to develop a multi-mode upper convected Maxwell (UCM) model of these tissues under shear loading. From 20 fresh bovine orbits, 30 samples of connective tissue were taken from rectus pulley regions and 30 samples of fatty tissues from the posterior orbit. Additional samples were defatted to determine connective tissue weight proportion, which was verified histologically. Mechanical testing in shear employed a triborheometer to perform: strain sweeps at 0.5–2.0 Hz; shear stress relaxation with 1% strain; viscometry at 0.01–0.5 s−1 strain rate; and shear oscillation at 1% strain. Average connective tissue weight proportion was 98% for predominantly connective tissue and 76% for fatty tissue. Connective tissue specimens reached a long-term relaxation modulus of 668 Pa after 1,500 s, while corresponding values for fatty tissue specimens were 290 Pa and 1,100 s. Shear stress magnitude for connective tissue exceeded that of fatty tissue by five-fold. Based on these data, we developed a multimode UCM model with variable viscosities and time constants, and a damped hyperelastic response that accurately described measured properties of both connective and fatty tissues. Model parameters differed significantly between the two tissues. Viscoelastic properties of predominantly connective orbital tissues under shear loading differ markedly from properties of orbital fat, but both are accurately reflected using UCM models. These viscoelastic models will facilitate realistic global modeling of EOM behavior in binocular alignment and strabismus. PMID:21207094

  17. Idiopathic interstitial pneumonias with connective tissue diseases features: A review.

    PubMed

    Cottin, Vincent

    2016-02-01

    A systematic approach is recommended to search for clinical and biological features of connective tissue disease (CTD) in any patient with interstitial lung disease (ILD). In the diagnostic approach to ILD, a diagnosis of CTD should be considered particularly in women and subjects younger than 50 years, and in those with an imaging and/or pathological pattern of non-specific interstitial pneumonia. However, the diagnosis of CTD may be difficult when ILD is the presenting or the dominant manifestation of CTD. A proportion of patients with ILD present symptoms that belong to the spectrum of CTD and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given CTD. Some imaging and histopathological patterns may also suggest the presence of an underlying CTD. Although studies published to date used heterogeneous definitions and terminology for this condition, evidence is accumulating that even limited CTD features are relevant regarding symptoms, imaging features, pathological pattern and possibly evolution to overt CTD, whereas the impact on prognosis needs confirmation. Conversely, autoantibodies alone do not seem to impact the prognosis or management in patients with otherwise typical idiopathic pulmonary fibrosis and no extra-pulmonary manifestation. A collective international multidisciplinary effort has proposed a uniform definition and criteria for 'interstitial pneumonia with autoimmune features', a condition characterized by limited CTD features occurring in the setting of ILD, with the aim of fostering future clinical studies. Referral of ILD patients suspect to have CTD to a rheumatologist and possibly multidisciplinary discussion may contribute to a better management.

  18. Neutrophilic Skin Lesions in Autoimmune Connective Tissue Diseases

    PubMed Central

    Hau, Estelle; Vignon Pennamen, Marie-Dominique; Battistella, Maxime; Saussine, Anne; Bergis, Maud; Cavelier-Balloy, Benedicte; Janier, Michel; Cordoliani, Florence; Bagot, Martine; Rybojad, Michel; Bouaziz, Jean-David

    2014-01-01

    Abstract The pathophysiology of neutrophilic dermatoses (NDs) and autoimmune connective tissue diseases (AICTDs) is incompletely understood. The association between NDs and AICTDs is rare; recently, however, a distinctive subset of cutaneous lupus erythematosus (LE, the prototypical AICTD) with neutrophilic histological features has been proposed to be included in the spectrum of lupus. The aim of our study was to test the validity of such a classification. We conducted a monocentric retrospective study of 7028 AICTDs patients. Among these 7028 patients, a skin biopsy was performed in 932 cases with mainly neutrophilic infiltrate on histology in 9 cases. Combining our 9 cases and an exhaustive literature review, pyoderma gangrenosum, Sweet syndrome (n = 49), Sweet-like ND (n = 13), neutrophilic urticarial dermatosis (n = 6), palisaded neutrophilic granulomatous dermatitis (n = 12), and histiocytoid neutrophilic dermatitis (n = 2) were likely to occur both in AICTDs and autoinflammatory diseases. Other NDs were specifically encountered in AICTDs: bullous LE (n = 71), amicrobial pustulosis of the folds (n = 28), autoimmunity-related ND (n = 24), ND resembling erythema gyratum repens (n = 1), and neutrophilic annular erythema (n = 1). The improvement of AICTDS neutrophilic lesions under neutrophil targeting therapy suggests possible common physiopathological pathways between NDs and AICTDs. PMID:25546688

  19. Aging of connective tissues: experimental facts and theoretical considerations.

    PubMed

    Labat-Robert, J; Robert, L

    2014-01-01

    In this chapter, we describe in detail the age-dependent modifications of connective tissues, separately for their cellular and extracellular compartments. Cell aging was studied by the in vitro method established by Hayflick as well as by ex vivo explant cultures, and results with both methods are discussed. Follows then the description of age changes of macromolecular components of extracellular matrix as well as the decline with age of receptor-mediated cell-matrix interactions. These interactions mediated by several types of receptors, as integrins, the elastin receptor and others, play a crucial role for the definition and regulation of the differentiated cell phenotype. Age-related modifications of both matrix components and receptors are discussed in order to explain the mechanisms of the age-dependent modulations of cell-matrix interactions. Finally, we discuss the relations between age changes of matrix components and the onset of age-related diseases, especially cardiovascular pathologies mostly involved in age-dependence of functions and limitation of longevity.

  20. Molecular regulation of CCN2 in the intervertebral disc: lessons learned from other connective tissues.

    PubMed

    Tran, Cassie M; Shapiro, Irving M; Risbud, Makarand V

    2013-08-01

    Connective tissue growth factor (CCN2/CTGF) plays an important role in extracellular matrix synthesis, especially in skeletal tissues such as cartilage, bone, and the intervertebral disc. As a result there is a growing interest in examining the function and regulation of this important molecule in the disc. This review discusses the regulation of CCN2 by TGF-β and hypoxia, two critical determinants that characterize the disc microenvironment, and discusses known functions of CCN2 in the disc. The almost ubiquitous regulation of CCN2 by TGF-β, including that seen in the disc, emphasizes the importance of the TGF-β-CCN2 relationship, especially in terms of extracellular matrix synthesis. Likewise, the unique cross-talk between CCN2 and HIF-1 in the disc highlights the tissue and niche specific mode of regulation. Taken together the current literature supports an anabolic role for CCN2 in the disc and its involvement in the maintenance of tissue homeostasis during both health and disease. Further studies of CCN2 in this tissue may reveal valuable targets for the biological therapy of disc degeneration.

  1. [Peculiarities of the action of hyaluronidase of different origin to the connective tissue].

    PubMed

    Habriyev, R U; Kamayev, N O; Danilova, T I; Kakhoyan, E G

    2016-01-01

    The lecture is devoted to consideration of mechanism of therapeutic action of the enzyme hyaluronidase in hyperplastic connective tissue. Drugs based on hyaluronidase increase bioavailability of other drugs used in adjuvant therapy; they significantly increase effectiveness of treatment, and also provide targeted synthesis of hyaluronic acid, ths regulating the regeneration process of connective tissue.

  2. Pulmonary manifestations of Sjögren syndrome, systemic lupus erythematosus, and mixed connective tissue disease.

    PubMed

    Mira-Avendano, Isabel C; Abril, Andy

    2015-05-01

    Interstitial lung disease is a common and often life-threatening manifestation of different connective tissue disorders, often affecting its overall prognosis. Systemic lupus erythematosus, Sjögren syndrome, and mixed connective tissue disease, although all unique diseases, can have lung manifestations as an important part of these conditions. This article reviews the different pulmonary manifestations seen in these 3 systemic rheumatologic conditions.

  3. Brown adipose tissue growth and development.

    PubMed

    Symonds, Michael E

    2013-01-01

    Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by photoperiod. Increased understanding of the primary factors that regulate both the appearance and the disappearance of UCP1 in early life may therefore enable sustainable strategies in order to prevent excess white adipose tissue deposition through the life cycle.

  4. [The effect of the biopolymer chondroitin sulfate on reparative regeneration of connective tissue].

    PubMed

    Belova, S V; Norkin, I A; Puchinyan, D M

    2015-01-01

    The research objective is a study of an intra-articular method of introduction of the preparation "mukosat" for stimulation of reparative regeneration of connective tissue of knee joints in rabbits with an experimental arthritis. It is ascertained that intra-articular maintenance of chondroitin sulfate (the preparation "mukosat") acts as a stimulus for reparative regeneration of connective tissue thus showing up positive changes in the status of connective tissue elements of joints: decrease in glycosaminoglycan content in blood serum and normalization of the composition of glycosaminoglycan carbohydrate component. It probably depends on stimulation of biosynthesis of autologous normal glycosaminoglycans in tissues of animal knee joints.

  5. Experiment K-7-29: Connective Tissue Studies. Part 3; Rodent Tissue Repair: Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Stauber, W.; Fritz, V. K.; Burkovskaya, T. E.; Ilyina-Kakueva, E. I.

    1994-01-01

    Myofiber injury-repair was studied in the rat gastrocnemius following a crush injury to the lower leg prior to flight in order to understand if the regenerative responses of muscles are altered by the lack of gravitational forces during Cosmos 2044 flight. After 14 days of flight, the gastrocnemius muscle was removed from the 5 injured flight rodents and various Earth-based treatment groups for comparison. The Earth-based animals consisted of three groups of five rats with injured muscles from a simulated, tail-suspended, and vivarium as well as an uninjured basal group. The gastrocnemius muscle from each was evaluated by histochemical and immunohistochemical techniques to document myofiber, vascular, and connective tissue alterations following injury. In general the repair process was somewhat similar in all injured muscle samples with regard to extracellular matrix organization and myofiber regeneration. Small and large myofibers were present with a newly organized extracellular matrix indicative of myogenesis and muscle regeneration. In the tail-suspended animals, a more complete repair was observed with no enlarged area of non-muscle cells or matrix material visible. In contrast, the muscle samples from the flight animals were less well differentiated with more macrophages and blood vessels in the repair region but small myofibers and proteoglycans, nevertheless, were in their usual configuration. Thus, myofiber repair did vary in muscles from the different groups, but for the most part, resulted in functional muscle tissue.

  6. Connective tissue and bacterial deposits on rubber dam sheet and ePTFE barrier membranes in guided periodontal tissue regeneration.

    PubMed

    Apinhasmit, Wandee; Swasdison, Somporn; Tamsailom, Suphot; Suppipat, Nophadol

    2002-01-01

    The aim of this study was to compare the connective tissue and bacterial deposits on rubber dam sheets and expanded polytetrafluoroethylene membranes used as barrier membranes in guided tissue regeneration for periodontal treatment. Twenty patients having intrabony defects and/or furcation defects were surgically treated by guided tissue regeneration employing either rubber dam sheets (10 patients) or expanded polytetrafluoroethylene membranes (10 patients) as barrier membranes. Four to six weeks after the first operation, membranes were retrieved from the lesion sites and processed for scanning electron microscopy. The lesion-facing surfaces of membranes were examined for the presence of connective tissue and bacterial deposits. The differences between the numbers of fields and the distributions of connective tissue and bacteria on both types of membranes were analysed by the Chi-square test at the level of 0.05 significance. The results showed a lot of fibroblasts with their secreted extracellular matrices, known as components of the connective tissue on rubber dam sheets and expanded polytetrafluoroethylene membranes. There was no significant difference in the total number of connective tissue on both types of membranes (P = 0.456). Many bacterial forms including cocci, bacilli, filaments and spirochetes with the interbacterial matrices were identified. The total number of bacteria on rubber dam sheets was statistically less than that on expanded polytetrafluoroethylene membranes (P < 0.001). The comparable number of connective tissue on both types of membranes suggests that the healing process under both types of membranes was also comparable. Therefore, the rubber dam sheet might be used as a barrier membrane in guided tissue regeneration.

  7. Connective tissue diseases, arthritis require special patient counseling.

    PubMed

    Neinstein, L S; Katz, B

    1985-07-01

    Systemic lupus erythematous occurs most frequently in reproductive aged women, giving rise to concern about contraception and pregnancy. Most of the literature on contraceptive choices for patients with connective tissue diseases specifically considers oral contraceptives (OCs) with systemic lupus. A possible role of female sex hormones in systemic lupus disease activity is suggested by the constant female-male disease ratio of 9 to 1, the tendency for increased disease activity premenstrually and postpartum, and the report of a 54% prevalence of clinical or serological exacerbation during pregnancy compared with a 4% prevalence in the 6 months preceding pregnancy. Another study however failed to confirm increased prevalence of major nonrenal manifestations of systemic lupus with pregnancy, and the results of 3 studies showed permanent deterioration in 15 of 114 pregnancies. In most cases, therefore, renal function did not deteriorate with pregnancy. The effect of OCs on lupus patients is also unclear despite several reports of exacerbation of lupus by OCs or induction of serologic markers. Studies of women attending family planning clinics do not indicate either developing rheumatologic symptoms or developing positive serologic tests in healthy women on OCs. IUDs should be avoided in lupus patients with moderate or severe anemia or thrombocytopenia, and the possible decreased effectiveness of IUDs for patients on steroids should be considered. Lupus patients should avoid pregnancy until the disease is in clinical remission. Combined OCs should probably be avoided because of the possible exacerbation of symptoms in known lupus. The progestagen-only pill can be considered for lupus patients without renal or liver disease or hypertension if the patient is closely watched. Barrier methods are possible for patients who are reliable and will comply with directions. No absolute contraindications appear to exist for women with rheumatoid arthritis. Women using OCs are

  8. Connection between stochastic and deterministic modelling of microbial growth.

    PubMed

    Kutalik, Zoltán; Razaz, Moe; Baranyi, József

    2005-01-21

    We present in this paper various links between individual and population cell growth. Deterministic models of the lag and subsequent growth of a bacterial population and their connection with stochastic models for the lag and subsequent generation times of individual cells are analysed. We derived the individual lag time distribution inherent in population growth models, which shows that the Baranyi model allows a wide range of shapes for individual lag time distribution. We demonstrate that individual cell lag time distributions cannot be retrieved from population growth data. We also present the results of our investigation on the effect of the mean and variance of the individual lag time and the initial cell number on the mean and variance of the population lag time. These relationships are analysed theoretically, and their consequence for predictive microbiology research is discussed.

  9. Leucine Supplementation Accelerates Connective Tissue Repair of Injured Tibialis Anterior Muscle

    PubMed Central

    Pereira, Marcelo G.; Silva, Meiricris T.; Carlassara, Eduardo O. C.; Gonçalves, Dawit A.; Abrahamsohn, Paulo A.; Kettelhut, Isis C.; Moriscot, Anselmo S.; Aoki, Marcelo S.; Miyabara, Elen H.

    2014-01-01

    This study investigated the effect of leucine supplementation on the skeletal muscle regenerative process, focusing on the remodeling of connective tissue of the fast twitch muscle tibialis anterior (TA). Young male Wistar rats were supplemented with leucine (1.35 g/kg per day); then, TA muscles from the left hind limb were cryolesioned and examined after 10 days. Although leucine supplementation induced increased protein synthesis, it was not sufficient to promote an increase in the cross-sectional area (CSA) of regenerating myofibers (p > 0.05) from TA muscles. However, leucine supplementation reduced the amount of collagen and the activation of phosphorylated transforming growth factor-β receptor type I (TβR-I) and Smad2/3 in regenerating muscles (p < 0.05). Leucine also reduced neonatal myosin heavy chain (MyHC-n) (p < 0.05), increased adult MyHC-II expression (p < 0.05) and prevented the decrease in maximum tetanic strength in regenerating TA muscles (p < 0.05). Our results suggest that leucine supplementation accelerates connective tissue repair and consequent function of regenerating TA through the attenuation of TβR-I and Smad2/3 activation. Therefore, future studies are warranted to investigate leucine supplementation as a nutritional strategy to prevent or attenuate muscle fibrosis in patients with several muscle diseases. PMID:25268835

  10. Bubble growth and mechanical properties of tissue in decompression.

    PubMed

    Vann, R D; Clark, H G

    1975-09-01

    A survey of decompression literature leads to the conclusion that when tissue is subjected to gaseous supersaturation, pre-existing gas micronuclei grow into the gas bubbles which are routinely observed in decompression studies. These micronuclei may originate from mechanically induced tribonucleation or cavitation within joints. A new tissue model for decompression sickness based upon failure theory in rubber is proposed. The model shows theoretically that pre-existing sea-level nuclei can be stabilized at depth by elastic forces in tissue. These same elastic forces restrain the growth of nuclei when supersaturation occurs. Mechanical stress will lower the gaseous supersaturation required for growth of nuclei. Gaseous supersaturation, mechanical stress, and the elastic properties of various tissues interact to produce unbounded bubble growth leading to tissue lesions when combined gaseous and mechanical supersaturation exceeds a threshold value. The recommendation is made that the high levels of supersaturation generally used for the decompression of men be reduced.

  11. Stichopin-containing nerves and secretory cells specific to connective tissues of the sea cucumber.

    PubMed

    Tamori, Masaki; Saha, Apurba Kumar; Matsuno, Akira; Noskor, Sukumar Chandra; Koizumi, Osamu; Kobayakawa, Yoshitaka; Nakajima, Yoko; Motokawa, Tatsuo

    2007-09-22

    Stichopin, a 17-amino acid peptide isolated from a sea cucumber, affects the stiffness change of the body-wall catch connective tissues and the contraction of the body-wall muscles. The localization of stichopin in sea cucumbers was studied by indirect immunohistochemistry using antiserum against stichopin. Double staining was performed with both stichopin antiserum and 1E11, the monoclonal antibody specific to echinoderm nerves. A stichopin-like immunoreactivity (stichopin-LI) was exclusively found in the connective tissues of various organs. Many fibres and cells with processes were stained by both the anti-stichopin antibody and 1E11. They were found in the body-wall dermis and the connective tissue layer of the cloacae and were suggested to be connective tissue-specific nerves. Oval cells with stichopin-LI (OCS) without processes were found in the body-wall dermis, the connective tissue sheath of the longitudinal body-wall muscles, the connective tissue layer of the tube feet and tentacles, and the connective tissue in the radial nerves separating the ectoneural part from the hyponeural part. Electron microscopic observations of the OCSs in the radial nerves showed that they were secretory cells. The OCSs were located either near the well-defined neural structures or near the water-filled cavities, such as the epineural sinus and the canals of the tube feet. The location near the water-filled cavities might suggest that stichopin was secreted into these cavities to function as a hormone.

  12. Clinical Features of Neuropsychiatric Syndromes in Systemic Lupus Erythematosus and Other Connective Tissue Diseases

    PubMed Central

    Kasama, Tsuyoshi; Maeoka, Airi; Oguro, Nao

    2016-01-01

    Systemic lupus erythematosus (SLE) and related disorders are chronic inflammatory diseases characterized by abnormalities and, in some cases, even complete failure of immune responses as the underlying pathology. Although almost all connective tissue diseases and related disorders can be complicated by various neuropsychiatric syndromes, SLE is a typical connective tissue disease that can cause neurological and psychiatric syndromes. In this review, neuropsychiatric syndromes complicating connective tissue diseases, especially SLE are outlined, and pathological and other conditions that should be considered in the differential diagnosis are also discussed. PMID:26819561

  13. Wrinkling pattern evolution of cylindrical biological tissues with differential growth

    NASA Astrophysics Data System (ADS)

    Jia, Fei; Li, Bo; Cao, Yan-Ping; Xie, Wei-Hua; Feng, Xi-Qiao

    2015-01-01

    Three-dimensional surface wrinkling of soft cylindrical tissues induced by differential growth is explored. Differential volumetric growth can cause their morphological stability, leading to the formation of hexagonal and labyrinth wrinkles. During postbuckling, multiple bifurcations and morphological transitions may occur as a consequence of continuous growth in the surface layer. The physical mechanisms underpinning the morphological evolution are examined from the viewpoint of energy. Surface curvature is found to play a regulatory role in the pattern evolution. This study may not only help understand the morphogenesis of soft biological tissues, but also inspire novel routes for creating desired surface patterns of soft materials.

  14. Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model.

    PubMed

    Corey, Sarah M; Vizzard, Margaret A; Bouffard, Nicole A; Badger, Gary J; Langevin, Helene M

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

  15. Stretching of the Back Improves Gait, Mechanical Sensitivity and Connective Tissue Inflammation in a Rodent Model

    PubMed Central

    Corey, Sarah M.; Vizzard, Margaret A.; Bouffard, Nicole A.; Badger, Gary J.; Langevin, Helene M.

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy. PMID:22238664

  16. Mechanical feedback as a possible regulator of tissue growth

    NASA Astrophysics Data System (ADS)

    Shraiman, Boris I.

    2005-03-01

    Regulation of cell growth and proliferation has a fundamental role in animal and plant development and in the progression of cancer. In the context of development, it is important to understand the mechanisms that coordinate growth and patterning of tissues. Imaginal discs, which are larval precursors of fly limbs and organs, have provided much of what we currently know about these processes. Here, we consider the mechanism that is responsible for the observed uniformity of growth in wing imaginal discs, which persists in the presence of gradients in growth inducing morphogens in spite of the stochastic nature of cell division. The phenomenon of "cell competition," which manifests in apoptosis of slower-growing cells in the vicinity of faster growing tissue, suggests that uniform growth is not a default state but a result of active regulation. How can a patch of tissue compare its growth rate with that of its surroundings? A possible way is furnished by mechanical interactions. To demonstrate this mechanism, we formulate a mathematical model of nonuniform growth in a layer of tissue and examine its mechanical implications. We show that a clone growing faster or slower than the surrounding tissue is subject to mechanical stress, and we propose that dependence of the rate of cell division on local stress could provide an "integral-feedback" mechanism stabilizing uniform growth. The proposed mechanism of growth control is not specific to imaginal disc growth and could be of general relevance. Several experimental tests of the proposed mechanism are suggested. Drosophila melanogaster | imaginal disc | mechanics | stress

  17. Treatment of gingival recession in two surgical stages: Free gingival graft and connective tissue grafting.

    PubMed

    Henriques, Paulo Sergio Gomes; Nunes, Marcelo Pereira; Pelegrine, Andre Antonio

    2011-01-01

    This report describes a clinical case of severe Miller Class II gingival recession treated by two stages of surgery that combined a free gingival graft and connective tissue grafting. First, a free gingival graft (FGG) was performed to obtain an adequate keratinized tissue level. Three months later, a connective tissue graft (CTG) was performed to obtain root coverage. The results indicated that the FGG allows for a gain in the keratinized tissue level and the CTG allows for root coverage with decreased recession level after 16 months. Therefore, for this type of specific gingival recession, the combination of FGG and CTG can be used.

  18. Mechanistic micro-structural theory of soft tissues growth and remodeling: tissues with unidirectional fibers.

    PubMed

    Lanir, Yoram

    2015-04-01

    A new mechanistic theory was developed for soft tissues growth and remodeling (G&R). The theory considers tissues with unidirectional fibers. It is based on the loading-dependent local turnover events of each constituent and on the resulting evolution of the tissue micro-structure, the tissue dimensions and its mechanical properties. The theory incorporates the specific mechanical properties and turnover kinetics of each constituent, thereby establishing a general framework which can serve for future integration of additional mechanisms involved in G&R. The feasibility of the theory was examined by considering a specific realization of tissues with one fibrous constituent (collagen fibers), assuming a specific loading-dependent first-order fiber's turnover kinetics and the fiber's deposition characteristics. The tissue was subjected to a continuous constant rate growth. Model parameters were adopted from available data. The resulting predictions show qualitative agreement with a number of well-known features of tissues including the fibers' non-uniform recruitment density distribution, the associated tissue convex nonlinear stress-stretch relationship, and the development of tissue pre-stretch and pre-stress states. These results show that mechanistic micro-structural modeling of soft tissue G&R based on first principles can successfully capture the evolution of observed tissues' structure and size, and of their associated mechanical properties.

  19. Aortic tear and dissection related to connective tissues abnormalities resembling Marfan syndrome in a Great Dane.

    PubMed

    Lenz, Jennifer A; Bach, Jonathan F; Bell, Cynthia M; Stepien, Rebecca L

    2015-06-01

    Aortic tears and acute aortic dissection are rarely reported in dogs. This report describes a case of aortic dissection and probable sinus of Valsalva rupture in a young Great Dane with associated histopathologic findings suggestive of a connective tissue abnormality.

  20. Life-threatening acute pneumonitis in mixed connective tissue disease: a case report and literature review.

    PubMed

    Rath, Eva; Zandieh, Shahin; Löckinger, Alexander; Hirschl, Mirko; Klaushofer, Klaus; Zwerina, Jochen

    2015-10-01

    Mixed connective tissue disease (MCTD) is a rare connective tissue disease frequently involving the lungs. The main characteristic is a systemic sclerosis-like picture of slowly progressing interstitial lung disease consistent with lung fibrosis, while pulmonary arterial hypertension is rare. Herein, we present a case of a newly diagnosed MCTD patient developing life-threatening acute pneumonitis similar to lupus pneumonitis. Previous literature on this exceptionally rare complication of MCTD is reviewed and differential diagnosis and management discussed.

  1. Growth factor effects on costal chondrocytes for tissue engineering fibrocartilage.

    PubMed

    Johns, D E; Athanasiou, K A

    2008-09-01

    Tissue-engineered fibrocartilage could become a feasible option for replacing tissues such as the knee meniscus or temporomandibular joint disc. This study employed five growth factors (insulin-like growth factor-I, transforming growth factor-beta1, epidermal growth factor, platelet-derived growth factor-BB, and basic fibroblast growth factor) in a scaffoldless approach with costal chondrocytes, attempting to improve biochemical and mechanical properties of engineered constructs. Samples were quantitatively assessed for total collagen, glycosaminoglycans, collagen type I, collagen type II, cells, compressive properties, and tensile properties at two time points. Most treated constructs had lower biomechanical and biochemical properties than the controls with no growth factors, suggesting a detrimental effect, but the treatment with insulin-like growth factor-I tended to improve the constructs. Additionally, the 6-week time point was consistently better than that at 3 weeks, with total collagen, glycosaminoglycans, and aggregate modulus doubling during this time. Further optimization of the time in culture and exogenous stimuli will be important in making a more functional replacement tissue. PMID:18597118

  2. Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

    PubMed

    Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I

    2013-04-01

    We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

  3. A survey of clearing techniques for 3D imaging of tissues with special reference to connective tissue.

    PubMed

    Azaripour, Adriano; Lagerweij, Tonny; Scharfbillig, Christina; Jadczak, Anna Elisabeth; Willershausen, Brita; Van Noorden, Cornelis J F

    2016-08-01

    For 3-dimensional (3D) imaging of a tissue, 3 methodological steps are essential and their successful application depends on specific characteristics of the type of tissue. The steps are 1° clearing of the opaque tissue to render it transparent for microscopy, 2° fluorescence labeling of the tissues and 3° 3D imaging. In the past decades, new methodologies were introduced for the clearing steps with their specific advantages and disadvantages. Most clearing techniques have been applied to the central nervous system and other organs that contain relatively low amounts of connective tissue including extracellular matrix. However, tissues that contain large amounts of extracellular matrix such as dermis in skin or gingiva are difficult to clear. The present survey lists methodologies that are available for clearing of tissues for 3D imaging. We report here that the BABB method using a mixture of benzyl alcohol and benzyl benzoate and iDISCO using dibenzylether (DBE) are the most successful methods for clearing connective tissue-rich gingiva and dermis of skin for 3D histochemistry and imaging of fluorescence using light-sheet microscopy.

  4. Focal dermal hypoplasia: ultrastructural abnormalities of the connective tissue.

    PubMed

    del Carmen Boente, María; Asial, Raúl A; Winik, Beatriz C

    2007-02-01

    We followed over 10 years three girls with focal dermal hypoplasia syndrome. The histopathological changes demonstrated at the optical level an hypoplastic dermis with thin and scarce collagen bundles and a marked diminution of elastic fibers. Mature adipose tissue was found scattered within the papillary and reticular dermis. No alterations in the basal membrane were observed by immunocytochemical or ultrastructural techniques. Ultrastructurally, in the skin-affected areas, loosely arranged collagen bundles composed of few fibrils were seen scattered in the extracellular matrix. Scarce elastic fibers of normal morphology were also observed. Fibroblasts were smaller, oval-shaped, and diminished in number with a poorly developed cytoplasm. In these fibroblasts, the most conspicuous feature was a remarkable and irregular thickening of the nuclear fibrous lamina. Taking into account that a common link between all laminopaties may be a failure of stem cells to regenerate mesenchymal tissue, this failure would induce the dermal hypoplasia observed in our patients presenting Goltz syndrome.

  5. Biodynamic profiling of three-dimensional tissue growth techniques

    NASA Astrophysics Data System (ADS)

    Sun, Hao; Merrill, Dan; Turek, John; Nolte, David

    2016-03-01

    Three-dimensional tissue culture presents a more biologically relevant environment in which to perform drug development than conventional two-dimensional cell culture. However, obtaining high-content information from inside three dimensional tissue has presented an obstacle to rapid adoption of 3D tissue culture for pharmaceutical applications. Biodynamic imaging is a high-content three-dimensional optical imaging technology based on low-coherence interferometry and digital holography that uses intracellular dynamics as high-content image contrast. In this paper, we use biodynamic imaging to compare pharmaceutical responses to Taxol of three-dimensional multicellular spheroids grown by three different growth techniques: rotating bioreactor, hanging-drop and plate-grown spheroids. The three growth techniques have systematic variations among tissue cohesiveness and intracellular activity and consequently display different pharmacodynamics under identical drug dose conditions. The in vitro tissue cultures are also compared to ex vivo living biopsies. These results demonstrate that three-dimensional tissue cultures are not equivalent, and that drug-response studies must take into account the growth method.

  6. Connective tissue responses to some heavy metals. II. Lead: histology and ultrastructure.

    PubMed Central

    Ellender, G.; Ham, K. N.

    1987-01-01

    Lead loaded ion exchange resin beads implanted into the loose connective tissue of the rat pinna induced local lesions which differed widely from those of the control (sodium loaded) beads (Ellender & Ham 1987). These lesions were characterized by changes in the granulation tissue and the approximating connective tissue. Granulation tissue contained mononuclear phagocytes in various guises, and some cells with intranuclear inclusion bodies. The matrix of the granulation tissue contained collagen fibrils having a wide range of diameters suggestive of altered collagen biosynthesis. Foci of collagen mineralization occurred in zones of combined trauma and lead impregnation. Once mineralized they became enveloped by giant cells and epithelioid cells. Lead in damaged tissues is thought to modify the protective mechanism of calcification inhibition and the biosynthesis of the matrix. Images Fig. 6 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:3040063

  7. Lipid signaling in adipose tissue: Connecting inflammation & metabolism.

    PubMed

    Masoodi, Mojgan; Kuda, Ondrej; Rossmeisl, Martin; Flachs, Pavel; Kopecky, Jan

    2015-04-01

    Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n-6 and n-3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the formation of "healthy" adipocytes. This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance." PMID:25311170

  8. Delivery of growth factors for tissue regeneration and wound healing.

    PubMed

    Koria, Piyush

    2012-06-01

    Growth factors are soluble secreted proteins capable of affecting a variety of cellular processes important for tissue regeneration. Consequently, the self-healing capacity of patients can be augmented by artificially enhancing one or more processes important for healing through the application of growth factors. However, their application in clinics remains limited due to lack of robust delivery systems and biomaterial carriers. Interestingly, all clinically approved therapies involving growth factors utilize some sort of a biomaterial carrier for growth factor delivery. This suggests that biomaterial delivery systems are extremely important for successful usage of growth factors in regenerative medicine. This review outlines the role of growth factors in tissue regeneration, and their application in both pre-clinical animal models of regeneration and clinical trials is discussed. Additionally, current status of biomaterial substrates and sophisticated delivery systems such as nanoparticles for delivery of exogenous growth factors and peptides in humans are reviewed. Finally, issues and possible future research directions for growth factor therapy in regenerative medicine are discussed.

  9. Cartilage, bone, and intermandibular connective tissue in the Australian lungfish, Neoceratodus forsteri (Osteichthyes: Dipnoi).

    PubMed

    Kemp, Anne

    2013-10-01

    The connective tissue that links the bones of the mandible in the Australian lungfish, Neoceratodus forsteri, has been described as an intermandibular cartilage, and as such has been considered important for phylogenetic analyses among lower vertebrates. However, light and electron microscopy of developing lungfish jaws demonstrates that the intermandibular tissue, like the connective tissue that links the bones of the upper jaw, contains fibroblasts and numerous bundles of collagen fibrils, extending from the trabeculae of the bones supporting the tooth plates. It differs significantly in structure and in staining reactions from the cartilage and the bone found in this species. In common with the cladistian Polypterus and with actinopterygians and some amphibians, lungfish have no intermandibular cartilage. The connective tissue linking the mandibular bones has no phylogenetic significance for systematic grouping of lungfish, as it is present in a range of different groups among lower vertebrates.

  10. Efficacy of Connective Tissue with and without Periosteum in Regeneration of Intrabony Defects.

    PubMed

    Esfahanian, Vahid; Golestaneh, Hedayatollah; Moghaddas, Omid; Ghafari, Mohammad Reza

    2014-01-01

    Background and aims. Connective tissue grafts with and without periosteum is used in regenerative treatments of bone and has demonstrated successful outcomes in previous investigations. The aim of present study was to evaluate the effectiveness of connective tissue graft with and without periosteum in regeneration of intrabony defects. Materials and methods. In this single-blind randomized split-mouth clinical trial, 15 pairs of intrabony defects in 15 patients with moderate to advanced periodontitis were treated by periosteal connective tissue graft + ABBM (test group) or non-periosteal connective tissue graft + ABBM (control group). Probing pocket depth, clinical attachment level, free gingival margin position, bone crestal position, crest defect depth and defect depth to stent were measured at baseline and after six months by surgical re-entry. Data was analyzed by Student's t-test and paired t-tests (α=0.05). Results. Changes in clinical parameters after 6 months in the test and control groups were as follows: mean of PPD reduction: 3.1±0.6 (P<0.0001); 2.5±1.0 mm (P<0.0001), CAL gain: 2.3±0.9 (P<0.0001); 2.2±1.0 mm (P<0.0001), bone fill: 2.2±0.7 mm (P<0.0001); 2.2±0.7 mm (P<0.0001), respectively. No significant differences in the position of free gingival margin were observed during 6 months compared to baseline in both groups. Conclusion. Combinations of periosteal connective tissue graft + ABBM and non-periosteal connective tissue graft + ABBM were similarly effective in treating intrabony defects without any favor for any group. Connective tissue and perio-steum can be equally effective in regeneration of intrabony defects.

  11. Efficacy of Connective Tissue with and without Periosteum in Regeneration of Intrabony Defects

    PubMed Central

    Esfahanian, Vahid; Golestaneh, Hedayatollah; Moghaddas, Omid; Ghafari, Mohammad Reza

    2014-01-01

    Background and aims. Connective tissue grafts with and without periosteum is used in regenerative treatments of bone and has demonstrated successful outcomes in previous investigations. The aim of present study was to evaluate the effectiveness of connective tissue graft with and without periosteum in regeneration of intrabony defects. Materials and methods. In this single-blind randomized split-mouth clinical trial, 15 pairs of intrabony defects in 15 patients with moderate to advanced periodontitis were treated by periosteal connective tissue graft + ABBM (test group) or non-periosteal connective tissue graft + ABBM (control group). Probing pocket depth, clinical attachment level, free gingival margin position, bone crestal position, crest defect depth and defect depth to stent were measured at baseline and after six months by surgical re-entry. Data was analyzed by Student’s t-test and paired t-tests (α=0.05). Results. Changes in clinical parameters after 6 months in the test and control groups were as follows: mean of PPD reduction: 3.1±0.6 (P<0.0001); 2.5±1.0 mm (P<0.0001), CAL gain: 2.3±0.9 (P<0.0001); 2.2±1.0 mm (P<0.0001), bone fill: 2.2±0.7 mm (P<0.0001); 2.2±0.7 mm (P<0.0001), respectively. No significant differences in the position of free gingival margin were observed during 6 months compared to baseline in both groups. Conclusion. Combinations of periosteal connective tissue graft + ABBM and non-periosteal connective tissue graft + ABBM were similarly effective in treating intrabony defects without any favor for any group. Connective tissue and perio-steum can be equally effective in regeneration of intrabony defects. PMID:25587379

  12. The periprosthetic capsule and connective tissue diseases: a piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants.

    PubMed

    Bassetto, Franco; Scarpa, Carlotta; Vindigni, Vincenzo; Doria, Andrea

    2012-10-01

    Breast prostheses have been criticized for being responsible for triggering systemic autoimmune disease. The presence of breast implants causes a natural foreign body reaction characterized by the infiltration of macrophages and T-cells. Using PubMed, Medline and eMedicine, we performed a systematic literature review on the stages of periprosthetic capsule formation and cells involved in order to understand which immunological pathways could be responsible for giving rise to, and the development of, connective tissue disease such as systemic sclerosis. We focused on the relationship between tissue growth factor-β, interleukin (IL)-1, IL-6 and T helper 17 or T regulatory cells, as well as on their effects on the different steps of capsular tissue formation. A disturbance in the modulation of these key cytokines may be responsible, in susceptible individuals, for a perpetuation of the inflammatory reaction which can locally lead to capsular contracture and at the systemic level may contribute to triggering autoimmune diseases.

  13. Homeostatic pressure, tumor growth and fingering of epithelial tissues: Some generic physics arguments

    NASA Astrophysics Data System (ADS)

    Risler, Thomas

    2011-03-01

    We propose that one aspect of homeostasis is the regulation of tissues to preferred pressures, which can lead to a competition for space of purely mechanical origin and be an underlying mechanism for tumor growth. Surface and bulk contributions to pressure lead to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property qualitatively explains the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. It also potentially explains the observed preferential growth of metastases on tissue surfaces and membranes, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. Treating epithelial tissues as viscous fluids with effective cell division, we find a novel hydrodynamic instability that leads to the formation of fingering protrusions of the epithelium into the connective tissue. Arising from a combination of viscous friction effects and proliferation of the epithelial cells, this instability provides physical insight into a potential mechanism by which interfaces between epithelia and stroma undulate, and potentially by which tissue dysplasia leads to cancerous invasion. In collaboration with M. Basan, J.-F. Joanny, X. Sastre-Garau and J. Prost.

  14. Should Endovascular Therapy Be Considered for Patients With Connective Tissue Disorder?

    PubMed

    Gagné-Loranger, Maude; Voisine, Pierre; Dagenais, François

    2016-01-01

    Because of early diagnosis, strict imaging follow-up, and advances in medical and surgical management, life expectancy of Marfan patients has dramatically improved since the 1970s. Although disease of the root and ascending aorta are more frequent in patients with connective tissue disorders, a subset of patients present with diffuse disease that might involve any portion of the thoracoabdominal aorta. Thoracic endovascular aortic repair (TEVAR) has gained widespread acceptance for the treatment of different pathologies of the descending aorta. In contrast, TEVAR in patients with connective tissue disorders is associated with a high risk of early and mid-term complications and reinterventions. Currently, a consensus of experts recommend that an open approach should be reserved for use in acceptable risk candidates with connective tissue disorders. TEVAR should be considered solely in patients in a complex repeat surgical setting or in patients judged to have prohibitive open surgical risk. Finally, as a bridge to a definite open repair, TEVAR might be life-saving in patients with connective tissue disorders who present with exsanguination or severe malperfusion. Future developments in stent-graft technology might decrease stent-graft-related complications in patients with connective tissue disorders, although securing a device with radial force in a fragile aorta in the long-term will be challenging.

  15. Morphometric analysis of connective tissue sheaths of sural nerve in diabetic and nondiabetic patients.

    PubMed

    Kundalić, Braca; Ugrenović, Slađana; Jovanović, Ivan; Stefanović, Natalija; Petrović, Vladimir; Kundalić, Jasen; Stojanović, Vesna; Živković, Vladimir; Antić, Vladimir

    2014-01-01

    One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves.

  16. Morphometric analysis of connective tissue sheaths of sural nerve in diabetic and nondiabetic patients.

    PubMed

    Kundalić, Braca; Ugrenović, Slađana; Jovanović, Ivan; Stefanović, Natalija; Petrović, Vladimir; Kundalić, Jasen; Stojanović, Vesna; Živković, Vladimir; Antić, Vladimir

    2014-01-01

    One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. PMID:25147820

  17. Cells of the connective tissue differentiate and migrate into pollen sacs

    NASA Astrophysics Data System (ADS)

    Iqbal, M. C. M.; Wijesekara, Kolitha B.

    2002-01-01

    In angiosperms, archesporial cells in the anther primordium undergo meiosis to form haploid pollen, the sole occupants of anther sacs. Anther sacs are held together by a matrix of parenchyma cells, the connective tissue. Cells of the connective tissue are not known to differentiate. We report the differentiation of parenchyma cells in the connective tissue of two Gordonia species into pollen-like structures (described as pseudopollen), which migrate into the anther sacs before dehiscence. Pollen and pseudopollen were distinguishable by morphology and staining. Pollen were tricolpate to spherical while pseudopollen were less rigid and transparent with a ribbed surface. Both types were different in size, shape, staining and surface architecture. The ratio of the number of pseudopollen to pollen was 1:3. During ontogeny in the connective tissue, neither cell division nor tetrad formation was observed and hence pseudopollen were presumed to be diploid. Only normal pollen germinated on a germination medium. Fixed preparations in time seemed to indicate that pseudopollen migrate from the connective tissue into the anther sac.

  18. Morphometric Analysis of Connective Tissue Sheaths of Sural Nerve in Diabetic and Nondiabetic Patients

    PubMed Central

    Kundalić, Braca; Ugrenović, Slađana; Jovanović, Ivan; Stefanović, Natalija; Petrović, Vladimir; Kundalić, Jasen; Stojanović, Vesna; Živković, Vladimir; Antić, Vladimir

    2014-01-01

    One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. PMID:25147820

  19. Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue.

    PubMed

    Treiber, Nicolai; Maity, Pallab; Singh, Karmveer; Kohn, Matthias; Keist, Alexander F; Ferchiu, Florentina; Sante, Lea; Frese, Sebastian; Bloch, Wilhelm; Kreppel, Florian; Kochanek, Stefan; Sindrilaru, Anca; Iben, Sebastian; Högel, Josef; Ohnmacht, Michael; Claes, Lutz E; Ignatius, Anita; Chung, Jin H; Lee, Min J; Kamenisch, York; Berneburg, Mark; Nikolaus, Thorsten; Braunstein, Kerstin; Sperfeld, Anne-Dorte; Ludolph, Albert C; Briviba, Karlis; Wlaschek, Meinhard; Florin, Lore; Angel, Peter; Scharffetter-Kochanek, Karin

    2011-04-01

    The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.

  20. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review.

    PubMed

    Bougea, Anastasia; Anagnostou, Evangelos; Spandideas, Nikolaos; Triantafyllou, Nikolaos; Kararizou, Evangelia

    2015-01-01

    Vasculitides comprise a heterogeneous group of autoimmune disorders, occurring as primary or secondary to a broad variety of systemic infectious, malignant or connective tissue diseases. The latter occur more often but their pathogenic mechanisms have not been fully established. Frequent and varied central and peripheral nervous system complications occur in vasculitides and connective tissue diseases. In many cases, the neurological disorders have an atypical clinical course or even an early onset, and the healthcare professionals should be aware of them. The purpose of this brief review was to give an update of the main neurological disorders of common vasculitis and connective tissue diseases, aiming at accurate diagnosis and management, with an emphasis on pathophysiologic mechanisms.

  1. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias.

    PubMed

    Merrell, Allyson J; Ellis, Benjamin J; Fox, Zachary D; Lawson, Jennifer A; Weiss, Jeffrey A; Kardon, Gabrielle

    2015-05-01

    The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH.

  2. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review

    PubMed Central

    Bougea, Anastasia; Anagnostou, Evangelos; Spandideas, Nikolaos; Triantafyllou, Nikolaos; Kararizou, Evangelia

    2015-01-01

    Vasculitides comprise a heterogeneous group of autoimmune disorders, occurring as primary or secondary to a broad variety of systemic infectious, malignant or connective tissue diseases. The latter occur more often but their pathogenic mechanisms have not been fully established. Frequent and varied central and peripheral nervous system complications occur in vasculitides and connective tissue diseases. In many cases, the neurological disorders have an atypical clinical course or even an early onset, and the healthcare professionals should be aware of them. The purpose of this brief review was to give an update of the main neurological disorders of common vasculitis and connective tissue diseases, aiming at accurate diagnosis and management, with an emphasis on pathophysiologic mechanisms. PMID:26313435

  3. Robotic Scaffolds for Tissue Engineering and Organ Growth

    NASA Technical Reports Server (NTRS)

    Stoica, Adrian

    2011-01-01

    The aim of tissue engineering (TE) is to restore tissue and organ functions with minimal host rejection. TE is seen as a future solution to solve the crisis of donor organs for transplant, which faces a shortage expected only to increase in the future. In this innovation, a flexible and configurable scaffold has been conceived that mechanically stresses cells that are seeded on it, stimulating them to increased growth. The influence of mechanical stress/ loading on cell growth has been observed on all forms of cells. For example, for cartilages, studies in animals, tissue explants, and engineered tissue scaffolds have all shown that cartilage cells (chondrocytes) modify their extracellular matrix in response to loading. The chondrocyte EMC production response to dynamics of the physical environment (in vivo cartilage development) illustrates a clear benefit (better growth) when stressed. It has been shown that static and dynamic compression regulates PRG4 biosynthesis by cartilage explants. Mechanical tissue stimulation is beneficial and (flexible) scaffolds with movable components, which are able to induce mechanical stimulation, offer advantages over the fixed, rigid scaffold design. In addition to improved cell growth from physical/mechanical stimulation, additional benefits include the ability to increase in size while preserving shape, or changing shape. By making scaffolds flexible, allowing relative movement between their components, adding sensing (e.g., for detecting response of cells to drug release and to mechanical actions), building controls for drug release and movement, and building even simple algorithms for mapping sensing to action, these structures can actually be made into biocompatible and biodegradable robots. Treating them as robots is a perspective shift that may offer advantages in the design and exploitation of these structures of the future.

  4. [The role of vitamin K in the metabolism of connective tissue biopolymers (review)].

    PubMed

    Sharaev, P N

    1984-01-01

    Metabolism of connective tissue biopolymers was studied under conditions of various content of vitamin K in the body. The data obtained suggest the existence of a new metabolic effect of vitamin K--its participation as an allosteric activator in regulation of glucosamine synthetase (EC 5.3.1.19). The anabolic effect of vitamin K on connective tissue is apparently related to an increase in the rate of biosynthesis of glucosamine-6-phosphate--general precursor of glycosaminoglycans, glycoproteins and hexosamine-containing glycolipids. PMID:6369774

  5. [The role of connective tissue nonspecific dysplasia in postoperative and recurrent abdominal hernias formation].

    PubMed

    Akhmedov, N I

    2011-04-01

    There were studied the rate of clinical indices diagnosis concerning nondifferentiated form of connective tissue dysplasia (NFCTD) as well as their significance in postoperative and recurrent abdominal hernias formation in 61 patients, ageing 20 - 78 years. It was established, that in 77% of patients the hernia have had formated on a NFCTD background, including in 16.4%--with a mild degree, in 27.8%--moderate degree and in 32.8%--a severe one. The authors recommend while abdominal hernia is present to study a characteristic phenotypical signs of a connective tissue dysplasia and, if more than 4 signs are diagnosed, to prefer the application of alloplastic methods.

  6. Cell density signal protein suitable for treatment of connective tissue injuries and defects

    DOEpatents

    Schwarz, Richard I.

    2002-08-13

    Identification, isolation and partial sequencing of a cell density protein produced by fibroblastic cells. The cell density signal protein comprising a 14 amino acid peptide or a fragment, variant, mutant or analog thereof, the deduced cDNA sequence from the 14 amino acid peptide, a recombinant protein, protein and peptide-specific antibodies, and the use of the peptide and peptide-specific antibodies as therapeutic agents for regulation of cell differentiation and proliferation. A method for treatment and repair of connective tissue and tendon injuries, collagen deficiency, and connective tissue defects.

  7. Association of cervical artery dissection with connective tissue abnormalities in skin and arteries.

    PubMed

    Brandt, T; Morcher, M; Hausser, I

    2005-01-01

    Spontaneous cervical artery dissections (sCAD) often occur in otherwise healthy individuals without known risk factors for stroke and frequently develop spontaneously without relevant trauma. An underlying arteriopathy leading to a so-called 'weakness of the vessel wall' and predisposing certain individuals to dissection has often been postulated. Therefore, the morphology of connective tissue, a main component of vessel wall and environment, was investigated in carotids and skin. While the overall morphology of dermal connective tissue is normal, about half of patients with sCAD show mild ultrastructural connective tissue alterations. These ultrastructural morphological aberrations can be designated either as 'Ehlers-Danlos syndrome (EDS) III-like', resembling mild findings in patients with the hypermobility type of EDS (EDS III); or coined 'EDS IV-like' with collagen fibers containing fibrils with highly variable diameters resembling mild findings in vascular EDS; or the abnormalities are restricted to the elastic fibers (with fragmentation and minicalcifications) without significant alterations in the morphology of the collagen fibrils. These findings had some similarity with the morphology found in heterozygous carriers of pseudoxanthoma elasticum. A grading scale according to the severity of the findings has been introduced. Similar connective tissue abnormalities were detected in some first-degree relatives of patients with sCAD showing hereditary at least in a subgroup. They can serve as a phenotypic marker for further genetic studies in patients with sCAD and large families to possibly identify the underlying basic molecular defect(s). Very few of patients (<5%) with sCAD and connective tissue abnormalities have clinical manifestations of skin, joint, or skeletal abnormalities of a defined heritable connective tissue disorder. In specimens of arterial walls of carotid, aortic, and renal arteries of patients with sCAD, pronounced systemic, histopathological

  8. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children

    PubMed Central

    Cabrera, Natalia; Duquesne, Agnes; Desjonquères, Marine; Larbre, Jean-Paul; Lega, Jean-Christophe; Fabien, Nicole; Belot, Alexandre

    2016-01-01

    Arthritis is one of the main manifestations of mixed connective tissue disease (MCTD) and overlap syndrome in children and can be responsible for functional disability. We report on 2 children with arthritis that were dramatically improved by a treatment with interleukin-6 (IL-6) blockers in the context of connective tissue disease. However, in both cases, other systemic autoimmune symptoms were not modified by the treatment and autoantibodies tend to increase, suggesting a differential effect of IL-6 inhibition on articular inflammation and systemic autoimmunity. PMID:27738519

  9. The connective tissue of the adductor canal--a morphological study in fetal and adult specimens.

    PubMed

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-03-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 microm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop.

  10. The connective tissue of the adductor canal – a morphological study in fetal and adult specimens

    PubMed Central

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-01-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 µm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop. PMID:19245505

  11. Esthetic Root Coverage with Double Papillary Subepithelial Connective Tissue Graft: A Case Report

    PubMed Central

    Mutthineni, Ramesh Babu; Dudala, Ram Babu; Ramisetty, Arpita

    2014-01-01

    Patients today have become excessively concerned about esthetics. These esthetic concerns of patients have become an integral part of periodontal practice. Gingival recession is an esthetic problem that can be successfully treated by means of several mucogingival surgical approaches, any of which can be used, provided that the biologic conditions for accomplishing root coverage are satisfied with no loss of soft and hard tissue height interdentally. There are currently different techniques for root coverage which include pedicle grafts, free gingival grafts, connective tissue grafts, and guided tissue regeneration (GTR). This paper reports a case in which a new double papillary connective tissue graft technique has been used in the treatment of gingival recession. PMID:24649378

  12. Cytoskeletal remodeling of connective tissue fibroblasts in response to static stretch is dependent on matrix material properties

    PubMed Central

    Abbott, Rosalyn D; Koptiuch, Cathryn; Iatridis, James C; Howe, Alan K; Badger, Gary J; Langevin, Helene M

    2012-01-01

    In areolar “loose” connective tissue, fibroblasts remodel their cytoskeleton within minutes in response to static stretch resulting in increased cell body cross-sectional area that relaxes the tissue to a lower state of resting tension. It remains unknown whether the loosely arranged collagen matrix, characteristic of areolar connective tissue, is required for this cytoskeletal response to occur. The purpose of this study was to evaluate cytoskeletal remodeling of fibroblasts in and dissociated from areolar and dense connective tissue in response to 2 hours of static stretch in both native tissue and collagen gels of varying crosslinking. Rheometric testing indicated that the areolar connective tissue had a lower dynamic modulus and was more viscous than the dense connective tissue. In response to stretch, cells within the more compliant areolar connective tissue adopted a large “sheet-like” morphology that was in contrast to the smaller dendritic morphology in the dense connective tissue. By adjusting the in vitro collagen crosslinking, and the resulting dynamic modulus, it was demonstrated that cells dissociated from dense connective tissue are capable of responding when seeded into a compliant matrix, while cells dissociated from areolar connective tissue can lose their ability to respond when their matrix becomes stiffer. This set of experiments indicated stretch-induced fibroblast expansion was dependent on the distinct matrix material properties of areolar connective tissues as opposed to the cells’ tissue of origin. These results also suggest that disease and pathological processes with increased crosslinks, such as diabetes and fibrosis, could impair fibroblast responsiveness in connective tissues. PMID:22552950

  13. A New Variant of Connective Tissue Nevus with Elastorrhexis and Predilection for the Upper Chest.

    PubMed

    Chu, Derek H; Goldbach, Hayley; Wanat, Karolyn A; Rubin, Adam I; Yan, Albert C; Treat, James R

    2015-01-01

    Localized changes in cutaneous elastic tissue often manifest with flesh-colored, hypopigmented, or yellow papules, plaques, and nodules. We present five children with clinically similar cobblestone plaques composed of multiple hypopigmented, nonfollicular, pinpoint papules located unilaterally over the upper chest. All lesions first appeared at birth or during early infancy. No associated extracutaneous abnormalities have been identified. Histopathology was remarkable for many, thick elastic fibers with elastorrhexis. We believe that these cases represent a distinct and unique variant of connective tissue nevi.

  14. Fibroblast Growth Factors: Biology, Function, and Application for Tissue Regeneration

    PubMed Central

    Yun, Ye-Rang; Won, Jong Eun; Jeon, Eunyi; Lee, Sujin; Kang, Wonmo; Jo, Hyejin; Jang, Jun-Hyeog; Shin, Ueon Sang; Kim, Hae-Won

    2010-01-01

    Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues. PMID:21350642

  15. Production of an optimized tissue-engineered pig connective tissue for the reconstruction of the urinary tract.

    PubMed

    Ouellet, Gabrielle; Dubé, Jean; Gauvin, Robert; Laterreur, Véronique; Bouhout, Sara; Bolduc, Stéphane

    2011-06-01

    Nonurological autologous tissues are used for urethral reconstruction to correct urinary tract disorders but are still leading to complications. Other substitutes have been studied on small animal models without great success. For preclinical tests, we selected the porcine model for its similarity to the human urinary tract. Up to now, porcine skin fibroblasts were not able to synthesize enough extracellular matrix under standard conditions to sustain the formation of an adequate tissue for transplantation purposes. Therefore, our goal was to optimize the harvesting site and culture conditions to obtain a thick and easy to handle porcine fibroblast tissue. The oral mucosa was found to be the ideal harvesting site, and a culture temperature of 39°C enabled the formation of a good porcine fibroblast sheet. We successfully superimpose three fibroblast sheets that merged into a thick and resistant tissue where physiological extracellular matrix was produced. Mechanical resistance evaluation by uniaxial traction on the three-layer fibroblast constructs also demonstrated its suitable properties. The production of this porcine connective tissue offers an interesting option in the field of urological tissue engineering. Autologous experiments on a larger animal model are now possible and accessible, allowing the performance of long-term in vivo studies.

  16. Transplantable tissue growth-a commercial space venture

    NASA Astrophysics Data System (ADS)

    Giuntini, Ronald E.; Vardaman, William K.

    1997-01-01

    Rantek was incorporated in 1984 to pursue research toward product development in space based biotechnology. The company has maintained an aggressive experiment flight program since 1989 having flown biotechnology experiments in six Consort rockets flights, one Joust rocket flight and eight Space Shuttle missions. The objective of these flights was to conduct a series of research experiments to resolve issues affecting transplantable tissue growth feasibility. The purpose of the flight research was to determine the behavior of lymphocyte mixing, activation, magnetic mixing and process control, drug studies in a model leukemia cell line, and various aspects of the hardware system process control in the low gravity of space. The company is now preparing for a two Space Shuttle flight program as precursors to a sustained, permanent, commercial venture at the Space Station. The shuttle flights will enable new, larger scale tissue growth systems to be tested to determine fundamental process control sensitivity and growth rates unique to a number of tissue types. The answer to these issues will ultimately determine the commercial viability of the Rantek Biospace program. This paper addresses considerations that will drive the cost of a space venture-the largest cost driver will be the cost to and from the station and the cost at the station.

  17. Modified connective tissue punch technique to increase the vestibular/buccal keratinized tissue on flapless implant surgery: a case series.

    PubMed

    Andreasi Bassi, M; Andrisani, C; Lopez, M A; Gaudio, R M; Lombardo, L; Lauritano, D

    2016-01-01

    The aim of this article is to show a simple and predictable technique to enhance both the vestibular/buccal (V/B) gingival thickness (GT) and keratinized tissue width (KTW) improving the soft-tissue profile after flapless implant placement. The technique proposed was named Modified Connective Tissue Punch (MCTP). Fourteen patients (6 men and 8 women) aged between 35 and 69 years (mean value 48.07±13.023 years) were enrolled in this case series. Seventeen implant sites were submitted to flapless procedure. The connective punch (CP) was harvested with a motor-driven circular tissue punch and then a full-split dissection was executed, in order to create a deep pouch, beyond the mucogingival junction, on the V/B side. In this recipient site the CP was placed. The normal flapless surgical protocol was used; implants were inserted and covered with transgingival healing cap screws. GT and KTW were measured: both immediately before and after surgery; at the time of the prosthetic finalization (3-4months, respectively, for mandible and maxilla); 1 year post surgery follow-up. GT was measured at 1 mm, 2 mm and 5 mm on the V/B side, from the outline of the punch. Both KTW and GT at 1 and 2 mm can be effectively increased, while no significant effects for GT at 5 mm can be expected from this technique. Furthermore, the mean values of KTW and GT at 1 mm and 2 mm show significant increases at 3-4 months post-operative, while no further significant increments are shown at 1 year post-operative follow-up. The Authors recommend the use of the MCTP technique to reduce the number of aesthetic complications and soft tissue defects in flapless implant surgery. Longer follow-ups are needed to evaluate the stability of peri-implant tissues over time. PMID:27469545

  18. Modified connective tissue punch technique to increase the vestibular/buccal keratinized tissue on flapless implant surgery: a case series.

    PubMed

    Andreasi Bassi, M; Andrisani, C; Lopez, M A; Gaudio, R M; Lombardo, L; Lauritano, D

    2016-01-01

    The aim of this article is to show a simple and predictable technique to enhance both the vestibular/buccal (V/B) gingival thickness (GT) and keratinized tissue width (KTW) improving the soft-tissue profile after flapless implant placement. The technique proposed was named Modified Connective Tissue Punch (MCTP). Fourteen patients (6 men and 8 women) aged between 35 and 69 years (mean value 48.07±13.023 years) were enrolled in this case series. Seventeen implant sites were submitted to flapless procedure. The connective punch (CP) was harvested with a motor-driven circular tissue punch and then a full-split dissection was executed, in order to create a deep pouch, beyond the mucogingival junction, on the V/B side. In this recipient site the CP was placed. The normal flapless surgical protocol was used; implants were inserted and covered with transgingival healing cap screws. GT and KTW were measured: both immediately before and after surgery; at the time of the prosthetic finalization (3-4months, respectively, for mandible and maxilla); 1 year post surgery follow-up. GT was measured at 1 mm, 2 mm and 5 mm on the V/B side, from the outline of the punch. Both KTW and GT at 1 and 2 mm can be effectively increased, while no significant effects for GT at 5 mm can be expected from this technique. Furthermore, the mean values of KTW and GT at 1 mm and 2 mm show significant increases at 3-4 months post-operative, while no further significant increments are shown at 1 year post-operative follow-up. The Authors recommend the use of the MCTP technique to reduce the number of aesthetic complications and soft tissue defects in flapless implant surgery. Longer follow-ups are needed to evaluate the stability of peri-implant tissues over time.

  19. Decreased receptivity of pathway connective tissue to sympathetic nerve ingrowth in the developing rat.

    PubMed

    Hiebert, J M; Fan, Q; Smith, P G

    1997-05-20

    Sympathetic axons can form atypical pathways to denervated orbital targets in neonatal rats but not in rats aged 30 or more days. The objective of this study was to determine if connective tissue pathways that carry sympathetic nerves lose their ability to sustain axonal sprouting during the early postnatal period. Regions of periorbital sheath known to contain large numbers of sympathetic axons that travel to distal orbital targets were excised from rats (sympathectomized 3 days previously) on postnatal days 6-7, 14-15, 30-31, and 48-49 and placed in anterior chambers of adult host rats. Tissues were removed 3, 6, or 10 days post-transplant and sympathetic ingrowth was analyzed by catecholamine histofluorescence in whole-mount or cryosectioned specimens. Connective tissue transplants from 6-15-day-old donors showed significant fiber ingrowth by 3 days in oculo, and innervation was maximal by 6 days. In contrast, sprouting into 30-49-day-old tissue was significantly slower, with most transplants lacking fibers at 3 days, and with small numbers of short fibers present at 6 days. We conclude that maturational changes occur in periorbital connective tissue pathways in the early postnatal period which make them less receptive to ingrowth by sympathetic nerves. The findings that connective tissue pathways are better substrates for sympathetic sprouting in the neonatal rat supports the view that developmental changes in these tissues are likely to contribute to the impaired reinnervation of orbital targets by contralateral neurons in juvenile and adult rats. PMID:9174244

  20. Elastin Cables Define the Axial Connective Tissue System in the Murine Lung.

    PubMed

    Wagner, Willi; Bennett, Robert D; Ackermann, Maximilian; Ysasi, Alexandra B; Belle, Janeil; Valenzuela, Cristian D; Pabst, Andreas; Tsuda, Akira; Konerding, Moritz A; Mentzer, Steven J

    2015-11-01

    The axial connective tissue system is a fiber continuum of the lung that maintains alveolar surface area during changes in lung volume. Although the molecular anatomy of the axial system remains undefined, the fiber continuum of the lung is central to contemporary models of lung micromechanics and alveolar regeneration. To provide a detailed molecular structure of the axial connective tissue system, we examined the extracellular matrix of murine lungs. The lungs were decellularized using a 24 hr detergent treatment protocol. Systematic evaluation of the decellularized lungs demonstrated no residual cellular debris; morphometry demonstrated a mean 39 ± 7% reduction in lung dimensions. Scanning electron microscopy (SEM) demonstrated an intact structural hierarchy within the decellularized lung. Light, fluorescence, and SEM of precision-cut lung slices demonstrated that alveolar duct structure was defined by a cable line element encased in basement membrane. The cable line element arose in the distal airways, passed through septal tips and inserted into neighboring blood vessels and visceral pleura. The ropelike appearance, collagenase resistance and anti-elastin immunostaining indicated that the cable was an elastin macromolecule. Our results indicate that the helical line element of the axial connective tissue system is composed of an elastin cable that not only defines the structure of the alveolar duct, but also integrates the axial connective tissue system into visceral pleura and peripheral blood vessels.

  1. Microstructure alterations in beef intramuscular connective tissue caused by hydrodynamic pressure processing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scanning electron microscopy (SEM) was utilized to evaluate microstructural changes in intramuscular connective tissue of beef semimembranosus muscle subjected to hydrodynamic pressure processing (HDP). Samples were HDP treated in a plastic container (HDP-PC) or a steel commercial unit (HDP-CU). C...

  2. Microstructure alterations in beef intramuscular connective tissue caused by hydrodynamic pressure processing.

    PubMed

    Zuckerman, H; Bowker, B C; Eastridge, J S; Solomon, M B

    2013-11-01

    Scanning electron microscopy (SEM) was utilized to evaluate microstructural changes in intramuscular connective tissue of beef semimembranosus muscle subjected to hydrodynamic pressure processing (HDP). Samples were HDP treated in a plastic container (HDP-PC) or a steel commercial unit (HDP-CU). Control and HDP samples were obtained immediately post-treatment and after 14days of aging for SEM and Warner-Bratzler shear force (WBSF) analysis. Immediately post-treatment, HDP treated samples exhibited lower (P<0.01) WBSF than did controls. After aging, HDP-PC samples had lower (P<0.01) WBSF than that of aged controls. SEM analysis indicated that HDP-PC treatment disrupted the integrity of the collagen fibril network of the endomysium in both the non-aged and aged samples. Aging effects on the intramuscular connective tissue were observed in the HDP-PC and control samples. Both WBSF and connective tissue changes were greater in the HDP-PC than in the HDP-CU treated samples. Data suggest that shockwave alterations to connective tissue contribute to the meat tenderization of HDP.

  3. Rn for treatment of periocular fibrous connective tissue sarcomas in the horse

    SciTech Connect

    Frauenfelder, H.C.; Blevins, W.E.; Page, E.H.

    1982-02-01

    Twelve periocular fibrous connective tissue sarcomas in 11 horses were treated with 222Rn. Follow-up periods ranged from 1 to 6 years; the overall nonrecurrence rate at 12 months after therapy was 92%. Two lesions recurred 2 years after treatment, and 1 after 3 years. One of the former lesions has not recurred after a 2nd 222Rn treatment.

  4. Structure of the rat subcutaneous connective tissue in relation to its sliding mechanism.

    PubMed

    Kawamata, Seiichi; Ozawa, Junya; Hashimoto, Masakazu; Kurose, Tomoyuki; Shinohara, Harumichi

    2003-08-01

    Mammalian skin can extensively slide over most parts of the body. To study the mechanism of this mobility of the skin, the structure of the subcutaneous connective tissue was examined by light microscopy. The subcutaneous connective tissue was observed to be composed of multiple layers of thin collagen sheets containing elastic fibers. These piled-up collagen sheets were loosely interconnected with each other, while the outer and inner sheets were respectively anchored to the dermis and epimysium by elastic fibers. Collagen fibers in each sheet were variable in diameter and oriented in different directions to form a thin, loose meshwork under conditions without mechanical stretching. When a weak shear force was loaded between the skin and the underlying abdominal muscles, each collagen sheet slid considerably, resulting in a stretching of the elastic fibers which anchor these sheets. When a further shear force was loaded, collagen fibers in each sheet seemed to align in a more parallel manner to the direction of the tension. With the reduction or removal of the force, the arrangement of collagen fibers in each sheet was reversed and the collagen sheets returned to their original shapes and positions, probably with the stabilizing effect of elastic fibers. Blood vessels and nerves in the subcutaneous connective tissue ran in tortuous routes in planes parallel to the unloaded skin, which seemed very adaptable for the movement of collagen sheets. These findings indicate that the subcutaneous connective tissue is extensively mobile due to the presence of multilayered collagen sheets which are maintained by elastic fibers.

  5. Connective tissue integrity is lost in vitamin B-6-deficient chicks

    NASA Technical Reports Server (NTRS)

    Masse, P. G.; Yamauchi, M.; Mahuren, J. D.; Coburn, S. P.; Muniz, O. E.; Howell, D. S.

    1995-01-01

    The objective of the present investigation was to characterize further the connective tissue disorder produced by pyridoxine (vitamin B-6) deficiency, as previously evidenced by electron microscopy. Following the second post-natal week, fast growing male chicks were deprived of pyridoxine for a 1-mo period. Six weeks post-natally, blood concentrations in the experimental deficiency group had declined to deficiency levels as registered by low concentrations of pyridoxal phosphate (coenzyme form) in erythrocytes, but did not reach levels associated with neurological symptoms. Light microscopic study showed abnormalities in the extracellular matrix of the connective tissues. Collagen cross-links and the aldehyde contents were not significantly lower in cartilage and tendon collagens of vitamin B-6-deficient animals than in age-matched controls; also, their proteoglycan degrading protease and collagenase activities measured in articular cartilages were not greater. Thus, proteolysis was an unlikely alternative mechanism to account for the loss of connective tissue integrity. These results point to the need for further investigation into adhesive properties of collagen associated proteoglycans or other proteins in vitamin B-6-deficient connective tissue.

  6. Ex Vivo Growth of Bioengineered Ligaments and Other Tissues

    NASA Technical Reports Server (NTRS)

    Altman, Gregory; Kaplan, David L.; Martin, Ivan; Vunjak-Novakovic, Gordana

    2005-01-01

    A method of growing bioengineered tissues for use in surgical replacement of damaged anterior cruciate ligaments has been invented. An anterior cruciate ligament is one of two ligaments (the other being the posterior cruciate ligament) that cross in the middle of a knee joint and act to prevent the bones in the knee from sliding forward and backward relative to each other. Anterior cruciate ligaments are frequently torn in sports injuries and traffic accidents, resulting in pain and severe limitations on mobility. By making it possible to grow replacement anterior cruciate ligaments that structurally and functionally resemble natural ones more closely than do totally synthetic replacements, the method could create new opportunities for full or nearly full restoration of functionality in injured knees. The method is also adaptable to the growth of bioengineered replacements for other ligaments (e.g., other knee ligaments as well as those in the hands, wrists, and elbows) and to the production of tissues other than ligaments, including cartilage, bones, muscles, and blood vessels. The method is based on the finding that the histomorphological properties of a bioengineered tissue grown in vitro from pluripotent cells within a matrix are affected by the direct application of mechanical force to the matrix during growth generation. This finding provides important new insights into the relationships among mechanical stress, biochemical and cell-immobilization methods, and cell differentiation, and is applicable to the production of the variety of tissues mentioned above. Moreover, this finding can be generalized to nonmechanical (e.g., chemical and electromagnetic) stimuli that are experienced in vivo by tissues of interest and, hence, the method can be modified to incorporate such stimuli in the ex vivo growth of replacements for the various tissues mentioned above. In this method, a three-dimensional matrix made of a suitable material is seeded with pluripotent stem

  7. A novel composition for in vitro and in vivo regeneration of skin and connective tissues.

    PubMed

    Gennero, Luisa; De Siena, Rocco; Denysenko, Tetyana; Roos, Maria Augusta; Calisti, Gian Franco; Martano, Manuela; Fiobellot, Simona; Panzone, Michele; Reguzzi, Stefano; Gabetti, Luisa; Vercelli, Andrea; Cavallo, Giovanni; Ricci, Elia; Pescarmona, Gian Piero

    2011-06-01

    The particular combination of polydeoxyribonucleotides, l-carnitine, calcium ions, proteolytic enzyme and other ingredients acts in a synergetic way in the regeneration of skin and connective tissues. This new formulation of active principles was tested in vitro as a cell and tissue culture medium and in vivo for various preparations in support of tissue regeneration. In vitro, the new blend allowed the maintenance of skin biopsies for more than 1 year in eutrophic conditions. Immunocytochemical analyses of fibroblasts isolated from these biopsies confirmed a significant increase of the epidermal and connective wound-healing markers such as collagen type I, collagen type IV, cytokeratin 1 (CK1), CK5, CK10 and CK14 versus controls. To examine the effects of the new compound in vivo, we studied impaired wound healing in genetically diabetic db/db mice. At day 18, diabetic mice treated with the new composition showed 100% closure of wounds and faster healing than mice treated with the other solutions. This complex of vital continuity factors or life-keeping factors could be used as a tissue-preserving solution or a cosmetic/drug/medical device to accelerate wound healing in the treatment of patients with deficient wound repair to promote the regeneration of cutaneous and connective tissues (injuries-wound, dermatitis) and prevent the recurrent relapses.

  8. Morphometric analysis of nonsclerosed Glomeruli size and connective tissue content during the aging process.

    PubMed

    Stojanović, Vesna R; Jovanović, Ivan D; Ugrenović, Sladjana Z; Vasović, Ljiljana P; Živković, Vladimir S; Jocić, Miodrag V; Kundalić, Braca K; Pavlović, Miljana N

    2012-01-01

    Number of sclerotic glomeruli increases during the aging process. Consequently, majority of remained nonsclerosed glomeruli become hypertrophic and some of them sclerotic, too. The aim of this study was to quantify the size and connective tissue content of nonsclerosed glomeruli and to evaluate the percentage of hypertrophic ones in examined human cases during the aging. Material was right kidney's tissue of 30 cadavers obtained during routine autopsies. Cadavers were without previously diagnosed kidney disease, diabetes, hypertension, or any other systemic disease. Tissue specimens were routinely prepared for histological and morphometric analysis. Images of the histological slices were analyzed and captured under 400x magnification with digital camera. Further they were morphometrically and statistically analyzed with ImageJ and NCSS-PASS software. Multiple and linear regression of obtained morphometric parameters showed significant increase of glomerular connective tissue area and percentage. Cluster analysis showed the presence of two types of glomeruli. Second type was characterized with significantly larger size, connective tissue content, and significantly lower cellularity, in relation to the first type. Such glomeruli might be considered as hypertrophic. First type of glomeruli was predominant in younger cases, while second type of glomeruli was predominant in cases older than 55 years. PMID:22654637

  9. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

    PubMed

    Alazami, Anas M; Al-Qattan, Sarah M; Faqeih, Eissa; Alhashem, Amal; Alshammari, Muneera; Alzahrani, Fatema; Al-Dosari, Mohammed S; Patel, Nisha; Alsagheir, Afaf; Binabbas, Bassam; Alzaidan, Hamad; Alsiddiky, Abdulmonem; Alharbi, Nasser; Alfadhel, Majid; Kentab, Amal; Daza, Riza M; Kircher, Martin; Shendure, Jay; Hashem, Mais; Alshahrani, Saif; Rahbeeni, Zuhair; Khalifa, Ola; Shaheen, Ranad; Alkuraya, Fowzan S

    2016-05-01

    Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.

  10. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

    PubMed

    Alazami, Anas M; Al-Qattan, Sarah M; Faqeih, Eissa; Alhashem, Amal; Alshammari, Muneera; Alzahrani, Fatema; Al-Dosari, Mohammed S; Patel, Nisha; Alsagheir, Afaf; Binabbas, Bassam; Alzaidan, Hamad; Alsiddiky, Abdulmonem; Alharbi, Nasser; Alfadhel, Majid; Kentab, Amal; Daza, Riza M; Kircher, Martin; Shendure, Jay; Hashem, Mais; Alshahrani, Saif; Rahbeeni, Zuhair; Khalifa, Ola; Shaheen, Ranad; Alkuraya, Fowzan S

    2016-05-01

    Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome. PMID:27023906

  11. Control of tissue growth by locally produced activator: Liver regeneration

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir P.

    2015-03-01

    In general, the tissue development is controlled by growth factors and depends on the biomechanics of cells. The corresponding kinetic models are focused primarily on the early stages of the development. The attempts to construct such models for the later stages are still rare. One of the notable examples here is liver regeneration. Referring to this process, the author proposes and analyzes a generic kinetic model describing the regulation of tissue growth by locally produced activator. The model includes activator diffusion and control of the rate of cell proliferation which is described by using the Hill expression. Although this control may be moderately or strongly non-linear, the qualitative changes in the regeneration kinetics are predicted to be modest. For moderately non-linear control, the evolution of the tissue volume to the steady-state value exhibits an initial relatively short linear stage and then becomes slightly slower so that the whole kinetics is close to exponential. For strongly non-linear control, the linear stage dominates and/or the kinetics may exhibit a S-like shape feature which is, however, rather weak. The identification of such qualitative features in experimentally measured kinetics is shown to be difficult, because the error bars in the experiments are typically too large.

  12. Tissue perfusion inhomogeneity during early tumor growth in rats.

    PubMed

    Endrich, B; Reinhold, H S; Gross, J F; Intaglietta, M

    1979-02-01

    Tissue perfusion in BA 1112 sarcomas of WAG inbred Rijswijk rats was determined from in vivo measurements of capillary density, length, and erythrocyte velocity in modified Algire chamber preparations. Studies were done with the use of television techniques in situ during a period of 26 days, both in control chambers and after implantation of a 0.1-mm3 piece of tumor tissue. Perfusion in control areas void of tumor tissue. Perfusion in control areas void of tumor was approximately 8-10 ml/minute/100 g of tissue. Flow in active tumor growth regions on the outward side of the tumor edge was through undifferentiated channels and had characteristics of flow through a porous medium. Despite enhanced arterial supply, the stabilized tumor microcirculation at the inward side of the growing tumor retained its perfusion rate constant (15-18 ml/min/100 g). Perfusion in central portions of the tumor was about 2-4 ml/minute/100 g during 12 days, whereas the tumor doubled in diameter. Our findings support the concept of temporal and functional blood flow inhomogeneity in the microcirculation of spreading tumors. PMID:283271

  13. Connective Tissue Reaction to White and Gray MTA Mixed With Distilled Water or Chlorhexidine in Rats

    PubMed Central

    Yavari, Hamid Reza; Shahi, Shahriar; Rahimi, Saeed; Shakouie, Sahar; Roshangar, Leila; Mesgari Abassi, Mehran; Sattari Khavas, Sahar

    2009-01-01

    INTRODUCTION: The purpose of this study was to compare the histocompatibility of white (WMTA) and gray (GMTA) mineral trioxide aggregate mixed with 0.12% chlorhexidine (CHX) and distilled water (DW) in subcutaneous connective tissues of rats. MATERIALS AND METHODS: The freshly mixed WMTA and GMTA with CHX or DW were inserted in polyethylene tubes and implanted into dorsal subcutaneous connective tissue of 50 Wistar Albino rats; tissue biopsies were collected and were then examined histologically 7, 15, 30, 60 and 90 days after the implantation procedure. The histology results were scored from 1-4; score 4 was considered as the worst finding. Data were analyzed using one-way ANOVA tests. RESULTS: All experimented materials were tolerated well by the connective tissues after 90-day evaluation, except for the WMTA/CHX group that had significantly more mean inflammatory scores (P<0.001). There was a statistically significant difference in the mean inflammation grades between experimental groups in each interval (P<0.001). After 90 days, GMTA/CHX group had the lowest inflammatory score. CONCLUSION: Although adding CHX to WMTA produces significantly higher inflammatory response, it seems a suitable substitute for DW in combination with GMTA. Further research is necessary to recommend this mixture for clinical use. PMID:23864873

  14. Aberrations of dermal connective tissue in patients with cervical artery dissection (sCAD).

    PubMed

    Uhlig, Phillip; Bruckner, Peter; Dittrich, Ralf; Ringelstein, E Bernd; Kuhlenbäumer, Gregor; Hansen, Uwe

    2008-03-01

    Spontaneous cervical artery dissection (sCAD) is a common cause of stroke in patients below 55 years of age. Hereditary connective tissue disorders, including Ehlers-Danlos syndrome type IV, have been associated with sCAD and suprastructural abnormalities of both collagen fibrils and elastic fibers have been found by transmission electron microscopy in the dermis of about 50% of sCAD patients. Here, we investigated dermal connective tissue abnormalities using a novel method. Transmission and immunogold electron microscopy were used to study mechanically generated fragments of dermal matrix suprastructures, in particular collagen fibrils. Analysis of dermal tissue of sCAD patients revealed structurally abnormal collagen fibrils with irregularly contoured surfaces and increased diameters, often associated with a faint or absent banding pattern. Interestingly, only a small number of fibrils displayed short abnormal sections along the length of the fibril. Collagens I and III were present in normal as well as abnormal sections of the fibrils.However, immunogold labeling for the two proteins was strongly increased in abnormal sections.A systematic blinded investigation of skin biopsies of 31 sCAD patients and 17 controls revealed abnormal collagen fibrils in 7 sCAD patients but none of the controls. We conclude that approximately 20% of sCAD patients show collagen fibril alterations, establishing a promising basis for further investigation of connective tissue aberrations in skin biopsies of sCAD patients.

  15. Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth.

    PubMed

    Jo, Junghyo; Gavrilova, Oksana; Pack, Stephanie; Jou, William; Mullen, Shawn; Sumner, Anne E; Cushman, Samuel W; Periwal, Vipul

    2009-03-01

    Adipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). Genetics and diet affect the relative contributions of these two mechanisms to the growth of adipose tissue in obesity. In this study, the size distributions of epididymal adipose cells from two mouse strains, obesity-resistant FVB/N and obesity-prone C57BL/6, were measured after 2, 4, and 12 weeks under regular and high-fat feeding conditions. The total cell number in the epididymal fat pad was estimated from the fat pad mass and the normalized cell-size distribution. The cell number and volume-weighted mean cell size increase as a function of fat pad mass. To address adipose tissue growth precisely, we developed a mathematical model describing the evolution of the adipose cell-size distributions as a function of the increasing fat pad mass, instead of the increasing chronological time. Our model describes the recruitment of new adipose cells and their subsequent development in different strains, and with different diet regimens, with common mechanisms, but with diet- and genetics-dependent model parameters. Compared to the FVB/N strain, the C57BL/6 strain has greater recruitment of small adipose cells. Hyperplasia is enhanced by high-fat diet in a strain-dependent way, suggesting a synergistic interaction between genetics and diet. Moreover, high-fat feeding increases the rate of adipose cell size growth, independent of strain, reflecting the increase in calories requiring storage. Additionally, high-fat diet leads to a dramatic spreading of the size distribution of adipose cells in both strains; this implies an increase in size fluctuations of adipose cells through lipid turnover.

  16. Fractal analysis of the structural complexity of the connective tissue in human carotid bodies

    PubMed Central

    Guidolin, Diego; Porzionato, Andrea; Tortorella, Cinzia; Macchi, Veronica; De Caro, Raffaele

    2014-01-01

    The carotid body (CB) may undergo different structural changes during perinatal development, aging, or in response to environmental stimuli. In the previous literature, morphometric approaches to evaluate these changes have considered quantitative first order parameters, such as volumes or densities, while changes in spatial disposition and/or complexity of structural components have not yet been considered. In the present study, different strategies for addressing morphological complexity of CB, apart from the overall amount of each tissue component, were evaluated and compared. In particular, we considered the spatial distribution of connective tissue in the carotid bodies of young control subjects, young opiate-related deaths and aged subjects, through analysis of dispersion (Morisita's index), gray level co-occurrence matrix (entropy, angular second moment, variance, correlation), and fractal analysis (fractal dimension, lacunarity). Opiate-related deaths and aged subjects showed a comparable increase in connective tissue with respect to young controls. However, the Morisita's index (p < 0.05), angular second moment (p < 0.05), fractal dimension (p < 0.01), and lacunarity (p < 0.01) permitted to identify significant differences in the disposition of the connective tissue between these two series. A receiver operating characteristic (ROC) curve was also calculated to evaluate the efficiency of each parameter. The fractal dimension and lacunarity, with areas under the ROC curve of 0.9651 (excellent accuracy) and 0.8835 (good accuracy), respectively, showed the highest discriminatory power. They evidenced higher level of structural complexity in the carotid bodies of opiate-related deaths than old controls, due to more complex branching of intralobular connective tissue. Further analyses will have to consider the suitability of these approaches to address other morphological features of the CB, such as different cell populations, vascularization, and innervation

  17. Comparing dynamic connective tissue in echinoderms and sponges: morphological and mechanical aspects and environmental sensitivity.

    PubMed

    Sugni, Michela; Fassini, Dario; Barbaglio, Alice; Biressi, Anna; Di Benedetto, Cristiano; Tricarico, Serena; Bonasoro, Francesco; Wilkie, Iain C; Candia Carnevali, Maria Daniela

    2014-02-01

    Echinoderms and sponges share a unique feature that helps them face predators and other environmental pressures. They both possess collagenous tissues with adaptable viscoelastic properties. In terms of morphology these structures are typical connective tissues containing collagen fibrils, fibroblast- and fibroclast-like cells, as well as unusual components such as, in echinoderms, neurosecretory-like cells that receive motor innervation. The mechanisms underpinning the adaptability of these tissues are not completely understood. Biomechanical changes can lead to an abrupt increase in stiffness (increasing protection against predation) or to the detachment of body parts (in response to a predator or to adverse environmental conditions) that are regenerated. Apart from these advantages, the responsiveness of echinoderm and sponge collagenous tissues to ionic composition and temperature makes them potentially vulnerable to global environmental changes.

  18. [Antinuclear antibodies without connective tissue disease : Antibodies against LEDGF/DSF70].

    PubMed

    Mierau, R

    2016-05-01

    Testing for antinuclear antibodies (ANA) by the indirect immunofluorescence test (IFT) is regarded as a fundamental serological screening method for diagnosing connective tissue diseases (CTD). In the case of a negative result exclusion of certain CTDs is indicated, especially systemic lupus erythematosus, and a positive ANA result is the starting point for further tests aimed at finding disease-specific autoantibodies. The recently discovered antibodies against lens epithelium-derived growth factor (LEDGF/DSF70) deviate from the normal interpretation pattern in ANA diagnostics. These antibodies give rise to a characteristic dense fine speckled (DSF) immunofluorescence pattern in IFT and target the ubiquitously expressed nuclear stress protector protein LEDGFp75. They can be detected, sometimes in high titers, not only in patients with diverse disorders of the skin or eyes and with neoplasms but also in persons with relatively mild or unspecific complaints and even in apparently healthy individuals; however, they are less frequent in CTD. These anti-LEDGF antibodies can be found in all age groups with a tendency to a higher prevalence in younger people and the frequency does not increase in advanced age. The vast majority of anti-LEDGF carriers are female. The CTDs with isolated anti-LEDGF antibodies, i. e. unaccompanied by autoantibodies typical for the respective CTD, are extremely rare. Detection of ANA exclusively with a DSF immunofluorescence pattern and confirmed by a specific anti-LEDGF binding assay, does not therefore indicate the presence of CTD but is indicative of exclusion of systemic lupus erythematosus, systemic sclerosis and an ANA-associated overlap syndrome, similar to a completely negative ANA result.

  19. In the beginning there were soft collagen-cell gels: towards better 3D connective tissue models?

    PubMed

    Brown, Robert A

    2013-10-01

    In the 40 years since Elsdale and Bard's analysis of fibroblast culture in collagen gels we have moved far beyond the concept that such 3D fibril network systems are better models than monolayer cultures. This review analyses key aspects of that progression of models, against a background of what exactly each model system tries to mimic. This story tracks our increasing understanding of fibroblast responses to soft collagen gels, in particularly their cytoskeletal contraction, migration and integrin attachment. The focus on fibroblast mechano-function has generated models designed to directly measure the overall force generated by fibroblast populations, their reaction to external loads and the role of the matrix structure. Key steps along this evolution of 3D collagen models have been designed to mimic normal skin, wound repair, tissue morphogenesis and remodelling, growth and contracture during scarring/fibrosis. As new models are developed to understand cell-mechanical function in connective tissues the collagen material has become progressively more important, now being engineered to mimic more complex aspects of native extracellular matrix structure. These have included collagen fibril density, alignment and hierarchical structure, controlling material stiffness and anisotropy. But of these, tissue-like collagen density is key in that it contributes to control of the others. It is concluded that across this 40 year window major progress has been made towards establishing a family of 3D experimental collagen tissue-models, suitable to investigate normal and pathological fibroblast mechano-functions.

  20. Transient inhibition of connective tissue infiltration and collagen deposition into porous poly(lactic-co-glycolic acid) discs.

    PubMed

    Love, Ryan J; Jones, Kim S

    2013-12-01

    Connective tissue rapidly proliferates on and around biomaterials implanted in vivo, which impairs the function of the engineered tissues, biosensors, and devices. Glucocorticoids can be utilized to suppress tissue ingrowth, but can only be used for a limited time because they nonselectively arrest cell proliferation in the local environment. The present study examined use of a prolyl-4-hydroxylase inhibitor, 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), to suppress connective tissue ingrowth in porous PLGA discs implanted in the peritoneal cavity for 28 days. The prolyl-4-hydroxylase inhibitor was found to be effective at inhibiting collagen deposition within and on the outer surface of the disc, and also limited connective tissue ingrowth, but not to the extent of glucocorticoid inhibition. Finally, it was discovered that 1,4-DPCA suppressed Scavenger Receptor A expression on a macrophage-like cell culture, which may account for the drug's ability to limit connective tissue ingrowth in vivo.

  1. Application of exogenous enzymes to beef muscle of high and low-connective tissue.

    PubMed

    Sullivan, G A; Calkins, C R

    2010-08-01

    Exogenous enzymes tenderize meat through proteolysis. Triceps brachii and Supraspinatus were randomly assigned to the seven enzyme treatments, papain, ficin, bromelain, homogenized fresh ginger, Bacillus subtilis protease, and two Aspergillus oryzae proteases or control to determine the extent of tenderization (Warner-Bratzler shear and sensory evaluation) and mode of action (myofibrillar or collagen degradation). Sensory evaluation showed improvement (P<0.0009) for tenderness and connective tissue component and all except ginger had a lower shear force than the control (P<0.003). Ginger produced more off-flavor than all other treatments (P<0.0001). Only papain increased soluble collagen (P<0.0001). Control samples were only significantly less than ficin for water soluble (P=0.0002) and A. oryzae concentrate for salt soluble proteins (P=0.0148). All enzyme treatments can increase tenderness via myofibrillar and collagenous protein degradation with no difference among high and low-connective tissue muscles. PMID:20416788

  2. Application of exogenous enzymes to beef muscle of high and low-connective tissue.

    PubMed

    Sullivan, G A; Calkins, C R

    2010-08-01

    Exogenous enzymes tenderize meat through proteolysis. Triceps brachii and Supraspinatus were randomly assigned to the seven enzyme treatments, papain, ficin, bromelain, homogenized fresh ginger, Bacillus subtilis protease, and two Aspergillus oryzae proteases or control to determine the extent of tenderization (Warner-Bratzler shear and sensory evaluation) and mode of action (myofibrillar or collagen degradation). Sensory evaluation showed improvement (P<0.0009) for tenderness and connective tissue component and all except ginger had a lower shear force than the control (P<0.003). Ginger produced more off-flavor than all other treatments (P<0.0001). Only papain increased soluble collagen (P<0.0001). Control samples were only significantly less than ficin for water soluble (P=0.0002) and A. oryzae concentrate for salt soluble proteins (P=0.0148). All enzyme treatments can increase tenderness via myofibrillar and collagenous protein degradation with no difference among high and low-connective tissue muscles.

  3. Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease.

    PubMed Central

    Jolliet, P.; Thorens, J. B.; Chevrolet, J. C.

    1995-01-01

    Pulmonary vascular reactivity tests were performed in a young woman with mixed connective tissue disease and severe pulmonary hypertension. Vasoreactivity was documented in response to intravenous prostacyclin (PGI2), oral nifedipine, and inhaled nitric oxide, with quantitative differences. Nitric oxide produced a moderate lowering of pulmonary arterial pressure and resistance without any deleterious systemic effect. The use of nitric oxide in testing for pulmonary vasoreactivity merits further evaluation. Images PMID:7886662

  4. Anti-Ku antibodies in connective tissue diseases. Report of three cases.

    PubMed

    Parodi, A; Rebora, A

    1989-08-01

    Three patients are described with clinical features of connective tissue diseases, namely, dermatomyositis, progressive systemic scleroderma, and systemic lupus erythematosus. In two patients the symptoms of disease overlapped. The rare anti-Ku antibody was found in all of them. Anti-Ku antibody characterizes those patients, with polymyositis-scleroderma overlap syndromes who have a good prognosis. One of our patients, who also had severe anti-Sm-positive systemic lupus erythematosus, seems to be an exception.

  5. [Morphological diagnosis of connective tissue dysplasia in patients, suffering postoperative abdominal hernia].

    PubMed

    Chetverikov, S H; Iashchenko, A M; Ier'omin, Iu V; Vododiuk, V Iu

    2012-05-01

    The results of treatment of 122 patients, to whom alloplasty for postoperative abdominal hernia (POAH) was performed, were analyzed. In 76 patients a connective tissue dysplasia (CTD) was diagnosed.Determination of a various types of collagen content in connective tissue of patients, suffering CTD, may confirm or exclude this diagnosis. Diagnostic significance has the enhancement of a collagen type III content in comparison with such of a type I by three times and more. The method of lectinohistochemical investigation of connective tissue was applied as a precision-enhancing method of a CTD diagnosis. Mosaic or diffuse loss of SNA, LABA, ConA receptors of lectins by collagen fascicles, which reflect carbohydrate determinants of dense and strong collagen fascicles, made of collagen type I, witness the CTD presence. Along with this, there was observed a lectin WGA receptors expression increase, which constitutes a marker of fascicular structures, made of collagen, predominantly type III and a lectin PNA receptors, which are revealed around vessels.

  6. [Clinical and serologic course of patients with mixed connective tissue disease].

    PubMed

    López-Longo, F J; Fernández, J; Monteagudo, I; Rodríguez-Mahou, M; Sánchez-Atrio, A I; Pérez, T; Escalona, M; González, C M; Lapointe, N; Carreño, L

    1994-09-01

    The so called mixed connective tissue disease (MCTD), continues to be a controversial entity, while some authors considered it a good characterized disease, others think that is an undifferentiated connective tissue disease. OBJECTIVE. To analyse the clinical and serological evolution of a group of patients diagnosed of MCTD, with particular consideration to the meaning of anti-nRNP and anti-Sm antibodies. METHOD. We have studied 20 patients diagnosed of MCTD and 112 with systemic lupus erythematosus (SLE). Anti-nRNP and anti-Sm antibodies were detected through counter immunoelectrophoresis, immunoblotting and ELISA. RESULTS. After an average time of evolution of 10 years, 70% (14/20) of the patients diagnosed of MCTD fulfill criteria for SLE (6 cases), scleroderma (6 cases) or polymyositis (2 cases). Anti-nRNP response is persistent, directed mainly against the 70 Kd and A-nRNP polypeptides and qualitatively higher in MCTD in SLE (absorbencies 2.64 vs 1.25. The immunoblotting test detected anti-Sm antibodies in 5 patients (25%) and ELISA test in 14 (70%). CONCLUSIONS. Clinical and serological evolution suggest that MCTD is an undifferentiated connective tissue disease. Anti-nRNP antibodies are characteristic, although anti-Sm antibodies can be detected with ELISA regardless whether on not patients fulfill SLE criteria.

  7. Interpretation of autoantibody positivity in interstitial lung disease and lung-dominant connective tissue disease*

    PubMed Central

    Pereira, Daniel Antunes Silva; Kawassaki, Alexandre de Melo; Baldi, Bruno Guedes

    2013-01-01

    The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease. PMID:24473767

  8. Different types of connective tissue alterations associated with cervical artery dissections.

    PubMed

    Hausser, Ingrid; Müller, Uta; Engelter, Stefan; Lyrer, Philippe; Pezzini, Alessandro; Padovani, Alessandro; Moormann, Birgit; Busse, Otto; Weber, Ralf; Brandt, Tobias; Grond-Ginsbach, Caspar

    2004-06-01

    This study describes the technical handling and the diagnostic evaluation of skin biopsies in order to standardize the assessment of the delicate morphologic abnormalities that are found in patients with spontaneous cervical artery dissections (sCAD). Skin biopsies from 126 patients with sCAD and from 29 healthy relatives were analyzed. The morphology of the connective tissue was normal in 54 patients with sCAD (43%) and aberrant in 72 patients with sCAD (57%). These latter patients were classified into three groups: in 43 patients, we repeatedly observed composite collagen fibrils and elastic fibers with fragmentation and minicalcifications. In 13 further patients, the dermis was significantly thinner than in healthy subjects. The collagen fibers contained fibrils with highly variable diameters. In a third group of 16 sCAD patients, the abnormalities were restricted to the elastic fibers (with fragmentation and minicalcifications) without significant alterations in the morphology of the collagen fibrils. The finding of different morphologic classes of aberrations among patients suggests that the connective tissue defects are genetically heterogeneous. The segregation of the connective tissue phenotype in three families suggested an autosomal dominant pattern of inheritance.

  9. Connective tissue graft vs. emdogain: A new approach to compare the outcomes

    PubMed Central

    Sayar, Ferena; Akhundi, Nasrin; Gholami, Sanaz

    2013-01-01

    Background: The aim of this clinical trial study was to clinically evaluate the use of enamel matrix protein derivative combined with the coronally positioned flap to treat gingival recession compared to the subepithelial connective tissue graft by a new method to obtain denuded root surface area. Materials and Methods: Thirteen patients, each with two or more similar bilateral Miller class I or II gingival recession (40 recessions) were randomly assigned to the test (enamel matrix protein derivative + coronally positioned flap) or control group (subepithelial connective tissue graft). Recession depth, width, probing depth, keratinized gingival, and plaque index were recorded at baseline and at one, three, and six months after treatment. A stent was used to measure the denuded root surface area at each examination session. Results were analyzed using Kolmogorov-Smirnov, Wilcoxon, Friedman, paired-sample t test. Results: The average percentages of root coverage for control and test groups were 63.3% and 55%, respectively. Both groups showed significant keratinized gingival increase (P < 0.05). Recession depth decreased significantly in both groups. Root surface area was improved significantly from baseline with no significant difference between the two study groups (P > 0.05). The results of Friedman test were significant for clinical indices (P < 0.05), except for probing depth in control group (P = 0.166). Conclusion: Enamel matrix protein derivative showed the same results as subepithelial connective tissue graft with relatively easy procedure to perform and low patient morbidity. PMID:23878562

  10. Promotion of Growth of Tumour Cells in Acutely Inflamed Tissues

    PubMed Central

    van den Brenk, H. A. S.; Stone, M.; Kelly, H.; Orton, C.; Sharpington, C.

    1974-01-01

    Acute inflammatory reactions were induced in rats by the intravenous injection of cellulose sulphate (CS) or an extract of normal rat lung homogenate (LH), or by intraperitoneal injections of Compound 48/80. These treatments greatly increased survival and clonogenic growth in the lungs of rats of intravenously injected allogeneic W-256 and Y-P388 tumour cells. Increase in the dose of intravenously injected CS caused a logarithmic increase in colony forming efficiency (CFE) of tumour cells in the lungs. CFE was not stimulated by the intravenous injection of rats with pharmacological mediators of inflammation (histamine, 5-hydroxytryptamine, bradykinin and prostaglandins PGE1 and PGF2α) which are released from tissues by agents which induce inflammation. Stimulation of CFE by CS occurred in adrenalectomized rats but was inhibited by treatment of rats with an anti-inflammatory steroid, dexamethasone. CFE was stimulated by CS in tumour immunized rats; the inflammatory state did not prevent the expression of immunity but “rescued” a proportion (approximately 20%) of the injected tumour cells from immunodestruction in the lungs. A higher proportion of tumours grew in the paws of rats when a small number of W-256 cells were injected interdigitally into the acute inflammatory swellings produced by the local injection of paws with LH or CS. CS is a “synthetic heparin” which causes marked prolongation of blood clotting time and also increases fibrinolytic activity of the blood. Anticoagulant treatment of rats with heparin did not affect CFE. Thus, there was no direct correlation between blood clotting time and CFE of blood borne tumour cells in the rat. The mechanisms which may be responsible for the nonspecific growth promoting effects of inflammatory reactions induced by various types of tissue injury on tumour induction and growth are discussed. ImagesFig. 2 PMID:4451630

  11. Mineralization and growth of cultured embryonic skeletal tissue in microgravity

    NASA Technical Reports Server (NTRS)

    Klement, B. J.; Spooner, B. S.

    1999-01-01

    Microgravity provides a unique environment in which to study normal and pathological phenomenon. Very few studies have been done to examine the effects of microgravity on developing skeletal tissue such as growth plate formation and maintenance, elongation of bone primordia, or the mineralization of growth plate cartilage. Embryonic mouse premetatarsal triads were cultured on three space shuttle flights to study cartilage growth, differentiation, and mineralization, in a microgravity environment. The premetatarsal triads that were cultured in microgravity all formed cartilage rods and grew in length. However, the premetatarsal cartilage rods cultured in microgravity grew less in length than the ground control cartilage rods. Terminal chondrocyte differentiation also occurred during culture in microgravity, as well as in the ground controls, and the matrix around the hypertrophied chondrocytes was capable of mineralizing in both groups. The same percentage of premetatarsals mineralized in the microgravity cultures as mineralized in the ground control cultures. In addition, the sizes of the mineralized areas between the two groups were very similar. However, the amount of 45Ca incorporated into the mineralized areas was significantly lower in the microgravity cultures, suggesting that the composition or density of the mineralized regions was compromised in microgravity. There was no significant difference in the amount of 45Ca liberated from prelabeled explants in microgravity or in the ground controls.

  12. Repair of dense connective tissues via biomaterial-mediated matrix reprogramming of the wound interface.

    PubMed

    Qu, Feini; Pintauro, Michael P; Haughan, Joanne E; Henning, Elizabeth A; Esterhai, John L; Schaer, Thomas P; Mauck, Robert L; Fisher, Matthew B

    2015-01-01

    Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues.

  13. Repair of Dense Connective Tissues via Biomaterial-Mediated Matrix Reprogramming of the Wound Interface

    PubMed Central

    Qu, Feini; Pintauro, Michael P.; Haughan, Joanne; Henning, Elizabeth A.; Esterhai, John L.; Schaer, Thomas P.; Mauck, Robert L.; Fisher, Matthew B.

    2014-01-01

    Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues. PMID:25477175

  14. High elastic modulus nanoparticles: a novel tool for subfailure connective tissue matrix damage.

    PubMed

    Empson, Yvonne M; Ekwueme, Emmanuel C; Hong, Jung K; Paynter, Danielle M; Kwansa, Albert L; Brown, Chalmers; Pekkanen, Allison M; Roman, Maren; Rylander, Nichole M; Brolinson, Gunnar P; Freeman, Joseph W

    2014-09-01

    Subfailure matrix injuries such as sprains and strains account for a considerable portion of ligament and tendon pathologies. In addition to the lack of a robust biological healing response, these types of injuries are often characterized by seriously diminished matrix biomechanics. Recent work has shown nanosized particles, such as nanocarbons and nanocellulose, to be effective in modulating cell and biological matrix responses for biomedical applications. In this article, we investigate the feasibility and effect of using high stiffness nanostructures of varying size and shape as nanofillers to mechanically reinforce damaged soft tissue matrices. To this end, nanoparticles (NPs) were characterized using atomic force microscopy and dynamic light scattering techniques. Next, we used a uniaxial tensile injury model to test connective tissue (porcine skin and tendon) biomechanical response to NP injections. After injection into damaged skin and tendon specimens, the NPs, more notably nanocarbons in skin, led to an increase in elastic moduli and yield strength. Furthermore, rat primary patella tendon fibroblast cell activity evaluated using the metabolic water soluble tetrazolium salt assay showed no cytotoxicity of the NPs studied, instead after 21 days nanocellulose-treated tenocytes exhibited significantly higher cell activity when compared with nontreated control tenocytes. Dispersion of nanocarbons injected by solution into tendon tissue was investigated through histologic studies, revealing effective dispersion and infiltration in the treated region. Such results suggest that these high modulus NPs could be used as a tool for damaged connective tissue repair.

  15. Connective tissue reaction of rats to a new zinc-oxide-eugenol endodontic sealer.

    PubMed

    Trichês, Karen Melina; Júnior, Jacy Simi; Calixto, João Batista; Machado, Ricardo; Rosa, Tiago Pereira; Silva, Emmanuel João Nogueira Leal; Vansan, Luiz Pascoal

    2013-12-01

    The aim of this study was to evaluate the biocompatibility in rat subcutaneous connective tissue of a new zinc oxide endodontic sealer (Endomethasone N) compared to those provided by Endofill and Sealer 26. Polyethylene tubes containing the test materials were implanted into dorsal subcutaneous connective tissue of Wistar albino rats. After 7 and 42 days, the implants with the surrounding tissue were collected, fixed, and processed for histologic evaluation. Sections were evaluated for the presence of inflammatory cells (poly or monomorfonuclear), blood vessels, necrosis area, and thickness of fibrous capsule. Comparisons between groups and time-periods were performed with Kruskal-Wallis and Mann-Whitney U non-parametric tests for 5% significance level. No differences in the biocompatibility patterns among the materials for the 2 experimental periods were observed. Independently of the sealer, the tissue behavior showed a tendency to decrease the irritation effect over time. It can be concluded that all sealers are irritant, but its toxicity decreased with time. Endomethásone N showed biocompatible characteristics comparable with those provided by Endofill and Sealer 26.

  16. Repair of dense connective tissues via biomaterial-mediated matrix reprogramming of the wound interface.

    PubMed

    Qu, Feini; Pintauro, Michael P; Haughan, Joanne E; Henning, Elizabeth A; Esterhai, John L; Schaer, Thomas P; Mauck, Robert L; Fisher, Matthew B

    2015-01-01

    Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues. PMID:25477175

  17. Direct microCT imaging of non-mineralized connective tissues at high resolution.

    PubMed

    Naveh, Gili R S; Brumfeld, Vlad; Dean, Mason; Shahar, Ron; Weiner, Steve

    2014-01-01

    The 3D imaging of soft tissues in their native state is challenging, especially when high resolution is required. An X-ray-based microCT is, to date, the best choice for high resolution 3D imaging of soft tissues. However, since X-ray attenuation of soft tissues is very low, contrasting enhancement using different staining materials is needed. The staining procedure, which also usually involves tissue fixation, causes unwanted and to some extent unknown tissue alterations. Here, we demonstrate that a method that enables 3D imaging of soft tissues without fixing and staining using an X-ray-based bench-top microCT can be applied to a variety of different tissues. With the sample mounted in a custom-made loading device inside a humidity chamber, we obtained soft tissue contrast and generated 3D images of fresh, soft tissues with a resolution of 1 micron voxel size. We identified three critical conditions which make it possible to image soft tissues: humidified environment, mechanical stabilization of the sample and phase enhancement. We demonstrate the capability of the technique using different specimens: an intervertebral disc, the non-mineralized growth plate, stingray tessellated radials (calcified cartilage) and the collagenous network of the periodontal ligament. Since the scanned specimen is fresh an interesting advantage of this technique is the ability to scan a specimen under load and track the changes of the different structures. This method offers a unique opportunity for obtaining valuable insights into 3D structure-function relationships of soft tissues.

  18. Direct microCT imaging of non-mineralized connective tissues at high resolution.

    PubMed

    Naveh, Gili R S; Brumfeld, Vlad; Dean, Mason; Shahar, Ron; Weiner, Steve

    2014-01-01

    The 3D imaging of soft tissues in their native state is challenging, especially when high resolution is required. An X-ray-based microCT is, to date, the best choice for high resolution 3D imaging of soft tissues. However, since X-ray attenuation of soft tissues is very low, contrasting enhancement using different staining materials is needed. The staining procedure, which also usually involves tissue fixation, causes unwanted and to some extent unknown tissue alterations. Here, we demonstrate that a method that enables 3D imaging of soft tissues without fixing and staining using an X-ray-based bench-top microCT can be applied to a variety of different tissues. With the sample mounted in a custom-made loading device inside a humidity chamber, we obtained soft tissue contrast and generated 3D images of fresh, soft tissues with a resolution of 1 micron voxel size. We identified three critical conditions which make it possible to image soft tissues: humidified environment, mechanical stabilization of the sample and phase enhancement. We demonstrate the capability of the technique using different specimens: an intervertebral disc, the non-mineralized growth plate, stingray tessellated radials (calcified cartilage) and the collagenous network of the periodontal ligament. Since the scanned specimen is fresh an interesting advantage of this technique is the ability to scan a specimen under load and track the changes of the different structures. This method offers a unique opportunity for obtaining valuable insights into 3D structure-function relationships of soft tissues. PMID:24437605

  19. The Effect of Connective Tissue Material Uncertainties on Knee Joint Mechanics under Isolated Loading Conditions

    PubMed Central

    Dhaher, Yasin Y.; Kwon, Tae-Hyun; Barry, Megan

    2012-01-01

    Although variability in connective tissue parameters is widely reported and recognized, systematic examination of the effect of such parametric uncertainties on predictions derived from a full anatomical joint model is lacking. As such, a sensitivity analysis was performed to consider the behavior of a three-dimensional, non-linear, finite element knee model with connective tissue material parameters that varied within a given interval. The model included the coupled mechanics of the tibio-femoral and patellofemoral degrees of freedom. Seven primary connective tissues modeled as nonlinear continua, articular cartilages described by a linear elastic model, and menisci modeled as transverse isotropic elastic materials were included. In this study, a multi-factorial global sensitivity analysis is proposed, which can detect the contribution of influential material parameters while maintaining the potential effect of parametric interactions. To illustrate the effect of material uncertainties on model predictions, exemplar loading conditions reported in a number of isolated experimental paradigms were used. Our findings illustrated that the inclusion of material uncertainties in a coupled tibio-femoral and patello-femoral model reveals biomechanical interactions that otherwise would remain unknown. For example, our analysis revealed that the effect of anterior cruciate ligament parameter variations on the patello-femoral kinematic and kinetic response sensitivities were significantly larger, over a range of flexion angles, when compared to variations associated with material parameters of tissues intrinsic to the patello-femoral joint. We argue that the systematic sensitivity framework presented herein will help identify key material uncertainties that merit further research, as well as provide insight on those uncertainties that may not be as relative to a given response. PMID:20810114

  20. The effect of connective tissue material uncertainties on knee joint mechanics under isolated loading conditions.

    PubMed

    Dhaher, Yasin Y; Kwon, Tae-Hyun; Barry, Megan

    2010-12-01

    Although variability in connective tissue parameters is widely reported and recognized, systematic examination of the effect of such parametric uncertainties on predictions derived from a full anatomical joint model is lacking. As such, a sensitivity analysis was performed to consider the behavior of a three-dimensional, non-linear, finite element knee model with connective tissue material parameters that varied within a given interval. The model included the coupled mechanics of the tibio-femoral and patello-femoral degrees of freedom. Seven primary connective tissues modeled as non-linear continua, articular cartilages described by a linear elastic model, and menisci modeled as transverse isotropic elastic materials were included. In this study, a multi-factorial global sensitivity analysis is proposed, which can detect the contribution of influential material parameters while maintaining the potential effect of parametric interactions. To illustrate the effect of material uncertainties on model predictions, exemplar loading conditions reported in a number of isolated experimental paradigms were used. Our findings illustrated that the inclusion of material uncertainties in a coupled tibio-femoral and patello-femoral model reveals biomechanical interactions that otherwise would remain unknown. For example, our analysis revealed that the effect of anterior cruciate ligament parameter variations on the patello-femoral kinematic and kinetic response sensitivities was significantly larger, over a range of flexion angles, when compared to variations associated with material parameters of tissues intrinsic to the patello-femoral joint. We argue that the systematic sensitivity framework presented herein will help identify key material uncertainties that merit further research and provide insight on those uncertainties that may not be as relative to a given response.

  1. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins.

    PubMed

    Halper, Jaroslava; Kjaer, Michael

    2014-01-01

    Collagens are the most abundant components of the extracellular matrix and many types of soft tissues. Elastin is another major component of certain soft tissues, such as arterial walls and ligaments. Many other molecules, though lower in quantity, function as essential components of the extracellular matrix in soft tissues. Some of these are reviewed in this chapter. Besides their basic structure, biochemistry and physiology, their roles in disorders of soft tissues are discussed only briefly as most chapters in this volume deal with relevant individual compounds. Fibronectin with its muldomain structure plays a role of "master organizer" in matrix assembly as it forms a bridge between cell surface receptors, e.g., integrins, and compounds such collagen, proteoglycans and other focal adhesion molecules. It also plays an essential role in the assembly of fibrillin-1 into a structured network. Laminins contribute to the structure of the extracellular matrix (ECM) and modulate cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis. Though the primary role of fibrinogen is in clot formation, after conversion to fibrin by thrombin, it also binds to a variety of compounds, particularly to various growth factors, and as such fibrinogen is a player in cardiovascular and extracellular matrix physiology. Elastin, an insoluble polymer of the monomeric soluble precursor tropoelastin, is the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of TGFβs through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Mutations in the elastin gene lead to cutis laxa. Fibrillins represent the predominant core of the microfibrils in elastic as well as non

  2. Visceral tissue growth and proliferation during the bovine lactation cycle.

    PubMed

    Baldwin, R L; McLeod, K R; Capuco, A V

    2004-09-01

    Twenty one multiparous, nonpregnant, lactating dairy cows were used to assess the impact of stage of lactation on visceral tissue mass and small intestinal cell proliferation. Cows were slaughtered at each of 4 stages of lactation: 14, 90, 120, and 240 d of lactation. With stage of lactation, DMI increased through d 90 and thereafter remained similar through d 240 (quadratic). Carcass weight and empty body weight (EBW) declined with stage of lactation through d 120 and increased thereafter (quadratic). As a percentage of EBW, rumen, small intestine, and liver weights increased with increasing stage of lactation (quadratic), increasing from 14 to 120 d and declining through 240 d. Stage of lactation did not have a measurable affect on reticulum, omasum, abomasum, or large intestine weights as a percentage of EBW. Visceral adipose mass as a percentage of EBW declined with stage of lactation to a minimum at 120 d and increased by 240 d (quadratic). Concentrations of RNA and DNA of digestive tract organs were largely unaffected by stage of lactation with the exception of the liver DNA concentration through d 120 (quadratic). The proliferative growth fraction (Ki67) was unaffected by stage of lactation. However, bromo-deoxyuridine labeling of jejunal crypts exhibited a cubic response with stage of lactation and tritiated thymidine incorporation by duodenal epithelium increased with stage of lactation through d 120, declining thereafter (quadratic). Mass of visceral tissues increase to meet the energetic demands of lactation and that increased absorption capacity of the intestines is achieved by hyperplastic growth of the intestinal epithelium.

  3. Fourier transform infrared imaging and infrared fiber optic probe spectroscopy identify collagen type in connective tissues.

    PubMed

    Hanifi, Arash; McCarthy, Helen; Roberts, Sally; Pleshko, Nancy

    2013-01-01

    Hyaline cartilage and mechanically inferior fibrocartilage consisting of mixed collagen types are frequently found together in repairing articular cartilage. The present study seeks to develop methodology to identify collagen type and other tissue components using Fourier transform infrared (FTIR) spectral evaluation of matrix composition in combination with multivariate analyses. FTIR spectra of the primary molecular components of repair cartilage, types I and II collagen, and aggrecan, were used to develop multivariate spectral models for discrimination of the matrix components of the tissues of interest. Infrared imaging data were collected from bovine bone, tendon, normal cartilage, meniscus and human repair cartilage tissues, and composition predicted using partial least squares analyses. Histology and immunohistochemistry results were used as standards for validation. Infrared fiber optic probe spectral data were also obtained from meniscus (a tissue with mixed collagen types) to evaluate the potential of this method for identification of collagen type in a minimally-invasive clinical application. Concentration profiles of the tissue components obtained from multivariate analysis were in excellent agreement with histology and immunohistochemistry results. Bone and tendon showed a uniform distribution of predominantly type I collagen through the tissue. Normal cartilage showed a distribution of type II collagen and proteoglycan similar to the known composition, while in repair cartilage, the spectral distribution of both types I and II collagen were similar to that observed via immunohistochemistry. Using the probe, the outer and inner regions of the meniscus were shown to be primarily composed of type I and II collagen, respectively, in accordance with immunohistochemistry data. In summary, multivariate analysis of infrared spectra can indeed be used to differentiate collagen type I and type II, even in the presence of proteoglycan, in connective tissues

  4. Fibroblast growth factors as tissue repair and regeneration therapeutics.

    PubMed

    Nunes, Quentin M; Li, Yong; Sun, Changye; Kinnunen, Tarja K; Fernig, David G

    2016-01-01

    Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West. PMID:26793421

  5. Fibroblast growth factors as tissue repair and regeneration therapeutics

    PubMed Central

    Kinnunen, Tarja K.

    2016-01-01

    Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West. PMID:26793421

  6. CONDITIONS GOVERNING THE GROWTH OF DISPLACED NORMAL TISSUE.

    PubMed

    Craster, C V

    1912-10-01

    We are unwilling to draw any very definite conclusions from the experiments, partly because they show a survival of implanted skin of so much shorter duration than that which seems to occur in the case of spontaneous implantation cysts, and partly because the method of reëxposing the submerged grafts is rather a crude way of testing their vitality. Nevertheless, the following points seem clear: 1. The repeated transplantation of a piece of skin from one animal to another confers no exceptional power of growth upon that skin. 2. The repeated implantation of skin into one animal decreases, if anything, its receptivity for such grafts. 3. The burial of skin in the interior of the body causes, after a time, a change in the skin of such a nature that it cannot resume its normal function as an external covering tissue, even when its circulation \\ is well maintained and it is buried in the body of the same animal. The experiments do not determine how long the cells of the skin actually remain alive, and indeed it is conceivable that the mere maceration of the protective horny layer puts the skin, when reëxposed, into the position of a moist tissue, such as the intestinal mucosa, so that it readily dries up and succumbs. Nor do the experiments throw any light upon the possible existence of cytolytic substances in the circulating fluids, although, naturally, the idea of such an action has always been present in our minds in observing the gradual loss of vitality in the transplanted tissues.

  7. Differences in infrared spectroscopic data of connective tissues in transflectance and transmittance modes.

    PubMed

    Hanifi, Arash; McGoverin, Cushla; Ou, Ya-Ting; Safadi, Fayez; Spencer, Richard G; Pleshko, Nancy

    2013-05-24

    Fourier transform infrared imaging spectroscopy (FT-IRIS) has been used extensively to characterize the composition and orientation of macromolecules in thin tissue sections. Earlier and current studies of normal and polarized FT-IRIS data have primarily used tissues sectioned onto infrared transmissive substrates, such as salt windows. Recently, the use of low-emissivity ("low-e") substrates has become of great interest because of their low cost and favorable infrared optical properties. However, data are collected in transflectance mode when using low-e slides and in transmittance mode using salt windows. In the current study we investigated the comparability of these two modes for assessment of the composition of connective tissues. FT-IRIS data were obtained in transflectance and transmittance modes from serial sections of cartilage, bone and tendon, and from a standard polymer, polymethylmethacrylate. Both non-polarized and polarized FTIR data differed in absorbance, and in some cases peak position, between transflectance and transmittance modes. However, the FT-IRIS analysis of the collagen fibril orientation in cartilage resulted in the expected zonal arrangement of fibrils in both transmittance and transflectance. We conclude that numerical comparison of FT-IRIS-derived parameters of tissue composition should account for substrate type and data collection mode, while analysis of overall tissue architecture may be more invariant between modes.

  8. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD).

    PubMed

    Ohno, Yoshiharu; Koyama, Hisanobu; Yoshikawa, Takeshi; Seki, Shinichiro

    2015-12-01

    Involvement of the respiratory system is common in connective tissue diseases (CTDs), and the resultant lung injury can affect every part of the lung: the pleura, alveoli, interstitium, vasculature, lymphatic tissue, and large and/or small airways. Most of the parenchymal manifestations of CTD are similar to those found in interstitial lung diseases (ILDs), especially idiopathic interstitial pneumonias, and can be classified using the same system. Although there is some overlap, each CTD is associated with a characteristic pattern of pulmonary involvement. For this reason, thin-section CT as well as pulmonary function tests and serum markers are utilized for diagnosis, disease severity assessment, and therapeutic efficacy evaluation of ILD associated with CTD. In addition, newly developed pulmonary magnetic resonance imaging (MRI) procedures have been recommended as useful alternative imaging options for patients with CTD. This review article will (1) address radiological findings for chest radiography and conventional or thin-section CT currently used for six major types of CTD, rheumatoid arthritis, scleroderma (progressive systemic sclerosis), polymyositis/dermatomyositis, systemic lupus erythematosus, Sjögren syndrome and mixed connective tissue disease; (2) briefly deal with radiation dose reduction for thin-section CT examination; and (3) discuss clinically applicable or state-of-the-art MR imaging for CTD patients.

  9. Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions

    PubMed Central

    Monument, Michael J.; Hart, David A.; Salo, Paul T.; Befus, A. Dean; Hildebrand, Kevin A.

    2015-01-01

    Significance: The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. Recent Advances: As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell-myofibroblast signaling pathway. Critical Issues: The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Future Directions: Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies. PMID:25785237

  10. The action of vitamin E on the ageing of connective tissues in the mouse.

    PubMed

    Blackett, A D; Hall, D A

    1980-01-01

    In an attempt to determine the relevance of the free radical theory of ageing to age changes discernible in connective tissue parameters, a small colony of C3H/He and LAF1 mice was set up, with sample culled at intervals throughout the lifespan to provide experimental samples. To half of the stock a dietary supplement of vitamin E, a naturally occurring antioxidant, was given at a level of 2500 mg/kg of diet. Tests were carried out on culled samples to provide data on the total collagen levels of bone and skin, on thermal shrinkage temperature and maximal degree of shrinkage of tendon fibres, and on the recovery of skin from stress. Vitamin E was found to have no effect on any of the parameters measured on C3H/He mice but to exert an influence on the parameters of LAF1 mice around the age of 10 months. This influence, however, is not regarded as being relevant to the ageing of the tissues and thus no evidence can be derived for a free-radical mechanism playing a role in the ageing of connective tissues.

  11. Resorption of elastic fibers in monkey gingival connective tissue: ultrastructural and immunocytochemical evidence.

    PubMed

    Sawada, Takashi

    2011-04-01

    Little is known about the remodeling of elastic fibers in gingival connective tissue. In this study, elastic fibers in the lamina propria of monkey gingiva were examined by transmission electron microscopy and immunocytochemistry. Some elastic fibers were localized at invagination on the surface of the narrow processes of fibroblasts distributed among dense assemblies of collagen fibrils, and also within coated pits, which were pinching off as coated vesicles. At a higher magnification, the coated vesicles contained filamentous structures, as well as pentagonal structures similar those previously reported in elastic fibers. Immunoelectron microscopy demonstrated positive staining for fibrillin, one of the main components of microfibril, localized either in the coated pits or vesicles. These observations indicate that at least some elastic fibers were resorbed by fibroblasts, and that, in spite of the general belief that little remodeling of elastic fibers occurs under normal conditions, resorption of elastic fibers does occur in monkey gingival connective tissue. The functional significance of this is not yet clear, but it may be involved in facilitating the delicate and efficient adaptation of tissue to physical requirements during mastication.

  12. Multimodal and Multi-tissue Measures of Connectivity Revealed by Joint Independent Component Analysis

    PubMed Central

    Ling, Josef; Caprihan, Arvind; Calhoun, Vince D.; Jung, Rex E.; Heileman, Gregory L.

    2009-01-01

    The human brain functions as an efficient system where signals arising from gray matter are transported via white matter tracts to other regions of the brain to facilitate human behavior. However, with a few exceptions, functional and structural neuroimaging data are typically optimized to maximize the quantification of signals arising from a single source. For example, functional magnetic resonance imaging (FMRI) is typically used as an index of gray matter functioning whereas diffusion tensor imaging (DTI) is typically used to determine white matter properties. While it is likely that these signals arising from different tissue sources contain complementary information, the signal processing algorithms necessary for the fusion of neuroimaging data across imaging modalities are still in a nascent stage. In the current paper we present a data-driven method for combining measures of functional connectivity arising from gray matter sources (FMRI resting state data) with different measures of white matter connectivity (DTI). Specifically, a joint independent component analysis (J-ICA) was used to combine these measures of functional connectivity following intensive signal processing and feature extraction within each of the individual modalities. Our results indicate that one of the most predominantly used measures of functional connectivity (activity in the default mode network) is highly dependent on the integrity of white matter connections between the two hemispheres (corpus callosum) and within the cingulate bundles. Importantly, the discovery of this complex relationship of connectivity was entirely facilitated by the signal processing and fusion techniques presented herein and could not have been revealed through separate analyses of both data types as is typically performed in the majority of neuroimaging experiments. We conclude by discussing future applications of this technique to other areas of neuroimaging and examining potential limitations of the

  13. Familial occurrence and heritable connective tissue disorders in cervical artery dissection

    PubMed Central

    Goeggel Simonetti, Barbara; Schilling, Sabrina; Martin, Juan José; Kloss, Manja; Sarikaya, Hakan; Hausser, Ingrid; Engelter, Stefan; Metso, Tiina M.; Pezzini, Alessandro; Thijs, Vincent; Touzé, Emmanuel; Paolucci, Stefano; Costa, Paolo; Sessa, Maria; Samson, Yves; Béjot, Yannick; Altintas, Ayse; Metso, Antti J.; Hervé, Dominique; Lichy, Christoph; Jung, Simon; Fischer, Urs; Lamy, Chantal; Grau, Armin; Chabriat, Hugues; Caso, Valeria; Lyrer, Philippe A.; Stapf, Christian; Tatlisumak, Turgut; Brandt, Tobias; Tournier-Lasserve, Elisabeth; Germain, Dominique P.; Frank, Michael; Baumgartner, Ralf W.; Grond-Ginsbach, Caspar; Bousser, Marie-Germaine; Leys, Didier; Dallongeville, Jean; Bersano, Anna

    2014-01-01

    Objective: In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders. Methods: We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups. Results: Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%–1.5%) from 17 families (0.9%, 0.5%–1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only. Conclusions: In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases. PMID:25355833

  14. Antinuclear antibodies in scleroderma, mixed connective tissue disease and "primary" Raynaud's phenomenon.

    PubMed

    Cruz, M; Mejia, G; Lavalle, C; Cortes, J J; Reyes, P A

    1988-03-01

    The diversity of antibodies in patients with scleroderma, mixed connective tissue disease or "primary" Raynaud's phenomenon could be used as a laboratory aid in the clinical diagnosis. In serum samples of 75 patients we screened for antinuclear antibodies (HEp 2 cells), anti DNA, soluble nucleoprotein and extractable nuclear antigens (Sm, rRNP, U1-nRNP, SSA/Ro, SSB/La and Scl-70). Distinctive antinuclear antibodies pattern was identified in each group of patients. This immunologic profile is valuable for clinical diagnosis and the preferential association of certain autoantibodies with some diseases and not with others, suggest an antigen-driven stimulus for its production.

  15. Biological effects of hyaluronan in connective tissues, eye, skin, venous wall. Role in aging.

    PubMed

    Robert, L; Robert, A-M; Renard, G

    2010-06-01

    Hyaluronan, as most macromolecules of the extracellular matrix, are produced by the differentiated mesenchymal cells. These cells produce also enzymes degrading hyaluronan. This results in the presence of several hyaluronan pools of different molecular weights, all capable of interacting with surrounding cells, mediated by hyaluronan binding proteins and receptors. These interactions modulate cell phenotype and produce a variety of effects conditioning the specific functions of tissues. We shall discuss here several examples studied in our laboratory, concerning skin, cornea and the venous wall. Some of these actions might even be harmful, and could play an important role in aging of connective tissues with loss of function. Some of these age-dependent modifications mediated by hyaluronan will be reviewed and commented, especially the upregulation of matrix degrading enzymes as MMP-2 and MMP-9. We shall also mention some of our experiments for finding molecules capable of counteracting the harmful effects mediated by hyaluronan.

  16. The muscular force transmission system: role of the intramuscular connective tissue.

    PubMed

    Turrina, Andrea; Martínez-González, Miguel Antonio; Stecco, Carla

    2013-01-01

    The objective of this review is to analyze in detail the microscopic structure and relations among muscular fibers, endomysium, perimysium, epimysium and deep fasciae. In particular, the multilayer organization and the collagen fiber orientation of these elements are reported. The endomysium, perimysium, epimysium and deep fasciae have not just a role of containment, limiting the expansion of the muscle with the disposition in concentric layers of the collagen tissue, but are fundamental elements for the transmission of muscular force, each one with a specific role. From this review it appears that the muscular fibers should not be studied as isolated elements, but as a complex inseparable from their fibrous components. The force expressed by a muscle depends not only on its anatomical structure, but also the angle at which its fibers are attached to the intramuscular connective tissue and the relation with the epimysium and deep fasciae.

  17. Mutation of fibulin-1 causes a novel syndrome involving the central nervous system and connective tissues.

    PubMed

    Bohlega, Saeed; Al-Ajlan, Huda; Al-Saif, Amr

    2014-05-01

    Fibulin-1 is an extracellular matrix protein that has an important role in the structure of elastic fibers and basement membranes of various tissues. Using homozygosity mapping and exome sequencing, we discovered a missense mutation, p.(Cys397Phe), in fibulin-1 in three patients from a consanguineous family presented with a novel syndrome of syndactyly, undescended testes, delayed motor milestones, mental retardation and signs of brain atrophy. The mutation discovered segregated with the phenotype and was not found in 374 population-matched alleles. The affected cysteine is highly conserved across vertebrates and its mutation is predicted to abolish a disulfide bond that defines the tertiary structure of fibulin-1. Our findings emphasize the crucial role fibulin-1 has in development of the central nervous system and various connective tissues.

  18. [Connective tissue dysplasia in patients with celiac desease as a problem of violation of adaptation reserve islands of the body].

    PubMed

    Tkachenko, E; Oreshko, L S; Soloveva, E A; Shabanova, A A; Zhuravleva, M S

    2015-01-01

    Clinically significant dysplasia of connective tissue in patients with celiac disease is often responsible for various visceral disorders. Different disturbances of motor and evacuation functions are often determined in this patients (gastroesophageal reflux, duodenogastral reflux, spastic and hyperkinetic dyskinesia). The clinical course of the celiac disease, associated with connective tissue dysplasia, is characterized by asthenovegetative syndrome, reduced tolerance to physical activity, general weakness, fatigue and emotional instability. These data should be considered in choosing a treatment. PMID:25993866

  19. Meat Science and Muscle Biology Symposium: manipulating meat tenderness by increasing the turnover of intramuscular connective tissue.

    PubMed

    Purslow, P P; Archile-Contreras, A C; Cha, M C

    2012-03-01

    Controlled reduction of the connective tissue contribution to cooked meat toughness is an objective that would have considerable financial impact in terms of added product value. The amount of intramuscular connective tissue in a muscle appears connected to its in vivo function, so reduction of the overall connective tissue content is not thought to be a viable target. However, manipulation of the state of maturity of the collagenous component is a biologically viable target; by increasing connective tissue turnover, less mature structures can be produced that are functional in vivo but more easily broken down on cooking at temperatures above 60°C, thus improving cooked meat tenderness. Recent work using cell culture models of fibroblasts derived from muscle and myoblasts has identified a range of factors that alter the activity of the principal enzymes responsible for connective tissue turnover, the matrix metalloproteinases (MMP). Fibroblasts cultured from 3 different skeletal muscles from the same animal show different cell proliferation and MMP activity, which may relate to the different connective tissue content and architecture in functionally different muscles. Expression of MMP by fibroblasts is increased by vitamins that can counter the negative effects of oxidative stress on new collagen synthesis. Preliminary work using in situ zymography of myotubes in culture also indicates increased MMP activity in the presence of epinephrine and reactive oxidative species. Comparison of the relative changes in MMP expression from muscle cells vs. fibroblasts shows that myoblasts are more responsive to a range of stimuli. Muscle cells are likely to produce more of the total MMP in muscle tissue as a whole, and the expression of latent forms of the enzymes (i.e., pro-MMP) may vary between oxidative and glycolytic muscle fibers within the same muscle. The implication is that the different muscle fiber composition of different muscles eaten as meat may influence the

  20. Clinical ultrashort echo time imaging of bone and other connective tissues.

    PubMed

    Robson, Matthew D; Bydder, Graeme M

    2006-11-01

    The background underpinning the clinical use of ultrashort echo time, SPRITE and other pulse sequences for imaging bone and other connective tissues with short T2 is reviewed. Features of the basic physics relevant to UTE imaging are described, including the consequences when the radiofrequency pulse duration is of the order of T2 so that rotation of tissue magnetization into the transverse plane is incomplete. Consequences of the broad linewidth of short T2 components are also discussed, including partial saturation by off-resonance fat suppression pulses as well as those used in multislice and multiecho imaging. The need for rapid data acquisition of the order of T2 is explained. The basic two-dimensional UTE pulse sequence with its half excitation pulse and radial imaging from the centre of k-space is described, together with options that suppress fat and/or reduce the signal from long T2 components. The basic features of SPRITE and other sequences with very short TE are described. Image interpretation is discussed. Clinical features of the imaging of cortical bone, tendons, ligaments, menisci, periosteum and the spine are illustrated. The source of the short T2 signal in these tissues is predominantly collagen and water tightly bound to collagen. Short T2 components in all of these tissues are detectible and may show high signals. Possible future developments are outlined, as are technical limitations of clinical magnetic resonance systems. PMID:17075960

  1. Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues.

    PubMed

    Klement, John F; Matsuzaki, Yasushi; Jiang, Qiu-Jie; Terlizzi, Joseph; Choi, Hae Young; Fujimoto, Norihiro; Li, Kehua; Pulkkinen, Leena; Birk, David E; Sundberg, John P; Uitto, Jouni

    2005-09-01

    Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6(-/-) mice but was not observed in Abcc6(+/-) or Abcc6(+/+) mice up to 2 years of age. A total body computerized tomography scan of Abcc6(-/-) mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease.

  2. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain.

    PubMed

    Castori, Marco; Morlino, Silvia; Ghibellini, Giulia; Celletti, Claudia; Camerota, Filippo; Grammatico, Paola

    2015-03-01

    Ehlers-Danlos syndrome (EDS) is an umbrella term for a growing group of hereditary disorders of the connective tissue mainly manifesting with generalized joint hypermobility, skin hyperextensibility, and vascular and internal organ fragility. In contrast with other well known heritable connective tissue disorders with severe cardiovascular involvement (e.g., Marfan syndrome), most EDS patients share a nearly normal life span, but are severely limited by disabling features, such as pain, fatigue and headache. In this work, pertinent literature is reviewed with focus on prevalence, features and possible pathogenic mechanisms of headache in EDSs. Gathered data are fragmented and generally have a low level of evidence. Headache is reported in no less than 1/3 of the patients. Migraine results the most common type in the hypermobility type of EDS. Other possibly related headache disorders include tension-type headache, new daily persistent headache, headache attributed to spontaneous cerebrospinal fluid leakage, headache secondary to Chiari malformation, cervicogenic headache and neck-tongue syndrome, whose association still lacks of reliable prevalence studies. The underlying pathogenesis seems complex and variably associated with cardiovascular dysautonomia, cervical spine and temporomandibular joint instability/dysfunction, meningeal fragility, poor sleep quality, pain-killer drugs overuse and central sensitization. Particular attention is posed on a presumed subclinical cervical spine dysfunction. Standard treatment is always symptomatic and usually unsuccessful. Assessment and management procedures are discussed in order to put some basis for ameliorating the actual patients' needs and nurturing future research. PMID:25655119

  3. Evaluation of muscular lesions in connective tissue diseases: thallium 201 muscular scans

    SciTech Connect

    Guillet, G.; Guillet, J.; Sanciaume, C.; Maleville, J.; Geniaux, M.; Morin, P.

    1988-04-01

    We performed thallium 201 muscle scans to assess muscular involvement in 40 patients with different connective tissue diseases (7 with dermatomyositis, 7 with systemic lupus erythematosus, 12 with progressive systemic scleroderma, 2 with calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome, 3 with monomelic scleroderma, 6 with morphea, and 3 with Raynaud's disease). Only 12 of these patients complained of fatigability and/or myalgia. Electromyography was performed and serum levels of muscle enzymes were measured in all patients. Comparison of thallium 201 exercise recording with the other tests revealed that scan sensitivity is greater than electromyographic and serum muscle enzymes levels. Thallium 201 scans showed abnormal findings in 32 patients and revealed subclinical lesions in 18 patients, while electromyography findings were abnormal in 25 of these 32 patients. Serum enzyme levels were raised in only 8 patients. Thallium 201 scanning proved to be a useful guide for modifying therapy when laboratory data were conflicting. It was useful to evaluate treatment efficacy. Because our data indicate a 100% positive predictive value, we believe that thallium 201 scanning should be advised for severe systemic connective tissue diseases with discordant test results.

  4. SY 11-4 CONNECTIVE TISSUE DISEASE AND ITS ASSOCIATION WITH ARTERIAL HYPERTENSION.

    PubMed

    Ryan, Michael J

    2016-09-01

    Connective tissue diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and scleroderma, have a strong predilection for women and are associated with a marked increase in the prevalence of hypertension. The mechanisms leading to the increased risk of hypertension in these patients remain unclear; however, they are likely related to immune mediated changes in cardiovascular and renal function. Over the past several years, we have elucidated a number of factors that contribute to the development of hypertension during SLE using a widely established experimental model of SLE, the female NZBWF1 mouse. These factors include impaired systemic vascular function, altered renal hemodynamics, and increased oxidative stress and inflammatory cytokines. Recent work from our laboratory has focused on identifying fundamental immunological changes during SLE that ultimately lead to increased cardiovascular risk. This presentation will review clinical and basic evidence for the risk of hypertension during connective tissue diseases and provide experimental evidence that autoantibodies have a central mechanistic role in the pathogenesis of hypertension associated with SLE. PMID:27643119

  5. Alveolar Ridge Contouring with Free Connective Tissue Graft at Implant Placement: A 5-Year Consecutive Clinical Study.

    PubMed

    Hanser, Thomas; Khoury, Fouad

    2016-01-01

    This study evaluated volume stability after alveolar ridge contouring with free connective tissue grafts at implant placement in single-tooth gaps. A total of 52 single-tooth gaps with labial volume deficiencies in the maxilla (incisors, canines, and premolars) were consecutively treated with implants and concomitant free palatal connective tissue grafts in 46 patients between 2006 and 2009. Implants had to be covered with at least 2 mm peri-implant local bone after insertion. At implant placement, a free connective tissue graft from the palate was fixed inside a labial split-thickness flap to form an existing concave buccal alveolar ridge contour due to tissue volume deficiency into a convex shape. Standardized volumetric measurements of the labial alveolar contour using a template were evaluated before connective tissue grafting and at 2 weeks, 1 year, and 5 years after implantprosthetic incorporation. Tissue volume had increased significantly (P < .05) in all six reference points representing the outer alveolar soft tissue contour of the implant before connective tissue grafting to baseline (2 weeks after implant-prosthetic incorporation). Statistically, 50% of the reference points (P > .05) kept their volume from baseline to 1 year after prosthetic incorporation and from baseline to 5 years after prosthetic incorporation, respectively, whereas reference points located within the area of the implant sulcus showed a significant (P < .05) decrease in volume. Clinically, 5 years after prosthetic incorporation the originally concave buccal alveolar contour was still convex in all implants, leading to a continuous favorable anatomical shape and improved esthetic situation. Intraoral radiographs confirmed osseointegration and stable peri-implant parameters with a survival rate of 100% after a follow-up of approximately 5 years. Implant placement with concomitant free connective tissue grafting appears to be an appropriate long-term means to contour preexisting buccal

  6. The integrin-collagen connection--a glue for tissue repair?

    PubMed

    Zeltz, Cédric; Gullberg, Donald

    2016-02-15

    The α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens. Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1). Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events--such as wound healing--where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamily--integrins α10β1 and α11β1. PMID:26857815

  7. Mechanical properties of human autologous tubular connective tissues (human biotubes) obtained from patients undergoing peritoneal dialysis.

    PubMed

    Nakayama, Yasuhide; Kaneko, Yoshiyuki; Takewa, Yoshiaki; Okumura, Noriko

    2016-10-01

    Completely autologous in vivo tissue-engineered connective tissue tubes (Biotubes) have promise as arterial vascular grafts in animal implantation studies. In this clinical study of patients undergoing peritoneal dialysis (PD) (n = 11; age: 39-83 years), we evaluated human Biotubes' (h-Biotubes) mechanical properties to determine whether Biotubes with feasibility as vascular grafts could be formed in human bodies. We extracted PD catheters, embedded for 4-47 months, and obtained tubular connective tissues as h-Biotubes (internal diameter: 5 mm) from around the catheter' silicone tubular parts. h-Biotubes were composed mainly of collagen with smooth luminal surfaces. The average wall thickness was 278 ± 178 μm. No relationship was founded between the tubes' mechanical properties and patients' ages or PD catheter embedding periods statistically. However, the elastic modulus (2459 ± 970 kPa) and tensile strength (623 ± 314 g) of h-Biotubes were more than twice as great as those from animal Biotubes, formed from the same PD catheters by embedding in the beagle subcutaneous pouches for 1 month, or beagle arteries. The burst strength (6338 ± 1106 mmHg) of h-Biotubes was almost the same as that of the beagle thoracic or abdominal aorta. h-Biotubes could be formed in humans over a 4-month embedding period, and they satisfied the mechanical requirements for application as vascular grafts. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1431-1437, 2016.

  8. [Stomach cancer in patients with systemic non-differentiated connective tissue dysplasia].

    PubMed

    Zil'ber, V S

    2014-01-01

    The study was designed as a comparative analysis of clinical and anamnestic data and results of morphological studies of surgically obtained tissues from 61 patients with stomach cancer (SC) aged 29-78 yr with (group 1) and without (group 2) signs of connective tissue dysplasia (CTD). The groups had an identical structure of SC hystological types, but in group 1 the tumours were localized mainly in the stomach body (60.6%, p < 0.05) and in group 2 in the cardia (32.1%, p < 0.05). In group 1, SC was more frequently associated with chronic (sometimes multiple) ulcers outside the tumor (18.2 compared with 7.1% in group 2). Comparative analysis revealed the following features of SC in patients with CTD: predominance of stigmatization signs in the urogenital system (57.6%) and gastrointestinal tract (42.4%), cyst formation in different organs (75.8%) especially in kidneys (48.5%), high frequency of gastric problems in medical history (chronic gastritis, ulcer disease) (72.7 and 35.7% in groups 1 and 2 respectively, p < 0.05) and concomitant pathology of urogenital system (42.4%, p < 0.05). These peculiarities may be used as the marker for the inclusion of patients in the risk group for SC. Taking into account plastic, morphogenetic, and protective functions of connective tissue under physiological conditions, the above epithelial-stromal relationships and peculiarities of reparative processes in gastric mucosa one can not exclude effect of CTD on gastric cancerogenesis. This implies the necessity of further studies.

  9. The integrin-collagen connection--a glue for tissue repair?

    PubMed

    Zeltz, Cédric; Gullberg, Donald

    2016-02-15

    The α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens. Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1). Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events--such as wound healing--where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamily--integrins α10β1 and α11β1.

  10. Reproduction, growth, and tissue residues of deer fed dieldrin

    USGS Publications Warehouse

    Murphy, D.A.; Korschgen, L.J.

    1970-01-01

    Feeding tests were conducted from January, 1966, to January, 1969, to ascertain the effects of daily ingestions of sublethal amounts of dieldrin on white-tailed deer (Odocoileus virginianus). Groups of deer on 0 ppm dieldrin (controls), 5 ppm, and 25 ppm dieldrin were maintained at these respective levels, as were their progeny. Treated food was readily accepted. Dieldrin intoxication was not observed, and 9 of 10 animals of each group survived 3 years of treatment. No differences in conception or in utero mortality were found between groups. Fawns from dieldrin-fed does were smaller at birth and greater post-partum mortality occurred. Fertility of male progeny was not affected. Growth was slower and remained reduced in dieldrin-treated females which were immature when the study began. Hematologic values and serum protein concentrations were not significantly (P > 0.05) related to treatment. Liver/body weight ratios were significantly (P < 0.05) larger for the 25-ppm-dieldrin group. Pituitary glands were smaller and thyroids were larger in dieldrin-fed deer. Weight gains of fawns were significantly (P < 0.05) reduced 2 of 3 years in dieldrin-treated groups. Placental transfer of dieldrin occurred. Whole milk from does fed 25 ppm dieldrin contained residues of 17 ppm. Residue levels in brain, liver, and thigh muscle tissues showed no evidence of increasing with length of treatment, but showed definite relationships to levels of dieldrin in daily diets. Nursing fawns had higher residues in brain tissues than did older deer on 5 ppm a d 25 ppm dieldrin. Highest brain residues (12.60 and 12.10 ppm, wet weight) occurred in fawns only a few days of age at death. Equilibrium between ingestion and storage or excretion of dieldrin occurred prior to 200 days and continued until nearly 1,100 days. There was no evidence of a sharp decline in residues after a long period of continued dosage. Daily ingestion of 100 and 200 ppm of dieldrin proved fatal to yearling male deer at 27

  11. Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.

    PubMed

    Elfving, P; Marjoniemi, O; Niinisalo, H; Kononoff, A; Arstila, L; Savolainen, E; Rutanen, J; Kaipiainen-Seppänen, O

    2016-07-01

    Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4-7.0), idiopathic inflammatory myopathies 1.9 (0.5-5.0), systemic sclerosis 4.4 (2.0-8.3), mixed connective tissue disease 1.0 (0.1-3.5), Sjögren's syndrome 10.7 (6.7-16.1) and undifferentiated connective tissue disease 13.6 (9.0-19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3-4.3), central nervous system vasculitis 0.5 (0-2.7) and Henoch-Schönlein purpura 1.5 (0.3-4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2-14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis.

  12. Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.

    PubMed

    Elfving, P; Marjoniemi, O; Niinisalo, H; Kononoff, A; Arstila, L; Savolainen, E; Rutanen, J; Kaipiainen-Seppänen, O

    2016-07-01

    Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4-7.0), idiopathic inflammatory myopathies 1.9 (0.5-5.0), systemic sclerosis 4.4 (2.0-8.3), mixed connective tissue disease 1.0 (0.1-3.5), Sjögren's syndrome 10.7 (6.7-16.1) and undifferentiated connective tissue disease 13.6 (9.0-19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3-4.3), central nervous system vasculitis 0.5 (0-2.7) and Henoch-Schönlein purpura 1.5 (0.3-4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2-14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis. PMID:27053177

  13. Response of bone marrow derived connective tissue progenitor cell morphology and proliferation on geometrically modulated microtextured substrates

    PubMed Central

    Kim, Eun Jung; Fleischman, Aaron J.; Muschler, George F.; Roy, Shuvo

    2013-01-01

    Varying geometry and layout of microposts on a cell culture substrate provides an effective technique for applying mechanical stimuli to living cells. In the current study, the optimal geometry and arrangement of microposts on the polydimethylsiloxane (PDMS) surfaces to enhance cell growth behavior were investigated. Human bone marrow derived connective tissue progenitor cells were cultured on PDMS substrates comprising unpatterned smooth surfaces and cylindrical post microtextures that were 10 µm in diameter, 4 heights (5, 10, 20 and 40 µm) and 3 pitches (10, 20, and 40 µm). With the same 10 µm diameter, post heights ranging from 5 to 40 µm resulted in a more than 535000 fold range of rigidity from 0.011 nNµm−1 (40 µm height) up to 5888 nNµm−1(5 µm height). Even though shorter microposts result in higher effective stiffness, decreasing post heights below the optimal value, 5 µm height micropost in this study decreased cell growth behavior. The maximum number of cells was observed on the post microtextures with 20 µm height and 10 µm inter-space, which exhibited a 675% increase relative to the smooth surfaces. The cells on all heights of post microtextures with 10 µm and 20 µm inter-spaces exhibited highly contoured morphology. Elucidating the cellular response to various external geometry cues enables us to better predict and control cellular behavior. In addition, knowledge of cell response to surface stimuli could lead to the incorporation of specific size post microtextures into surfaces of implants to achieve surface-textured scaffold materials for tissue engineering applications. PMID:23378044

  14. Connexin's Connection in Breast Cancer Growth and Progression

    PubMed Central

    2016-01-01

    Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease. PMID:27642298

  15. Connexin's Connection in Breast Cancer Growth and Progression

    PubMed Central

    2016-01-01

    Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease.

  16. Connexin's Connection in Breast Cancer Growth and Progression.

    PubMed

    Banerjee, Debarshi

    2016-01-01

    Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease. PMID:27642298

  17. Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling.

    PubMed

    Le Gall, Sylvain M; Szabo, Roman; Lee, Melody; Kirchhofer, Daniel; Craik, Charles S; Bugge, Thomas H; Camerer, Eric

    2016-06-23

    The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation. PMID:27114461

  18. Peptide-modified Substrate for Modulating Gland Tissue Growth and Morphology In Vitro

    PubMed Central

    Taketa, Hiroaki; Sathi, Gulsan Ara; Farahat, Mahmoud; Rahman, Kazi Anisur; Sakai, Takayoshi; Hirano, Yoshiaki; Kuboki, Takuo; Torii, Yasuhiro; Matsumoto, Takuya

    2015-01-01

    In vitro fabricated biological tissue would be a valuable tool to screen newly synthesized drugs or understand the tissue development process. Several studies have attempted to fabricate biological tissue in vitro. However, controlling the growth and morphology of the fabricated tissue remains a challenge. Therefore, new techniques are required to modulate tissue growth. RGD (arginine-glycine-aspartic acid), which is an integrin-binding domain of fibronectin, has been found to enhance cell adhesion and survival; it has been used to modify substrates for in vitro cell culture studies or used as tissue engineering scaffolds. In addition, this study shows novel functions of the RGD peptide, which enhances tissue growth and modulates tissue morphology in vitro. When an isolated submandibular gland (SMG) was cultured on an RGD-modified alginate hydrogel sheet, SMG growth including bud expansion and cleft formation was dramatically enhanced. Furthermore, we prepared small RGD-modified alginate beads and placed them on the growing SMG tissue. These RGD-modified beads successfully induced cleft formation at the bead position, guiding the desired SMG morphology. Thus, this RGD-modified material might be a promising tool to modulate tissue growth and morphology in vitro for biological tissue fabrication. PMID:26098225

  19. Microdissection specimens of connective, chondrous, or Bone Tissue of human osteosarcomas and chondrosarcomas transplanted to athymic nude mice.

    PubMed

    Nilsson, O S; Lindholm, T S; Nilsonne, U

    1982-01-01

    Five osteosarcomas and two chondrosarcomas were microdissected to separate tumor compartments of calcified, chondrous, and connective tissue. The compartments were lyophilized separately and transplanted subcutaneously or intramuscularly into nude mice for three, four, and five weeks, respectively. In three of the osteosarcomas and in one of the chrondrosarcomas, calcified tissue induced ectopic bone formation by the host, while cartilaginous tissue induced ectopic bone formation in one of the osteosarcomas and in one of the chondrosarcomas. The tumor-derived connective tissue did not induce osteogenic response in the host tissue. Thus, the ability to develop an osteoinductive response and to produce bone morphogenetic protein seems to be restricted to the population of cells that eventually will, or have, differentiated into bone or cartilage.

  20. Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing.

    PubMed

    Colombani, Julien; Andersen, Ditte S; Léopold, Pierre

    2012-05-01

    Little is known about how organ growth is monitored and coordinated with the developmental timing in complex organisms. In insects, impairment of larval tissue growth delays growth and morphogenesis, revealing a coupling mechanism. We carried out a genetic screen in Drosophila to identify molecules expressed by growing tissues participating in this coupling and identified dilp8 as a gene whose silencing rescues the developmental delay induced by abnormally growing tissues. dilp8 is highly induced in conditions where growth impairment produces a developmental delay. dilp8 encodes a peptide for which expression and secretion are sufficient to delay metamorphosis without affecting tissue integrity. We propose that Dilp8 peptide is a secreted signal that coordinates the growth status of tissues with developmental timing.

  1. Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease.

    PubMed

    Li, Xue-Ren; Peng, Shou-Chun; Wei, Lu-Qing

    2015-01-01

    Here, we reported two cases of nonspecific interstitial pneumonia overlap organizing pneumonia (NSIP/OP) with lung-dominant connective tissue disease (LD-ILD). The first case is a patient with hands of chapped skin, right-sided pleuritic chest discomfort, weakness, positive ANA and antibodies to Ro/SS-A (+++) and Ro-52 (++). In the second case, there were Reynaud's disease, and nucleolus-ANA increased (1:800). Chest high resolution CT scan in both cases showed ground-glass opacifications, predominantly in basal and subpleural region and the pathologic manifestation were correlated with NSIP/OP, which were previously discovered in Sjogren syndrome, PM/DM and other rheumatic diseases. The two cases of NSIP/OP with LD-CTD we reported expand disease spectrum of NSIP/OP pathological types in ILD. However, it is necessary to process large-scale studies.

  2. The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome.

    PubMed

    Szodoray, P; Hajas, A; Toth, L; Szakall, S; Nakken, B; Soltesz, P; Bodolay, E

    2014-09-01

    The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti-β2-glycoprotein (anti-β2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27high plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects.

  3. Treatment of noncarious cervical lesions by a subepithelial connective tissue graft versus a composite resin restoration.

    PubMed

    Leybovich, Martin; Bissada, Nabil F; Teich, Sorin; Demko, Catherine A; Ricchetti, Paul A

    2014-01-01

    This study compared two treatments for mild noncarious cervical lesions (NCCLs): a subepithelial connective tissue graft (CTG) versus a Class V composite resin restoration (CRR). Twenty-six sites with NCCLs were randomly assigned to be treated by CTG or CRR. Periodontal health parameters and dentinal hypersensitivity (DH) were recorded at baseline and 3 months postoperatively. Esthetics was also evaluated at 3 months. Results showed a significant improvement in all periodontal health parameters in the CTG treatment. The CTG treatment attained a mean 82% defect coverage with 75% of sites achieving complete coverage. Patients rated the CTG treatment to be significantly more esthetic (P = .03), while a clinician panel did not see an esthetic difference (P = .86). There was no difference in DH reduction between the two treatments (P = .81). In conclusion, the CTG treatment is superior to the CRR treatment for NCCLs based on periodontal health parameters. From a patient point of view, the CTG is the more esthetic treatment.

  4. Ischemic Colitis Due to a Mesenteric Arteriovenous Malformation in a Patient with a Connective Tissue Disorder

    PubMed Central

    Poullos, Peter D.; Thompson, Atalie C.; Holz, Grant; Edelman, Lauren A.; Jeffrey, R. Brooke

    2014-01-01

    Ischemic colitis is a rare, life-threatening, consequence of mesenteric arteriovenous malformations. Ischemia ensues from a steal phenomenon through shunting, and may be compounded by the resulting portal hypertension. Computed tomographic angiography is the most common first-line test because it is quick, non-invasive, and allows for accurate anatomic characterization. Also, high-resolution three-dimensional images can be created for treatment planning. Magnetic resonance angiography is similarly sensitive for vascular mapping. Conventional angiography remains the gold standard for diagnosis and also allows for therapeutic endovascular embolization. Our patient underwent testing using all three of these modalities. We present the first reported case of this entity in a patient with a vascular connective tissue disorder. PMID:25926912

  5. Antinuclear antibodies and their detection methods in diagnosis of connective tissue diseases: a journey revisited

    PubMed Central

    Kumar, Yashwant; Bhatia, Alka; Minz, Ranjana Walker

    2009-01-01

    It has been more than 50 years since antinuclear antibodies were first discovered and found to be associated with connective tissue diseases. Since then different methods have been described and used for their detection or confirmation. For many decades immunofluorescent antinuclear antibody test has been the "gold standard" in the diagnosis of these disorders. However to increase the sensitivity and specificity of antinuclear antibody detection further approaches were explored. Today a battery of newer techniques are available some of which are now considered better and are competing with the older methods. This article provides an overview on advancement in antinuclear antibody detection methods, their future prospects, advantages, disadvantages and guidelines for use of these tests. PMID:19121207

  6. Cardiovascular risk and its modification in patients with connective tissue diseases.

    PubMed

    O'Sullivan, Miriam; Bruce, Ian N; Symmons, Deborah P M

    2016-02-01

    It is well documented that patients with systemic lupus erythematosus (SLE) are at an increased risk of atherosclerotic cardiovascular (CV) disease. There is evidence that traditional risk factors and disease-related factors are involved in this increased risk. Less is known about CV risk and outcomes in other connective tissue diseases (CTDs). Future longitudinal observational studies may help to answer these important questions; however, because CTDs are rare, collaboration between clinicians with similar research interests is needed to ensure sufficiently large cohorts are available to address these issues. Here, we review the evidence available for CV risk in CTDs and discuss the benefits of longitudinal observational studies in identifying CV outcomes. Structured care protocols for the management of CV risk in CTDs are lacking. We propose a target-based approach to assessing and managing CV risk in CTDs. PMID:27421218

  7. Pulmonary nocardiosis in patients with connective tissue disease: A report of two cases

    PubMed Central

    Hagiwara, Shinya; Tsuboi, Hiroto; Hagiya, Chihiro; Yokosawa, Masahiro; Hirota, Tomoya; Ebe, Hiroshi; Takahashi, Hiroyuki; Ogishima, Hiroshi; Asashima, Hiromitsu; Kondo, Yuya; Umeda, Naoto; Suzuki, Takeshi; Hitomi, Shigemi; Matsumoto, Isao; Sumida, Takayuki

    2014-01-01

    Summary Reported here are 2 patients with connective tissue disease who developed pulmonary nocardiosis. Case 1 involved a 73-year-old man with malignant rheumatoid arthritis treated with prednisolone 25 mg/day. Chest X-rays revealed a pulmonary cavity and bronchoscopy detected Nocardia species. The patient was successfully treated with trimethoprim/sulfamethoxazole. Case 2 involved a 41-year-old woman with systemic lupus erythematosus. The patient received remission induction therapy with 50 mg/day of prednisolone and tacrolimus. Six weeks later, a chest CT scan revealed a pulmonary cavity; bronchoscopy resulted in a diagnosis of pulmonary nocardiosis. The patient had difficulty tolerating trimethoprim/sulfamethoxazole, so she was switched to and successfully treated with imipenem/cilastatin and amikacin. PMID:25343123

  8. CCN2: a mechanosignaling sensor modulating integrin-dependent connective tissue remodeling in fibroblasts?

    PubMed

    Leask, Andrew

    2013-08-01

    Tensegrity (tensional integrity) is an emerging concept governing the structure of the body. Integrin-mediated mechanical tension is essential for connective tissue function in vivo. For example, in adult skin fibroblasts, the integrin β1 subunit mediates adhesion to collagen and fibronectin. Moreover, integrin β1, through its abilities to activate latent TGFβ1 and promote collagen production through focal adhesion kinase/rac1/nicotinamide adenine dinucleotide phosphate oxidase (NOX)/reactive oxygen species (ROS), is essential for dermal homeostasis, repair and fibrosis. The integrin β1-interacting protein CCN2, a member of the CCN family of proteins, is induced by TGFβ1; yet, CCN2 is not a simple downstream mediator of TGFβ1, but instead synergistically promote TGFβ1-induced adhesive signaling and fibrosis. Due to its selective ability to sense mechanical forces in the microenvironment, CCN2 may represent an exquisitely precise target for therapeutic intervention. PMID:23729366

  9. [Viscoelastic properties of isolated papillary muscle: contributions of connective tissue skeleton and intracellular matrix].

    PubMed

    Protsenko, Iu L; Kobelev, A V; Lukin, O N; Balakin, A A; Smoliuk, L T

    2009-07-01

    Peculiarities of viscoelastic behavior of rabbit papillary muscle in passive state are studied by transversal versus longitudinal deformation curves, stress-strain and hysteresis curves, and stress relaxation curves under ramp stretching. The papillary muscle was chosen because of mostly longitudinal orientation of fibers and its elongated shape, which both make it as an appropriate model for uniaxial tests. The problem of evaluation of connective tissue protein structures and intracellular matrix contribution into the properties under consideration is solved by using the maceration method to remove intracellular structures. The different contribution of intracellular and extracellular protein features into total properties of a papillary muscle leads to nonlinearity of myocardial viscoelastic properties, such as the increase of differential elastic module and relaxation time with deformation.

  10. Spontaneous Esophageal Perforation in a Patient with Mixed Connective Tissue Disease

    PubMed Central

    Lyman, David

    2011-01-01

    Spontaneous esophageal perforation is a rare and life-threatening disorder. Failure to diagnosis within the first 24-48 hours of presentation portends a poor prognosis. A patient with mixed connective tissue disease (MCTD) on low-dose prednisone and methotrexate presented moribund with chest and shoulder pain, a left hydropneumothorax, progressive respiratory failure and shock. Initial management focussed on presumed community acquired pneumonia (CAP) in a patient on immunosuppressants. Bilateral yeast empyemas were treated and attributed to immunosuppression. On day 26, the patient developed mediastinitis, and the diagnosis of esophageal perforation was first considered. A review of the literature suggests that the diagnosis and management of spontaneous esophageal perforation could have been more timely and the outcome less catastrophic. PMID:22279514

  11. Treatment of noncarious cervical lesions by a subepithelial connective tissue graft versus a composite resin restoration.

    PubMed

    Leybovich, Martin; Bissada, Nabil F; Teich, Sorin; Demko, Catherine A; Ricchetti, Paul A

    2014-01-01

    This study compared two treatments for mild noncarious cervical lesions (NCCLs): a subepithelial connective tissue graft (CTG) versus a Class V composite resin restoration (CRR). Twenty-six sites with NCCLs were randomly assigned to be treated by CTG or CRR. Periodontal health parameters and dentinal hypersensitivity (DH) were recorded at baseline and 3 months postoperatively. Esthetics was also evaluated at 3 months. Results showed a significant improvement in all periodontal health parameters in the CTG treatment. The CTG treatment attained a mean 82% defect coverage with 75% of sites achieving complete coverage. Patients rated the CTG treatment to be significantly more esthetic (P = .03), while a clinician panel did not see an esthetic difference (P = .86). There was no difference in DH reduction between the two treatments (P = .81). In conclusion, the CTG treatment is superior to the CRR treatment for NCCLs based on periodontal health parameters. From a patient point of view, the CTG is the more esthetic treatment. PMID:25171035

  12. A structure-based extracellular matrix expansion mechanism of fibrous tissue growth.

    PubMed

    Kalson, Nicholas S; Lu, Yinhui; Taylor, Susan H; Starborg, Tobias; Holmes, David F; Kadler, Karl E

    2015-01-01

    Embryonic growth occurs predominately by an increase in cell number; little is known about growth mechanisms later in development when fibrous tissues account for the bulk of adult vertebrate mass. We present a model for fibrous tissue growth based on 3D-electron microscopy of mouse tendon. We show that the number of collagen fibrils increases during embryonic development and then remains constant during postnatal growth. Embryonic growth was explained predominately by increases in fibril number and length. Postnatal growth arose predominately from increases in fibril length and diameter. A helical crimp structure was established in embryogenesis, and persisted postnatally. The data support a model where the shape and size of tendon is determined by the number and position of embryonic fibroblasts. The collagen fibrils that these cells synthesise provide a template for postnatal growth by structure-based matrix expansion. The model has important implications for growth of other fibrous tissues and fibrosis. PMID:25992598

  13. [Lower limb varicose veins as a manifestation of undifferentiated connective tissue dysplasia].

    PubMed

    Potapov, M P; Potapov, P P; Staver, E V; Mazepina, L S

    2016-01-01

    Analysed herein are the data of 737 patients (a total of 745 lower limbs) suffering from lower-limb varicose veins (LLVV) and subjected to treatment at the Surgical Department consisting of crossectomy, truncal and tributary phlebectomy, dissection of perforant veins exclusively in the basin of the great saphenous vein. Relapses during five-year follow up occurred in 13.8% (102/745) of cases. Based on clinical signs and laboratory findings we studied the effect of the factor of undifferentiated connective tissue dysplasia (UDCTD) on the development of lower-limb varicosity. We carried out comparative analysis in the groups with relapsing LLVV (n=43), without relapses (n=39) and control group comprising volunteers not suffering from LLVV (n=37). The median of blood serum total oxiprolin concentration in LLVV patients both with and without relapses was elevated and amounted to 18.4 (IR 14.9-19.65) and 14.3 (IR 13.1-16.5) versus 8.35 (5.75-9.75) μmol/l, respectively. The mode of the clinical parameter of UDCTD degree in accordance with the rating scale of Smolnova T.Yu. (2003) in the group of patients with LLVV relapses turned out to be higher (Mo=19) than in the group of patients without relapses (Mo=10, p=0.003). The lowest score was in the control group. In patients having immediate relatives with LLVV the level of blood serum total oxiprolin and clinical scores of LLVV turned out to be statistically significantly higher. Hence, based on the obtained during the study clinical and laboratory findings it may be supposed that undifferentiated connective tissue dysplasia plays an important part in the development of both lower limb varicosity and relapses thereof. PMID:27100544

  14. Epithelial-connective tissue cross-talk is essential for regeneration of intestinal epithelium.

    PubMed

    Ishizuya-Oka, Atsuko

    2005-02-01

    Epithelial cells of the gastrointestine undergo a rapid cell-renewal and originate from stem cells throughout the life of the organisms. Previous studies have provided a solid body of evidence to show that the epithelial cell-renewal is under the strict control of cell-cell and cell-extracellular matrix (ECM) interactions between the epithelium and the connective tissue. Especially, the microenvironment around the stem cells called "niche" is thought to play important roles in this control, and its disruption leads to diseases or disorders such as cancer in the human gastrointestine. Although understanding how the niche affects the stem cells is clinically important, its mechanisms still remain mostly unknown at the molecular level, possibly due to difficulties in the identification of the stem cells in the gastrointestine. Recent progress in cell and molecular biology is gradually beginning to shed light on some of the key signaling pathways in the cell-renewal of the intestinal epithelium, such as Wnt/T-cell factor (TCF)/beta-catenin, Notch, Sonic hedgehog (Shh)/bone morphogenetic protein (BMP) signaling pathways, which are also involved in embryonic organogenesis and/or adult carcinogenesis. At present, only fragmentary information is available on their precise functions in the intestine. Nevertheless, there is a growing body of evidence that such signaling pathways have conservative functions in the intestine throughout terrestrial vertebrates, suggesting the usefulness of experimental animals to clarify molecular mechanisms regulating epithelial cell-renewal. In this article, I review some recent findings in this field, with particular focus on our studies using the Xenopus laevis intestine, where the stem cells form the mammalian-type intestinal epithelium under the control of connective tissue during metamorphosis. This Xenopus experimental system will certainly serve as a useful model for the study of the intestinal niche, whose clarification is urgently

  15. Petroleum distillate solvents as risk factors for undifferentiated connective tissue disease (UCTD).

    PubMed

    Lacey, J V; Garabrant, D H; Laing, T J; Gillespie, B W; Mayes, M D; Cooper, B C; Schottenfeld, D

    1999-04-15

    Occupational solvent exposure may increase the risk of connective tissue disease (CTD). The objective of this case-control study was to investigate the relation between undifferentiated connective tissue disease (UCTD) and solvent exposure in Michigan and Ohio. Women were considered to have UCTD if they did not meet the American College of Rheumatology classification criteria for any CTD but had at least two documented signs, symptoms, or laboratory abnormalities suggestive of a CTD. Detailed information on solvent exposure was ascertained from 205 cases, diagnosed between 1980 and 1992, and 2,095 population-based controls. Age-adjusted odds ratios (OR) and 95 percent confidence intervals (CI) were calculated for all exposures. Among 16 self-reported occupational activities with potential solvent exposure, furniture refinishing (OR = 9.73, 95 percent CI 1.48-63.90), perfume, cosmetic, or drug manufacturing (OR = 7.71, 95 percent CI 2.24-26.56), rubber product manufacturing (OR = 4.70, 95 percent CI 1.75-12.61), work in a medical diagnostic or pathology laboratory (OR = 4.52, 95 percent CI 2.27-8.97), and painting or paint manufacturing (OR = 2.87, 95 percent CI 1.06-7.76) were significantly associated with UCTD. After expert review of self-reported exposure to ten specific solvents, paint thinners or removers (OR = 2.73, 95 percent CI 1.80-4.16) and mineral spirits (OR = 1.81, 95 percent CI 1.09-3.02) were associated with UCTD. These results suggest that exposure to petroleum distillates increases the risk of developing UCTD.

  16. [Lower limb varicose veins as a manifestation of undifferentiated connective tissue dysplasia].

    PubMed

    Potapov, M P; Potapov, P P; Staver, E V; Mazepina, L S

    2016-01-01

    Analysed herein are the data of 737 patients (a total of 745 lower limbs) suffering from lower-limb varicose veins (LLVV) and subjected to treatment at the Surgical Department consisting of crossectomy, truncal and tributary phlebectomy, dissection of perforant veins exclusively in the basin of the great saphenous vein. Relapses during five-year follow up occurred in 13.8% (102/745) of cases. Based on clinical signs and laboratory findings we studied the effect of the factor of undifferentiated connective tissue dysplasia (UDCTD) on the development of lower-limb varicosity. We carried out comparative analysis in the groups with relapsing LLVV (n=43), without relapses (n=39) and control group comprising volunteers not suffering from LLVV (n=37). The median of blood serum total oxiprolin concentration in LLVV patients both with and without relapses was elevated and amounted to 18.4 (IR 14.9-19.65) and 14.3 (IR 13.1-16.5) versus 8.35 (5.75-9.75) μmol/l, respectively. The mode of the clinical parameter of UDCTD degree in accordance with the rating scale of Smolnova T.Yu. (2003) in the group of patients with LLVV relapses turned out to be higher (Mo=19) than in the group of patients without relapses (Mo=10, p=0.003). The lowest score was in the control group. In patients having immediate relatives with LLVV the level of blood serum total oxiprolin and clinical scores of LLVV turned out to be statistically significantly higher. Hence, based on the obtained during the study clinical and laboratory findings it may be supposed that undifferentiated connective tissue dysplasia plays an important part in the development of both lower limb varicosity and relapses thereof.

  17. Smooth muscle myosin regulation by serum and cell density in cultured rat lung connective tissue cells.

    PubMed

    Babij, P; Zhao, J; White, S; Woodcock-Mitchell, J; Mitchell, J; Absher, M; Baldor, L; Periasamy, M; Low, R B

    1993-08-01

    RNA and protein analyses were used to detect expression of SM1 and SM2 smooth muscle myosin heavy chain (MHC) in cultured adult rat lung connective tissue cells (RL-90). Smooth muscle MHC mRNA expression in confluent cells grown in 10% serum was approximately 50% of the level in adult stomach. Similar results were obtained in cells cultured at low density (25% confluency) in 1% serum. However, in low-density cultures transferred to 10% serum for 24 h, the level of MHC mRNA decreased to approximately 20% of that in adult stomach. Smooth muscle alpha-actin showed a pattern of expression similar to that for smooth muscle MHC. Expression of nonmuscle MHC-A mRNA was higher in all culture conditions compared to stomach. MHC-A mRNA expression was less in low-density cultures in low serum and increased when low-density cultures were transferred to 10% serum for 24 h. MHC-B mRNA expression was less in low- vs. high-density cultures. In contrast to MHC-A, however, MHC-B mRNA expression in low-density cultures was higher in low serum. Immunofluorescence and immunoblotting with SM1-specific antibody demonstrated the presence of the SM1 protein isoform as well as reactivity to a protein band migrating slightly faster than SM2. These results demonstrate that cultured rat lung connective tissue cells express smooth muscle MHC and that expression is modulated by culture conditions.

  18. Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate

    PubMed Central

    Mederacke, Ingmar; Komatsu, Yoshihiro; Stice, Steve; Schwabe, Robert F.; Mistretta, Charlotte M.; Mishina, Yuji; Liu, Hong-Xiang

    2016-01-01

    Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0-Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC. PMID:26741369

  19. Higher maturity and connective tissue association distinguish resident from recently generated human tonsil plasma cells.

    PubMed

    Medina, Francisco; Segundo, Carmen; Jiménez-Gómez, Gema; González-García, Inés; Campos-Caro, Antonio; Brieva, José A

    2007-12-01

    Human plasma cells (PC) are present in cell suspensions obtained from the tonsil by mechanical disaggregation (PC(MECH)). The present study shows that a collagenase treatment of tonsillar debris remaining after mechanical disaggregation yielded similar proportions of PC (PC(COLL)). Moreover, PC(MECH) were present in suspensions highly enriched in germinal center cells whereas PC(COLL) contained most of the IgA-secreting cells, suggesting their predominant location in follicular and parafollicular areas and connective tissue-rich zones such as tonsil subepithelium, respectively. Tonsil PC(MECH) and PC(COLL) shared the phenotype CD38(high) CD19(+) CD20(low) CD45(high), expressed equivalent amounts of PRDI BF1/Blimp-1 transcription factor, and carried similarly mutated IgVH6 genes. However, they differed in several features. 1) PC(MECH) still expressed the early B cell transcription factor BSAP and were HLA-DR(high); in contrast, PC(COLL) were BSAP(-)and HLA-DR(low). 2) PC(MECH) were CD95(+) and Bcl-2(+/-) whereas PC(COLL) showed CD95(+/-) and Bcl-2(+) expression; in addition, PC(MECH) exhibited increased spontaneous apoptosis. 3) The two PC subsets exhibited distinctive adhesion molecule profiles, since PC(COLL) expressed higher levels of CD31, CD44, and CD49d, but a lower level of CD11a than PC(MECH). These results suggest that PC(MECH) are recently generated, short-living PC, and PC(COLL) constitutes a subset with higher maturity and survival, which resides in connective tissue-rich areas.

  20. Connective Tissue Reflex Massage for Type 2 Diabetic Patients with Peripheral Arterial Disease: Randomized Controlled Trial

    PubMed Central

    Castro-Sánchez, Adelaida María; Moreno-Lorenzo, Carmen; Matarán-Peñarrocha, Guillermo A.; Feriche-Fernández-Castanys, Belen; Granados-Gámez, Genoveva; Quesada-Rubio, José Manuel

    2011-01-01

    The objective of this study was to evaluate the efficacy of connective tissue massage to improve blood circulation and intermittent claudication symptoms in type 2 diabetic patients. A randomized, placebo-controlled trial was undertaken. Ninety-eight type 2 diabetes patients with stage I or II-a peripheral arterial disease (PAD) (Leriche-Fontaine classification) were randomly assigned to a massage group or to a placebo group treated using disconnected magnetotherapy equipment. Peripheral arterial circulation was determined by measuring differential segmental arterial pressure, heart rate, skin temperature, oxygen saturation and skin blood flow. Measurements were taken before and at 30 min, 6 months and 1 year after the 15-week treatment. After the 15-week program, the groups differed (P < .05) in differential segmental arterial pressure in right lower limb (lower one-third of thigh, upper and lower one-third of leg) and left lower limb (lower one-third of thigh and upper and lower one-third of leg). A significant difference (P < .05) was also observed in skin blood flow in digits 1 and 4 of right foot and digits 2, 4 and 5 of left foot. ANOVA results were significant (P < .05) for right and left foot oxygen saturation but not for heart rate and temperature. At 6 months and 1 year, the groups differed in differential segmental arterial pressure in upper third of left and right legs. Connective tissue massage improves blood circulation in the lower limbs of type 2 diabetic patients at stage I or II-a and may be useful to slow the progression of PAD. PMID:19933770

  1. Connective tissue reflex massage for type 2 diabetic patients with peripheral arterial disease: randomized controlled trial.

    PubMed

    Castro-Sánchez, Adelaida María; Moreno-Lorenzo, Carmen; Matarán-Peñarrocha, Guillermo A; Feriche-Fernández-Castanys, Belen; Granados-Gámez, Genoveva; Quesada-Rubio, José Manuel

    2011-01-01

    The objective of this study was to evaluate the efficacy of connective tissue massage to improve blood circulation and intermittent claudication symptoms in type 2 diabetic patients. A randomized, placebo-controlled trial was undertaken. Ninety-eight type 2 diabetes patients with stage I or II-a peripheral arterial disease (PAD) (Leriche-Fontaine classification) were randomly assigned to a massage group or to a placebo group treated using disconnected magnetotherapy equipment. Peripheral arterial circulation was determined by measuring differential segmental arterial pressure, heart rate, skin temperature, oxygen saturation and skin blood flow. Measurements were taken before and at 30 min, 6 months and 1 year after the 15-week treatment. After the 15-week program, the groups differed (P < .05) in differential segmental arterial pressure in right lower limb (lower one-third of thigh, upper and lower one-third of leg) and left lower limb (lower one-third of thigh and upper and lower one-third of leg). A significant difference (P < .05) was also observed in skin blood flow in digits 1 and 4 of right foot and digits 2, 4 and 5 of left foot. ANOVA results were significant (P < .05) for right and left foot oxygen saturation but not for heart rate and temperature. At 6 months and 1 year, the groups differed in differential segmental arterial pressure in upper third of left and right legs. Connective tissue massage improves blood circulation in the lower limbs of type 2 diabetic patients at stage I or II-a and may be useful to slow the progression of PAD. PMID:19933770

  2. Loss of Tumor Necrosis Factor α Potentiates Transforming Growth Factor β-mediated Pathogenic Tissue Response during Wound Healing

    PubMed Central

    Saika, Shizuya; Ikeda, Kazuo; Yamanaka, Osamu; Flanders, Kathleen C.; Okada, Yuka; Miyamoto, Takeshi; Kitano, Ai; Ooshima, Akira; Nakajima, Yuji; Ohnishi, Yoshitaka; Kao, Winston W.-Y.

    2006-01-01

    Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor α (TNFα) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNFα-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor β or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNFα in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of α-smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen Iα2 and connective tissue growth factor, and detection of collagen protein. TNFα in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor β, and for restoration of tissue architecture in a healing alkali-burned cornea in mice. PMID:16723700

  3. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog.

    PubMed

    LeGrice, I J; Smaill, B H; Chai, L Z; Edgar, S G; Gavin, J B; Hunter, P J

    1995-08-01

    We have studied the three-dimensional arrangement of ventricular muscle cells and the associated extracellular connective tissue matrix in dog hearts. Four hearts were potassium-arrested, excised, and perfusion-fixed at zero transmural pressure. Full-thickness segments were cut from the right and left ventricular walls at a series of precisely located sites. Morphology was visualized macroscopically and with scanning electron microscopy in 1) transmural planes of section and 2) planes tangential to the epicardial surface. The appearance of all specimens was consistent with an ordered laminar arrangement of myocytes with extensive cleavage planes between muscle layers. These planes ran radially from endocardium toward epicardium in transmural section and coincided with the local muscle fiber orientation in tangential section. Stereological techniques were used to quantify aspects of this organization. There was no consistent variation in the cellular organization of muscle layers (48.4 +/- 20.4 microns thick and 4 +/- 2 myocytes across) transmurally or in different ventricular regions (23 sites in 6 segments), but there was significant transmural variation in the coupling between adjacent layers. The number of branches between layers decreased twofold from subepicardium to midwall, whereas the length distribution of perimysial collagen fibers connecting muscle layers was greatest in the midwall. We conclude that ventricular myocardium is not a uniformly branching continuum but a laminar hierarchy in which it is possible to identify three axes of material symmetry at any point.

  4. Immunohistochemical identification of myoepithelial, epithelial, and connective tissue cells in canine mammary tumors.

    PubMed

    Destexhe, E; Lespagnard, L; Degeyter, M; Heymann, R; Coignoul, F

    1993-03-01

    Fifty-eight formalin-fixed paraffin-embedded canine mammary tumors, 19 malignant and 39 benign, were used in this study. Tumors were obtained from dogs submitted for surgical resection of lesions at private veterinary practices in Brussels or from the surgery unit of the Faculty of Veterinary Medicine, University of Liège. Immunohistochemical evaluation was performed, using monoclonal antibodies directed against keratins 8-18 and 19, vimentin, desmin, and alpha-actin and polyclonal antibodies directed against high-molecular-weight keratins and S-100 protein. The main cell types, epithelial, myoepithelial, and connective, were identified, and myoepithelial cells represented the major component of most tumors, both benign and malignant. Myoepithelial cells had five patterns: resting and proliferative suprabasal cells, spindle and star-shaped interstitial cells, and cartilage. Reactivity to keratin 19, vimentin, alpha-actin, and S-100 protein suggested a progressive transformation from resting cells to cartilage. Epithelial cell reactivities were limited to keratins; only keratinized cells were positive for polyclonal keratins. Myofibroblasts were positive for both vimentin and alpha-actin, and connective tissue cells were positive for vimentin. Myoepithelial cells appeared to be the major component of carcinomas, justifying reevaluation and simplification of histomorphologic classifications, with a "pleomorphic carcinoma" group including all carcinomas except squamous, mucinous, and comedo carcinomas. Immunohistochemical evaluation, in addition to routine hematoxylin and eosin histopathologic evaluation is recommended for precise classification of canine mammary tumors. PMID:7682367

  5. Impedance Changes and Fibrous Tissue Growth after Cochlear Implantation Are Correlated and Can Be Reduced Using a Dexamethasone Eluting Electrode

    PubMed Central

    Mugridge, Kenneth; Jolly, Claude; Fehr, Michael; Lenarz, Thomas; Scheper, Verena

    2016-01-01

    Background The efficiency of cochlear implants (CIs) is affected by postoperative connective tissue growth around the electrode array. This tissue formation is thought to be the cause behind post-operative increases in impedance. Dexamethasone (DEX) eluting CIs may reduce fibrous tissue growth around the electrode array subsequently moderating elevations in impedance of the electrode contacts. Methods For this study, DEX was incorporated into the silicone of the CI electrode arrays at 1% and 10% (w/w) concentration. Electrodes prepared by the same process but without dexamethasone served as controls. All electrodes were implanted into guinea pig cochleae though the round window membrane approach. Potential additive or synergistic effects of electrical stimulation (60 minutes) were investigated by measuring impedances before and after stimulation (days 0, 7, 28, 56 and 91). Acoustically evoked auditory brainstem responses were recorded before and after CI insertion as well as on experimental days 7, 28, 56, and 91. Additionally, histology performed on epoxy embedded samples enabled measurement of the area of scala tympani occupied with fibrous tissue. Results In all experimental groups, the highest levels of fibrous tissue were detected in the basal region of the cochlea in vicinity to the round window niche. Both DEX concentrations, 10% and 1% (w/w), significantly reduced fibrosis around the electrode array of the CI. Following 3 months of implantation impedance levels in both DEX-eluting groups were significantly lower compared to the control group, the 10% group producing a greater effect. The same effects were observed before and after electrical stimulation. Conclusion To our knowledge, this is the first study to demonstrate a correlation between the extent of new tissue growth around the electrode and impedance changes after cochlear implantation. We conclude that DEX-eluting CIs are a means to reduce this tissue reaction and improve the functional benefits of

  6. Tissue types (image)

    MedlinePlus

    There are 4 basic types of tissue: connective tissue, epithelial tissue, muscle tissue, and nervous tissue. Connective tissue supports other tissues and binds them together (bone, blood, and lymph tissues). Epithelial tissue ...

  7. Substrate-protecting antiproteolytic agents for the prevention of pathological degradation of connective tissues. A review.

    PubMed

    Robert, A-M

    2012-02-01

    Connective tissues play an important role in the physiological functions of the organism. The integrity of the macromolecular components of these tissues, also called extracellular matrix, is necessary for their functional efficiency. A number of proteinases present in the organism, and the activity of which increases with age and with several pathologies, specifically degrade the components of the extracellular matrix. For a long time, tentatives for the protection of the matrix-components against degradation were made with low molecular weight inhibitors, not very efficient in vivo and not devoid of inconveniencies. We initiated a different approach for the preservation of the macromolecules of the extracellular matrix against proteolytic degradation with substances which exert an intense antiproteolytic activity not only in vitro, but also in vivo. The particularity of these substances is the fact that they do not act on the enzymes, but combine with the macromolecules. This is the type of combination of substances with the macromolecules of the matrix that prevents their degradation by the proteinases. Because of this affinity of such antiproteolytic agents not for the enzymes but for the substrates, we called them "substrate protectors" (Robert et al., 1979). The aim of the present review is to summarise the essential of our experiments which led to the description of substrate protectors.

  8. [Reparative regeneration of connective tissue structures of mammals under antioxidant therapy conditions].

    PubMed

    Belova, S V; Norkin, I A; Puchin'ian, D M

    2015-01-01

    The influence of administration of the antioxidant complexes consisting of nonenzymatic antioxidants (alpha-tocopherol acetate preparation) and enzymatic antioxidants (ceruloplasmin) has been studied in rabbits with experimental arthritis. The introduction of alpha-tocopherol acetate (at a daily dose of 4 mg) improved metabolic processes in the organism (decreased in the rate of erythrocyte precipitation, total leukocytes and their stub and segmental forms; increased in erythrocyte count; reduced the glycosaminoglycan content as determined from uronic acid and hexose level; decreased ceruloplasmin activity and malonic dialdehyde level ion blood serum, all at p < 0.05), thus favoring reduction in the total activity of the inflammatory process as judged from hematological and biochemical data. Intra-articular introduction of ceruloplasmin (1.5 mg/kg, once per week) positively influenced the state of joint structures in damaged knee joints of the animals: decreased the activity of ceruloplasmin (from 5.28 ± 0.06 to 3.94 ± 0.01 AU), and malonic dialdehyde level (0.18 ± 0.02 to 0.08 ± 0.01 μM) in the articular fluid (all at p < 0.05). These effects are probably related to the elimination of inefficiency of the antioxidant system in the synovial medium, thus preventing inflammatory destruction of articular tissues, hindering the development of pannus, and assisting the activation of reparative regeneration of connective tissue structures.

  9. [Reparative regeneration of connective tissue structures of mammals under antioxidant therapy conditions].

    PubMed

    Belova, S V; Norkin, I A; Puchin'ian, D M

    2015-01-01

    The influence of administration of the antioxidant complexes consisting of nonenzymatic antioxidants (alpha-tocopherol acetate preparation) and enzymatic antioxidants (ceruloplasmin) has been studied in rabbits with experimental arthritis. The introduction of alpha-tocopherol acetate (at a daily dose of 4 mg) improved metabolic processes in the organism (decreased in the rate of erythrocyte precipitation, total leukocytes and their stub and segmental forms; increased in erythrocyte count; reduced the glycosaminoglycan content as determined from uronic acid and hexose level; decreased ceruloplasmin activity and malonic dialdehyde level ion blood serum, all at p < 0.05), thus favoring reduction in the total activity of the inflammatory process as judged from hematological and biochemical data. Intra-articular introduction of ceruloplasmin (1.5 mg/kg, once per week) positively influenced the state of joint structures in damaged knee joints of the animals: decreased the activity of ceruloplasmin (from 5.28 ± 0.06 to 3.94 ± 0.01 AU), and malonic dialdehyde level (0.18 ± 0.02 to 0.08 ± 0.01 μM) in the articular fluid (all at p < 0.05). These effects are probably related to the elimination of inefficiency of the antioxidant system in the synovial medium, thus preventing inflammatory destruction of articular tissues, hindering the development of pannus, and assisting the activation of reparative regeneration of connective tissue structures. PMID:25826874

  10. [Normal connective tissue in penis and its changes in patients with erectile dysfunction and Peyronie's disease].

    PubMed

    Neĭmark, A I; Klimachev, V V; Gerval'd, V Ia; Bobrov, I P; Avdalian, A M; Muzalevskaia, N I; Gerval'd, I V; Aliev, R T; Kazymov, M A

    2009-01-01

    The aim of this study was to examine the connective tissue of penis in normal individuals and in patients with erectile dysfunction (ED) and Peyronie's disease (PD) using computer methods of image analysis. Penis tissues were obtained from 20 males aged 20-40 years who died in accidents, penis biopsies were taken from 23 patients with ED and 9 patients with PD (average age: 51 +/- 11.5 years). In both groups of patients, the volumetric fraction of collagen fibers in the tunica albuginea and corpora cavernosa was increased, while that one of elastic fibers was decreased. At the same time, the changes of elastic fibers were noted: the fibers become thinner and formed "rods". The reduction of the amplitude and the wavelength in the collagen fibers of the tunica albuginea in patients with ED and the presence of fibrous plaques in corpora cavernosa in in patients with PD were registered. The methods of computer image analysis may improve the morphologic diagnosis of ED and PD.

  11. Connective tissue-bone onlay graft with enamel matrix derivative for treatment of gingival recession: a case report.

    PubMed

    Nozawa, Takeshi; Sugiyama, Takahiko; Satoh, Tohru; Tanaka, Koji; Enomoto, Hiroaki; Ito, Koichi

    2002-12-01

    We describe a case of gingival recession in which root coverage and coronal bone regrowth were achieved after treatment with a connective tissue-bone graft and enamel matrix derivative. The connective tissue-bone graft was harvested from a maxillary edentulous area and then curved to fit the root surfaces of the maxillary left central and lateral incisors. Enamel matrix derivative was applied to the root surfaces, and the connective tissue-bone graft was fixed to the interdental bone by a titanium screw. Six months later, the exposed roots were covered with thick gingiva, and coronal regrowth of thick bone was evident at reentry surgery. This technique is useful for esthetic restoration placement with an intracrevicular margin on teeth with a thin, receding gingiva.

  12. [The effect of colored light on growth and composition of plant tissue cultures].

    PubMed

    Bergmann, L; Bälz, A

    1966-09-01

    The growth of green cultures of callus tissue from Nicotiana tabacum var. "Samsun" is stimulated by light. To determine whether the increase in growth is caused by photosynthesis or by a blue light dependent increase of protein synthesis, a comparative study was made of the effect which blue and red light have on the growth and the composition of tobacco tissue. It is shown that the growth stimulation by light depends on the chlorophyll content of the tissues. Starting with chlorophyll-free tissue the cultures begin to grow faster in blue light only after they become visibly green. On the other hand, the growth of green tissue in red light decreases as soon as the chlorophyll content under this condition becomes less. There are no differences in the rate of growth of green tissues cultivated in blue and in red light of approximately the same flow of quanta; in both cases the cultures grow better than the controls in the dark. Furthermore there are no differences between the protein and carbohydrate content of tissues grown in blue or red light and in the dark. There is, however, a small but significant difference between the total nitrogen of green tissue and that of chlorophyll-free tissue which is due to a higher amount of soluble nitrogen in the green tissue. From these results it is concluded that the light dependent growth stimulation is caused by photosynthesis. As shown by a light dependent (14)CO2 incorporation in which sucrose is the main product, the green cells are able to fix CO2 photosynthetically. However, the rate of photosynthesis in the tissue cultures is small and does not balance the respiration. It seems very unlikely, therefore, that the formation of carbohydrates by photosynthesis is responsible for the observed growth increase.

  13. Ultrastructural Changes Associated with Reversible Stiffening in Catch Connective Tissue of Sea Cucumbers.

    PubMed

    Tamori, Masaki; Ishida, Kinji; Matsuura, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Takehana, Yasuhiro; Motokawa, Tatsuo; Osawa, Tokuji

    2016-01-01

    The dermis of sea cucumbers is a catch connective tissue or a mutable collagenous tissue that shows rapid, large and reversible stiffness changes in response to stimulation. The main component of the dermis is the extracellular material composed of collagen fibrils embedded in a hydrogel of proteoglycans. The stiffness of the extracellular material determines that of the dermis. The dermis has three mechanical states: soft (Sa), standard (Sb) and stiff (Sc). We studied the ultrastructural changes associated with the stiffness changes. Transverse sections of collagen fibrils in the dermis showed irregular perimeters with electron-dense protrusions or arms that cross-bridged between fibrils. The number of cross-bridges increased in stiffer dermis. The distance between the fibrils was shorter in Sc than that in other states, which was in accord with the previous report that water exuded from the tissue in the transition Sb→Sc. The ultrastructure of collagen fibrils that had been isolated from the dermis was also studied. Fibrils aggregated by tensilin, which causes the transition Sa→Sb possibly through an increase in cohesive forces between fibrils, had larger diameter than those dispersed by softenin, which antagonizes the effect of tensilin. No cross-bridges were found in isolated collagen fibrils. From the present ultrastructural study we propose that three different mechanisms work together to increase the dermal stiffness. 1.Tensilin makes collagen fibrils stronger and stiffer in Sa→Sb through an increase in cohesive forces between subfibrils that constituted fibrils; 2. Cross-bridging by arms caused the fibrils to be a continuous network of bundles both in Sa→Sb and in Sb→Sc; 3. The matrix embedding the fibril network became stiffer in Sb→Sc, which was produced by bonding associated with water exudation. PMID:27192546

  14. Ultrastructural Changes Associated with Reversible Stiffening in Catch Connective Tissue of Sea Cucumbers.

    PubMed

    Tamori, Masaki; Ishida, Kinji; Matsuura, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Takehana, Yasuhiro; Motokawa, Tatsuo; Osawa, Tokuji

    2016-01-01

    The dermis of sea cucumbers is a catch connective tissue or a mutable collagenous tissue that shows rapid, large and reversible stiffness changes in response to stimulation. The main component of the dermis is the extracellular material composed of collagen fibrils embedded in a hydrogel of proteoglycans. The stiffness of the extracellular material determines that of the dermis. The dermis has three mechanical states: soft (Sa), standard (Sb) and stiff (Sc). We studied the ultrastructural changes associated with the stiffness changes. Transverse sections of collagen fibrils in the dermis showed irregular perimeters with electron-dense protrusions or arms that cross-bridged between fibrils. The number of cross-bridges increased in stiffer dermis. The distance between the fibrils was shorter in Sc than that in other states, which was in accord with the previous report that water exuded from the tissue in the transition Sb→Sc. The ultrastructure of collagen fibrils that had been isolated from the dermis was also studied. Fibrils aggregated by tensilin, which causes the transition Sa→Sb possibly through an increase in cohesive forces between fibrils, had larger diameter than those dispersed by softenin, which antagonizes the effect of tensilin. No cross-bridges were found in isolated collagen fibrils. From the present ultrastructural study we propose that three different mechanisms work together to increase the dermal stiffness. 1.Tensilin makes collagen fibrils stronger and stiffer in Sa→Sb through an increase in cohesive forces between subfibrils that constituted fibrils; 2. Cross-bridging by arms caused the fibrils to be a continuous network of bundles both in Sa→Sb and in Sb→Sc; 3. The matrix embedding the fibril network became stiffer in Sb→Sc, which was produced by bonding associated with water exudation.

  15. Ultrastructural Changes Associated with Reversible Stiffening in Catch Connective Tissue of Sea Cucumbers

    PubMed Central

    Tamori, Masaki; Ishida, Kinji; Matsuura, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Takehana, Yasuhiro; Motokawa, Tatsuo; Osawa, Tokuji

    2016-01-01

    The dermis of sea cucumbers is a catch connective tissue or a mutable collagenous tissue that shows rapid, large and reversible stiffness changes in response to stimulation. The main component of the dermis is the extracellular material composed of collagen fibrils embedded in a hydrogel of proteoglycans. The stiffness of the extracellular material determines that of the dermis. The dermis has three mechanical states: soft (Sa), standard (Sb) and stiff (Sc). We studied the ultrastructural changes associated with the stiffness changes. Transverse sections of collagen fibrils in the dermis showed irregular perimeters with electron-dense protrusions or arms that cross-bridged between fibrils. The number of cross-bridges increased in stiffer dermis. The distance between the fibrils was shorter in Sc than that in other states, which was in accord with the previous report that water exuded from the tissue in the transition Sb→Sc. The ultrastructure of collagen fibrils that had been isolated from the dermis was also studied. Fibrils aggregated by tensilin, which causes the transition Sa→Sb possibly through an increase in cohesive forces between fibrils, had larger diameter than those dispersed by softenin, which antagonizes the effect of tensilin. No cross-bridges were found in isolated collagen fibrils. From the present ultrastructural study we propose that three different mechanisms work together to increase the dermal stiffness. 1.Tensilin makes collagen fibrils stronger and stiffer in Sa→Sb through an increase in cohesive forces between subfibrils that constituted fibrils; 2. Cross-bridging by arms caused the fibrils to be a continuous network of bundles both in Sa→Sb and in Sb→Sc; 3. The matrix embedding the fibril network became stiffer in Sb→Sc, which was produced by bonding associated with water exudation. PMID:27192546

  16. Connectivity

    ERIC Educational Resources Information Center

    Grush, Mary, Ed.

    2006-01-01

    Connectivity has dramatically changed the landscape of higher education IT. From "on-demand" services for net-gen students and advanced eLearning systems for faculty, to high-performance computing grid resources for researchers, IT now provides more networked services than ever to connect campus constituents to each other and to the world.…

  17. Connection and Regulation at Home and in School: Predicting Growth in Achievement for Adolescents

    ERIC Educational Resources Information Center

    Gregory, Anne; Weinstein, Rhona S.

    2004-01-01

    Qualities of adolescent-adult relationships across home and school environments are examined as predictors of academic growth in mathematics. An ethnically diverse sample of adolescents was drawn from the National Educational Longitudinal Study, 1988. In separate analyses, adolescents' perceptions of (a) connection with parents and teachers and…

  18. Connections between Student Explanations and Arguments from Evidence about Plant Growth

    ERIC Educational Resources Information Center

    Dauer, Jenny M.; Doherty, Jennifer H.; Freed, Allison L.; Anderson, Charles W.

    2014-01-01

    We investigate how students connect explanations and arguments from evidence about plant growth and metabolism--two key practices described by the "Next Generation Science Standards". This study reports analyses of interviews with 22 middle and high school students postinstruction, focusing on how their sense-making strategies led them…

  19. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary arterial hypertension associated with connective tissue diseases

    PubMed Central

    Boueiz, Adel; Hassoun, Paul M.

    2014-01-01

    The explosive growth of medical literature on pulmonary hypertension (PH) has led to a steady increase in awareness of this disease within the medical community during the past decade. The recent revision of the classification of PH is presented in in the main guidelines. Group 1 PH or pulmonary arterial hypertension (PAH) is a heterogeneous group and includes PH due to inheritable, drug-induced, and toxin-induced causes and to such underlying systemic causes as connective tissue diseases, human immunodeficiency viral infection, portal hypertension, congenital heart disease, and schistosomiasis. Systemic sclerosis (SSc) is an autoimmune multisystem disorder, which affects over 240 persons per million in the United States.[1] Its manifestations are not confined to the skin but may also involve the lungs, kidneys, peripheral circulation, musculoskeletal system, gastrointestinal tract, and heart. The outcome of PAH associated with SSc is worse when compared to other subtypes of PAH. In this review, we summarize available information about the pulmonary vascular and cardiac manifestations of SSc with special emphasis on their prognostic implications as well as the peculiarity of their detection. PMID:25076994

  20. Hierarchical mechanics of connective tissues: integrating insights from nano to macroscopic studies.

    PubMed

    Gohl, Kheng Lim; Listrat, Anne; Béchet, Daniel

    2014-10-01

    As the key component of the musculoskeletal system, the extracellular matrix of soft connective tissues such as ligaments and tendons is a biological example of fibre-reinforced composite but with a complex hierarchical architecture. To establish a comprehensive structure-function relationship at the respective levels (i.e., from molecule to tissue) of the hierarchical architecture is challenging and requires a multidisciplinary approach, involving the integration of findings from the fields of molecular biology, biochemistry, structural biology, materials science and biophysics. Accordingly, in recent years, some of these fields, namely structural biology, materials science and biophysics, have made significant progress in the microscale and nanoscale studies of extracellular matrix using new tools, such as microelectromechanical systems, optical tweezers and atomic force microscopy, complemented by new techniques in simultaneous imaging and mechanical testing and computer modelling. The intent of this paper is to review the key findings on the mechanical response of extracellular matrix at the respective levels of the hierarchical architecture. The main focus is on the structure and function--the findings are compared across the different levels to provide insights that support the goal of establishing a comprehensive structure-function relationship of extracellular matrix. For this purpose, the review is divided into two parts. The first part explores the features of key structural units of extracellular matrix, namely tropocollagen molecule (the lowest level), microfibril, collagen fibril, collagen fibre and fascicle. The second part examines the mechanics of the structural units at the respective levels. Finally a framework for extracellular matrix mechanics is proposed to support the goal to establish a comprehensive structure-function relationship. The framework describes the integration of the mechanisms of reinforcement by the structural units at the

  1. Hierarchical mechanics of connective tissues: integrating insights from nano to macroscopic studies.

    PubMed

    Gohl, Kheng Lim; Listrat, Anne; Béchet, Daniel

    2014-10-01

    As the key component of the musculoskeletal system, the extracellular matrix of soft connective tissues such as ligaments and tendons is a biological example of fibre-reinforced composite but with a complex hierarchical architecture. To establish a comprehensive structure-function relationship at the respective levels (i.e., from molecule to tissue) of the hierarchical architecture is challenging and requires a multidisciplinary approach, involving the integration of findings from the fields of molecular biology, biochemistry, structural biology, materials science and biophysics. Accordingly, in recent years, some of these fields, namely structural biology, materials science and biophysics, have made significant progress in the microscale and nanoscale studies of extracellular matrix using new tools, such as microelectromechanical systems, optical tweezers and atomic force microscopy, complemented by new techniques in simultaneous imaging and mechanical testing and computer modelling. The intent of this paper is to review the key findings on the mechanical response of extracellular matrix at the respective levels of the hierarchical architecture. The main focus is on the structure and function--the findings are compared across the different levels to provide insights that support the goal of establishing a comprehensive structure-function relationship of extracellular matrix. For this purpose, the review is divided into two parts. The first part explores the features of key structural units of extracellular matrix, namely tropocollagen molecule (the lowest level), microfibril, collagen fibril, collagen fibre and fascicle. The second part examines the mechanics of the structural units at the respective levels. Finally a framework for extracellular matrix mechanics is proposed to support the goal to establish a comprehensive structure-function relationship. The framework describes the integration of the mechanisms of reinforcement by the structural units at the

  2. Growth factor and small molecule influence on urological tissue regeneration utilizing cell seeded scaffolds.

    PubMed

    Sharma, Arun K; Cheng, Earl Y

    2015-03-01

    Regenerative medicine strategies combine various attributes from multiple disciplines including stem cell biology, chemistry, materials science and medicine. The junction at which these disciplines intersect provides a means to address unmet medical needs in an assortment of pathologies with the goal of creating sustainable, functional replacement tissues. Tissue damage caused by trauma for example, requires rapid responses in order to mitigate further tissue deterioration. Cell/scaffold composites have been utilized to initiate and stabilize regenerative responses in vivo with the hope that functional tissue can be attained. Along with the gross reconfiguration of regenerating tissues, small molecules and growth factors also play a pivotal role in tissue regeneration. Several regenerative studies targeting a variety of urological tissues demonstrate the utility of these small molecules or growth factors in an in vivo setting.

  3. Biomaterials for the programming of cell growth in oral tissues: The possible role of APA.

    PubMed

    Salerno, Marco; Giacomelli, Luca; Larosa, Claudio

    2011-01-06

    Examples of programmed tissue response after the interaction of cells with biomaterials are a hot topic in current dental research. We propose here the use of anodic porous alumina (APA) for the programming of cell growth in oral tissues. In particular, APA may trigger cell growth by the controlled release of specific growth factors and/or ions. Moreover, APA may be used as a scaffold to promote generation of new tissue, due to the high interconnectivity of pores and the high surface roughness displayed by this material.

  4. Development of oral and extra-oral endosseous craniofacial implants by using a mesh structure for connective tissue attachment.

    PubMed

    Mita, Atsushi; Yagihara, Atsushi; Wang, Wei; Takakuda, Kazuo

    2014-03-19

    Connective tissue attachment to a mesh structure incorporated on the surface of oral implants and extra-oral endosseous craniofacial implants (EOECI) was investigated. Two types of implants were prepared: TI and TI-Mesh. TI was composed of an upper and a lower component, both comprised of a titanium cylinder, which could be connected using a titanium screw. The composition of the TIMesh was similar, but the lower cylinder had a lateral groove that was covered with a titanium mesh. In animal experiments performed using rat calvaria, the lower component was first implanted and was left submerged for 3 weeks, then the upper component was mounted percutaneously. After an additional 2 weeks, each implant and the surrounding tissues were harvested and evaluated. Histological observations revealed collagen fibers originating from surrounding hypodermal tissues anchored to the mesh structures of the TI-Mesh whereas no such collagen fibers were observed around TI. Significantly greater values of the attachment strength, the thickness of the dermal tissue, the thickness of hypodermal tissue, and the attachment lengths were observed in TI-Mesh than those of TI. Thus connective tissue attachment with collagen fibers anchored to the mesh was achieved by incorporating mesh structures into the percutaneously placed implants.

  5. Mycobacterium chelonae cutaneous infection in a patient with mixed connective tissue disease*

    PubMed Central

    Lage, Renan; Biccigo, Danilo Guerreiro Zeolo; Santos, Felipe Borba Calixto; Chimara, Erica; Pereira, Elisangela Samartin Pegas; da Costa, Adilson

    2015-01-01

    Around 50 mycobacteria species cause human disease. Immunosuppressive states predispose to non-tuberculous mycobaterium infection, such as Mycobacterium chelonae: AFB, non-tuberculous, fast growth of low virulence and uncommon as a human pathogen. It may compromise the skin and soft tissues, lungs, lymph nodes and there is also a disseminated presentation. The diagnosis involves AFB identification and culture on Agar and Lowenstein-Jensen medium base. A 41-year-old female with MCTD (LES predominance) is reported, presenting painless nodules in the right forearm. She denied local trauma. Immunosuppressed with prednisone and cyclophosphamide for 24 months. Lesion biopsy has demonstrated positive bacilloscopy (Ziehl-Neelsen stain) and M.chelonae in culture (Lowenstein-Jensen medium base), therefore clarithromycin treatment has been started (best therapy choice in the literature). PMID:25672306

  6. Influence of maturation and aging on mechanical and biochemical properties of connective tissue in rats.

    PubMed

    Vogel, H G

    1980-01-01

    The influence of maturation and age on the physical and chemical properties of various organs of connective tissue has been studied in rats at ages of 4 weeks, 8 weeks, 4 monhs, 1 year and 2 years. The changes between young (4 weeks old) and adult (4 months to 1 year old) animals were considered as the effects of maturation, whereas the changes between adult and senescent (2 years old) rats were regarded as the effects of aging. Ultimate values, such as ultimate load, tensile strength and breaking strength, or ultimate modulus of elasticity, showed a sharp rise during maturation and a smaller but significant decrease during aging in all organs, such as skin strips, tail tendons, shaft bones, epiphyseal cartilage and aorta rings. Ultimate strain showed a similar pattern, but the maximum occurred earlier. These changes were parallel with the content of insoluble collagen. Other chemical parameters such as soluble collagen or glycosaminoglycans, showed a continuous decrease during the life span, whereas elastin rose continuously. More detailed analysis of mechanical properties in rat skin gave insight into the viscoelastic behaviour of skin. In creep experiments time until break under constant load rose continuously during the life span, whereas ultimate extension rate showed a sharp fall during maturation and a slow decrease during senescence. Stress at low extension degree and moduli of elasticity at low extension degree were decreased by maturation and increased by senescence, exactly the opposite of the changes at high extension degrees. The so-called step phenomenon was increased due to maturation and decreased due to aging. Relaxation and mechanical recovery were changed in the same direction by maturation and aging. Relative viscoelastic parameters, such as the hysteresis phenomenon and relative decrease of stress under cyclic strain, were barely influenced by the aging process. Changes of most of the mechanical parameters at high extension degrees during

  7. Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL

    PubMed Central

    Liu, Juliana; Parsons, Lori; Hassoun, Paul M.; McGoon, Michael; Badesch, David B.; Miller, Dave P.; Nicolls, Mark R.; Zamanian, Roham T.

    2010-01-01

    Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH). Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH). Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco

  8. Experiment K-6-02. Biomedical, biochemical and morphological alterations of muscle and dense, fibrous connective tissues during 14 days of spaceflight

    NASA Technical Reports Server (NTRS)

    Vailas, A.; Zernicke, R.; Grindeland, R.; Kaplanski, A.

    1990-01-01

    Findings on the connective tissue response to short-term space flight (12 days) are discussed. Specifically, data regarding the biochemical, biomechanical and morphological characteristics of selected connective tissues (humerus, vertebral body, tendon and skeletal muscle) of growing rats is given. Results are given concerning the humerus cortical bone, the vertebral bone, nutritional effects on bone biomechanical properties, and soft tense fiber connective tissue response.

  9. Postulating a Role for Connective Tissue Elements in Inferior Oblique Muscle Overaction (An American Ophthalmological Society Thesis)

    PubMed Central

    Stager, David; McLoon, Linda K.; Felius, Joost

    2013-01-01

    Purpose: To compare the localization and density of collagens I, IV, VI, and elastin, the major protein components of connective tissue, in the inferior oblique muscle of patients with overelevation in adduction and in controls and to characterize changes that develop following surgery. Biomechanical studies suggest that the connective tissue matrix plays a critical role in extraocular muscle function, determining tensile strength and force transmission during contraction. Methods: Prospective laboratory-based case-control study of inferior oblique muscle specimens from 31 subjects: 16 with primary inferior oblique overaction, 6 with craniofacial dysostosis, and 9 normal controls. Collagen I, IV, VI, and elastin were localized and quantified using immunohistochemical staining. Densities were compared using analysis of variance and post hoc comparisons. Results: In primary inferior oblique overaction, all connective tissue components in unoperated specimens were elevated compared to controls (P<.0001). Previously operated muscles showed normal levels of collagens IV and VI (P>.27) but increased collagen I. In unoperated craniofacial dysostosis specimens, only elastin was elevated (P=.03), whereas density of collagens IV and VI was lower in previously operated vs unoperated specimens (P=.015). Conclusions: Elevated collagen and elastin levels in the cohort with primary inferior oblique overaction are consistent with the clinical finding of muscle stiffness. Contrarily, normal connective tissue densities in craniofacial dysostosis support the hypothesis that overelevation in this group reflects anomalous muscle vectors rather than tissue changes. Surgical intervention was associated with changes in the connective tissue matrix in both cohorts. These results have ramifications for treating patients with overelevation in adduction. PMID:24385670

  10. The cytotoxic evaluation of mineral trioxide aggregate and bioaggregate in the subcutaneous connective tissue of rats

    PubMed Central

    Acar, Gözde; Yalcin, Yagmur; Dindar, Seckin; Sancakli, Hande; Erdemir, Ugur

    2013-01-01

    Objectives: The purpose of this study was to evaluate and compare the cytotoxic effects of ProRoot MTA and DiaRoot BA, a bioceramic nanoparticulate cement, on subcutaneous rat tissue. Study Design: Fifty Sprouge Dawley rats were used in this study. Polyethylene tubes filled with ProRoot MTA and DiaRoot BioAggregate, along with a control group of empty, were implanted into dorsal connective tissue of rats for 7, 15, 30, 60, and 90 days. After estimated time intervals the rats were sacrificed. The specimens were fixed, stained with hematoxylin and eosin, and then evaluated under a light microscope for inflammatory reactions and mineralization. Results: All groups evoked a severe to moderate chronic inflammatory reaction at 7 and 15 days, which decreased with time. Both the MTA and BioAggregate groups showed similar inflammatory reactions, except at 90 days when MTA showed statistically significant greater inflammation (p>0.05). The MTA group showed foreign body reaction at all times. Compared to BioAggregate, MTA showed significantly more foreign body reaction at 60 and 90 days (p<0.0001). After 30 days foreign body reaction of BioAggregate decreased significantly. Both MTA and BioAggregate groups showed similar necrosis at 7 and 15 days (p=0.094 and p=0.186 respectively). No necrosis was observed after 15 days. Similarly there was no fibrosis after 30 days for both MTA and BioAggregate groups (p>0.05). Conclusions: Since DiaRoot BioAggregate showed significantly better results than MTA, we can conclude that it is more biocompatible. However, further studies are required to confirm this result. Key words:Biocompatibility, mineral trioxide aggregate, bioAggregate. PMID:23722144

  11. Intramuscular Connective Tissue Differences in Spastic and Control Muscle: A Mechanical and Histological Study

    PubMed Central

    de Bruin, Marije; Smeulders, Mark J.; Kreulen, Michiel; Huijing, Peter A.; Jaspers, Richard T

    2014-01-01

    Cerebral palsy (CP) of the spastic type is a neurological disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks. Secondary to the spasticity, muscle adaptation is presumed to contribute to limitations in the passive range of joint motion. However, the mechanisms underlying these limitations are unknown. Using biopsies, we compared mechanical as well as histological properties of flexor carpi ulnaris muscle (FCU) from CP patients (n = 29) and healthy controls (n = 10). The sarcomere slack length (mean 2.5 µm, SEM 0.05) and slope of the normalized sarcomere length-tension characteristics of spastic fascicle segments and single myofibre segments were not different from those of control muscle. Fibre type distribution also showed no significant differences. Fibre size was significantly smaller (1933 µm2, SEM 190) in spastic muscle than in controls (2572 µm2, SEM 322). However, our statistical analyses indicate that the latter difference is likely to be explained by age, rather than by the affliction. Quantities of endomysial and perimysial networks within biopsies of control and spastic muscle were unchanged with one exception: a significant thickening of the tertiary perimysium (3-fold), i.e. the connective tissue reinforcement of neurovascular tissues penetrating the muscle. Note that this thickening in tertiary perimysium was shown in the majority of CP patients, however a small number of patients (n = 4 out of 23) did not have this feature. These results are taken as indications that enhanced myofascial loads on FCU is one among several factors contributing in a major way to the aetiology of limitation of movement at the wrist in CP and the characteristic wrist position of such patients. PMID:24977410

  12. Intramuscular connective tissue differences in spastic and control muscle: a mechanical and histological study.

    PubMed

    de Bruin, Marije; Smeulders, Mark J; Kreulen, Michiel; Huijing, Peter A; Jaspers, Richard T

    2014-01-01

    Cerebral palsy (CP) of the spastic type is a neurological disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks. Secondary to the spasticity, muscle adaptation is presumed to contribute to limitations in the passive range of joint motion. However, the mechanisms underlying these limitations are unknown. Using biopsies, we compared mechanical as well as histological properties of flexor carpi ulnaris muscle (FCU) from CP patients (n = 29) and healthy controls (n = 10). The sarcomere slack length (mean 2.5 µm, SEM 0.05) and slope of the normalized sarcomere length-tension characteristics of spastic fascicle segments and single myofibre segments were not different from those of control muscle. Fibre type distribution also showed no significant differences. Fibre size was significantly smaller (1933 µm2, SEM 190) in spastic muscle than in controls (2572 µm2, SEM 322). However, our statistical analyses indicate that the latter difference is likely to be explained by age, rather than by the affliction. Quantities of endomysial and perimysial networks within biopsies of control and spastic muscle were unchanged with one exception: a significant thickening of the tertiary perimysium (3-fold), i.e. the connective tissue reinforcement of neurovascular tissues penetrating the muscle. Note that this thickening in tertiary perimysium was shown in the majority of CP patients, however a small number of patients (n = 4 out of 23) did not have this feature. These results are taken as indications that enhanced myofascial loads on FCU is one among several factors contributing in a major way to the aetiology of limitation of movement at the wrist in CP and the characteristic wrist position of such patients.

  13. A stress driven growth model for soft tissue considering biological availability

    NASA Astrophysics Data System (ADS)

    Oller, S.; Bellomo, F. J.; Armero, F.; Nallim, L. G.

    2010-06-01

    Some of the key factors that regulate growth and remodeling of tissues are fundamentally mechanical. However, it is important to take into account the role of bioavailability together with the stresses and strains in the processes of normal or pathological growth. In this sense, the model presented in this work is oriented to describe the growth of soft biological tissue under "stress driven growth" and depending on the biological availability of the organism. The general theoretical framework is given by a kinematic formulation in large strain combined with the thermodynamic basis of open systems. The formulation uses a multiplicative decomposition of deformation gradient, splitting it in a growth part and visco-elastic part. The strains due to growth are incompatible and are controlled by an unbalanced stresses related to a homeostatic state. Growth implies a volume change with an increase of mass maintaining constant the density. One of the most interesting features of the proposed model is the generation of new tissue taking into account the contribution of mass to the system controlled through biological availability. Because soft biological tissues in general have a hierarchical structure with several components (usually a soft matrix reinforced with collagen fibers), the developed growth model is suitable for the characterization of the growth of each component. This allows considering a different behavior for each of them in the context of a generalized theory of mixtures. Finally, we illustrate the response of the model in case of growth and atrophy with an application example.

  14. Growth-related neural reorganization and the autism phenotype: a test of the hypothesis that altered brain growth leads to altered connectivity.

    PubMed

    Lewis, John D; Elman, Jeffrey L

    2008-01-01

    Theoretical considerations, and findings from computational modeling, comparative neuroanatomy and developmental neuroscience, motivate the hypothesis that a deviant brain growth trajectory will lead to deviant patterns of change in cortico-cortical connectivity. Differences in brain size during development will alter the relative cost and effectiveness of short- and long-distance connections, and should thus impact the growth and retention of connections. Reduced brain size should favor long-distance connectivity; brain overgrowth should favor short-distance connectivity; and inconsistent deviations from the normal growth trajectory - as occurs in autism - should result in potentially disruptive changes to established patterns of functional and physical connectivity during development. To explore this hypothesis, neural networks which modeled inter-hemispheric interaction were grown at the rate of either typically developing children or children with autism. The influence of the length of the inter-hemispheric connections was analyzed at multiple developmental time-points. The networks that modeled autistic growth were less affected by removal of the inter-hemispheric connections than those that modeled normal growth - indicating a reduced reliance on long-distance connections - for short response times, and this difference increased substantially at approximately 24 simulated months of age. The performance of the networks showed a corresponding decline during development. And direct analysis of the connection weights showed a parallel reduction in connectivity. These modeling results support the hypothesis that the deviant growth trajectory in autism spectrum disorders may lead to a disruption of established patterns of functional connectivity during development, with potentially negative behavioral consequences, and a subsequent reduction in physical connectivity. The results are discussed in relation to the growing body of evidence of reduced functional and

  15. Ectopic mineralization disorders of the extracellular matrix of connective tissue: molecular genetics and pathomechanisms of aberrant calcification.

    PubMed

    Li, Qiaoli; Jiang, Qiujie; Uitto, Jouni

    2014-01-01

    Ectopic mineralization of connective tissues is a complex process leading to deposition of calcium phosphate complexes in the extracellular matrix, particularly affecting the skin and the arterial blood vessels and common in age-associated disorders. A number of initiating and contributing metabolic and environmental factors are linked to aberrant mineralization in these diseases, making the identification of precise pathomechanistic pathways exceedingly difficult. However, there has been significant recent progress in understanding the ectopic mineralization processes through study of heritable single-gene disorders, which have allowed identification of discrete pathways and contributing factors leading to aberrant connective tissue mineralization. These studies have provided support for the concept of an intricate mineralization/anti-mineralization network present in peripheral connective tissues, providing a perspective to development of pharmacologic approaches to limit the phenotypic consequences of ectopic mineralization. This overview summarizes the current knowledge of ectopic heritable mineralization disorders, with accompanying animal models, focusing on pseudoxanthoma elasticum and generalized arterial calcification of infancy, two autosomal recessive diseases manifesting with extensive connective tissue mineralization in the skin and the cardiovascular system.

  16. [Features of fluor intoxication development in patients with nondifferentiated connective tissue dysplasia and physical therapy methods for these patients].

    PubMed

    Tereshina, L G; Budkar', L N; Obukhova, T Iu; Bugaeva, I V; Karpova, E A

    2013-01-01

    The article covers results of studies concerning time of fluorosis development in patients with signs of connective tissue dysplasia syndrome (CTDS). if compared with patients without CTDS, and of studies concerning hyperostosis coefficient in accordance with presence or absence of CTDS. Efficiency of physical therapy and balneotherapy for these patients are also reported by the authors.

  17. Nano-Fibrous Tissue Engineering Scaffolds Capable of Growth Factor Delivery

    PubMed Central

    Hu, Jiang

    2011-01-01

    Tissue engineering aims at constructing biological substitutes to repair damaged tissues. Three-dimensional (3D) porous scaffolds are commonly utilized to define the 3D geometry of tissue engineering constructs and provide adequate pore space and surface to support cell attachment, migration, proliferation, differentiation and neo tissue genesis. Biomimetic 3D scaffolds provide synthetic microenvironments that mimic the natural regeneration microenvironments and promote tissue regeneration process. While nano-fibrous (NF) scaffolds are constructed to mimic the architecture of NF extracellular matrix, controlled-release growth factors are incorporated to modulate the regeneration process. The present article summarizes current advances in methods to fabricate NF polymer scaffolds and the technologies to incorporate controlled growth factor delivery systems into 3D scaffolds, followed by examples of accelerated regeneration when the scaffolds with growth factor releasing capacity are applied in animal models. PMID:21234657

  18. Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus.

    PubMed Central

    Ruuska, P; Hämeenkorpi, R; Forsberg, S; Julkunen, H; Mäkitalo, R; Ilonen, J; Tiilikainen, A

    1992-01-01

    Patients with mixed connective tissue disease (MCTD, n = 32) or systemic lupus erythematosus (SLE, n = 60) were typed for HLA-A, B, C, Dw, and DR antigens. All patients with SLE fulfilled at least four criteria of SLE and the patients with MCTD met the criteria proposed by Alarcon-Segovia (1989). The presence of antibodies to Sm was not considered as an exclusion for MCTD. In the patients with SLE, Dw3, DR3, and the associated B8 and A1 antigens were increased, whereas in the patients with MCTD an increased frequency of Dw4 was found (45 v 18% in controls v 14% in SLE). Of the subtypes of DR4, Dw4 was present in all but one of the DR4 positive patients. The frequency of DR4 in patients with MCTD (52%) differed significantly from that of controls (28%). The strong association of MCTD to one DR4 subtype was further seen in the significantly increased frequency of the B15, DR4 combination. Thus the genetic background seems to be different in patients with MCTD from that in patients with SLE. This could partly explain the clinical differences between these diseases. PMID:1540038

  19. Relationships between physical and structural properties of intramuscular connective tissue and toughness of raw pork.

    PubMed

    Nishimura, Takanori; Fang, Suhong; Wakamatsu, Jun-ichi; Takahashi, Koui

    2009-02-01

    We studied the relationships between the shear-force value and physical and structural properties of the intramuscular connective tissue (IMCT) in six classes of porcine skeletal muscle to elucidate the contribution of IMCT to toughness of raw pork. The shear-force value of raw pork correlated significantly with that of the IMCT model prepared from each class of skeletal muscle (P < 0.05). The correlation suggested that the variable toughness of pork was caused by the mechanical strength of the endomysium and perimysium. The thickness of the secondary perimysium correlated significantly with the shear-force value of raw pork (P < 0.05) and with that of the IMCT model (P < 0.05). The shear-force value of raw pork correlated significantly with the total amount of collagen (P < 0.05) but not with the heat-solubility of collagen. We concluded therefore that the thickness of the secondary perimysium determines the mechanical strength of IMCT and contributes to toughness in raw pork.

  20. Interstitial lung disease in connective tissue disease--mechanisms and management.

    PubMed

    Wells, Athol U; Denton, Christopher P

    2014-12-01

    Pulmonary complications are an important extra-articular feature of autoimmune rheumatic diseases and a major cause of mortality. The underlying pathogenesis probably involves multiple cellular compartments, including the epithelium, lung fibroblasts, and the innate and adaptive immune system. Heterogeneity in the extent and progression of lung fibrosis probably reflects differences in underlying pathogenic mechanisms. Growing understanding of the key pathogenic drivers of lung fibrosis might lead to the development of more effective targeted therapies to replicate the treatment advances in other aspects of these diseases. Interstitial lung disease (ILD) in connective tissue disease (CTD) is characterized using the classification of the idiopathic interstitial pneumonias. Systemic sclerosis is most frequently associated with ILD and, in most of these patients, ILD manifests as a histological pattern of nonspecific interstitial pneumonia. Conversely, in rheumatoid arthritis, the pattern of ILD is most often usual interstitial pneumonia. The key goals of clinical assessment of patients with both ILD and CTD are the detection of ILD and prognostic evaluation to determine which patients should be treated. Data from treatment trials in systemic sclerosis support the use of immunosuppressive therapy, with the treatment benefit largely relating to the prevention of progression of lung disease.

  1. Connective tissue disease-associated pulmonary arterial hypertension in Chinese patients.

    PubMed

    Hao, Yan-Jie; Jiang, Xin; Zhou, Wei; Wang, Yong; Gao, Lan; Wang, Yu; Li, Guang-Tao; Hong, Tao; Huo, Yong; Jing, Zhi-Cheng; Zhang, Zhuo-Li

    2014-10-01

    We sought to investigate the characteristics, survival and risk factors for mortality in Chinese patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (APAH) in modern therapy era. 129 consecutive adult patients who visited one of three referral centres in China with a diagnosis of CTD-APAH confirmed by right heart catheterisation during the previous 5 years were enrolled. The end-point was all-cause death or data censoring. Systemic lupus erythematosus was the most common underlying CTD (49%) and systemic sclerosis just accounted for 6% in this cohort. The overall survival at 1 and 3 years was 92% and 80%, respectively. Pericardial effusion, a shorter 6-min walk distance, lower mixed venous oxygen saturation, higher pulmonary vascular resistance (PVR) and alkaline phosphatase (ALP), and lower total cholesterol levels were all associated with a higher risk of death among the study population. Higher PVR and ALP were independent predictors of mortality. In conclusion, unlike in western patients, systemic lupus erythematosus is the most common underlying disease in Chinese patients with CTD-APAH. The survival of Chinese patients with CTD-APAH in the modern treatment era is similar to that in western countries. Elevated PVR and ALP are independent risk factors for poor outcomes.

  2. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis.

    PubMed

    Marigliano, Benedetta; Soriano, Alessandra; Margiotta, Domenico; Vadacca, Marta; Afeltra, Antonella

    2013-09-01

    The lungs are frequently involved in Connective Tissue Diseases (CTDs). Interstitial lung disease (ILD) is one of the most common pleuropulmonary manifestations that affects prognosis significantly. In practice, rheumatologists and other physicians tend to underestimate the impact of CTD-ILDs and diagnose respiratory impairment when it has reached an irreversible fibrotic stage. Early investigation, through clinical evidence, imaging and - in certain cases - lung biopsy, is therefore warranted in order to detect a possible ILD at a reversible initial inflammatory stage. In this review, we focus on lung injury during CTDs, with particular attention to ILDs, and examine their prevalence, clinical manifestations and histological patterns, as well as therapeutic approaches and known complications till date. Although several therapeutic agents have been approved, the best treatment is still not certain and additional trials are required, which demand more knowledge of pulmonary involvement in CTDs. Our central aim is therefore to document the impact that lung damage has on CTDs. We will mainly focus on Rheumatoid Arthritis (RA), which - unlike other rheumatic disorders - resembles Idiopathic Pulmonary Fibrosis (IPF) in numerous aspects.

  3. Undifferentiated connective tissue disease-associated interstitial lung disease: changes in lung function.

    PubMed

    Kinder, Brent W; Shariat, Cyrus; Collard, Harold R; Koth, Laura L; Wolters, Paul J; Golden, Jeffrey A; Panos, Ralph J; King, Talmadge E

    2010-04-01

    Undifferentiated connective tissue disease (UCTD) is a distinct clinical entity that may be accompanied by interstitial lung disease (ILD). The natural history of UCTD-ILD is unknown. We hypothesized that patients with UCTD-ILD would be more likely to have improvement in lung function than those with idiopathic pulmonary fibrosis (IPF) during longitudinal follow-up. We identified subjects enrolled in the UCSF ILD cohort study with a diagnosis of IPF or UCTD. The primary outcome compared the presence or absence of a > or = 5% increase in percent predicted forced vital capacity (FVC) in IPF and UCTD. Regression models were used to account for potential confounding variables. Ninety subjects were identified; 59 subjects (30 IPF, 29 UCTD) had longitudinal pulmonary function data for inclusion in the analysis. After accounting for baseline pulmonary function tests, treatment, and duration between studies, UCTD was associated with substantial improvement in FVC (odds ratio = 8.23, 95% confidence interval, 1.27-53.2; p = 0.03) during follow-up (median, 8 months) compared with IPF. Patients with UCTD-ILD are more likely to have improved pulmonary function during follow-up than those with IPF. These findings demonstrate the clinical importance of identifying UCTD in patients presenting with an "idiopathic" interstitial pneumonia.

  4. Invasive pulmonary fungal infections in patients with connective tissue disease: a retrospective study from northern China

    PubMed Central

    Ge, H.F.; Liu, X.Q.; Zhu, Y.Q.; Chen, H.Q.; Chen, G.Z.

    2016-01-01

    Invasive pulmonary fungal infection (IPFI) is a potentially fatal complication in patients with connective tissue disease (CTD). The current study aimed to uncover the clinical characteristics and risk factors of patients with IPFI-CTD. The files of 2186 CTD patients admitted to a single center in northern China between January 2011 and December 2013 were retrospectively reviewed. A total of 47 CTD patients with IPFI were enrolled into this study and assigned to the CTD-IPFI group, while 47 uninfected CTD patients were assigned to the control group. Clinical manifestations were recorded, and risk factors of IPFI were calculated by stepwise logistical regression analysis. Forty-seven (2.15%) CTD patients developed IPFI. Systemic lupus erythematosus patients were responsible for the highest proportion (36.17%) of cases with IPFI. Candida albicans (72.3%) accounted for the most common fungal species. CTD-IPFI patients had significantly elevated white blood cell count, erythrocyte sedimentation rate, C-reactive protein and fasting glucose values compared to controls (P<0.05). Cough, sputum and blood in phlegm were the most common symptoms. Risk factors of IPFI in CTD included maximum prednisone dose ≥30 mg/day within 3 months prior to infection, anti-microbial drug therapy, and interstitial pneumonia. CTD patients who have underlying interstitial pneumonia, prior prednisone or multiple antibiotics, were more likely to develop IPFI. PMID:27683823

  5. An immunological study of glycosaminoglycans in the connective tissue of bovine and cod skeletal muscle.

    PubMed

    Hannesson, Kirsten O; Tingbø, Monica G; Olsen, Ragnar L; Enersen, Grethe; Baevre, Anne Birgit; Ofstad, Ragni

    2007-04-01

    The presence of sulfated glycosaminoglycans (GAGs) was demonstrated in the connective tissue of bovine and cod skeletal muscle by histochemical staining using Alcian blue added MgCl(2) (0.06 M and 0.4 M, respectively). For further identification of the sulfated GAGs, a panel of monoclonal antibodies, 1B5, 2B6, 3B3 and 5D4 was used that recognizes epitopes in chondroitin-0-sulfate (C0S), chondroitin-4-sulfate/dermatan sulfate (C4S/DS), chondroitin-6-sulfate (C6S) and keratan sulfate (KS), respectively. Light microscopy and Western blotting techniques showed that in bovine and cod muscle C0S and C6S were primarily localized pericellularly, whereas cod exhibited a more intermittent staining. C4S was expressed around the separate cells and also in the perimysium and myocommata. In contrast to bovine muscle, which hardly expressed highly sulfated KS, cod exhibited a very strong and consistent staining. Western blotting showed that C0S and C6S were mainly associated with proteoglycans (PGs) of high molecular sizes in both species. Contrary to bovine muscle, C4S in cod was associated with molecules of various sizes. Both cod and bovine muscle contained KSPGs of similar sizes as C4S. KSPGs of different sizes and buoyant densities, sensitive to keratanase I and II were found expressed in cod. PMID:17270478

  6. Repetitive differential finger motion increases shear strain between the flexor tendon and subsynovial connective tissue.

    PubMed

    Tat, Jimmy; Kociolek, Aaron M; Keir, Peter J

    2013-10-01

    Non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT) are characteristic in carpal tunnel syndrome (CTS) patients. These pathological changes have been linked to repetitive hand tasks that create shear forces between the flexor tendons and SSCT. We measured the relative motion of the flexor digitorum superficialis tendon and SSCT during two repetitive finger tasks using color Doppler ultrasound. Twelve participants performed flexion-extension cycles for 30 min with the long finger alone (differential movement) and with all four fingers together (concurrent movement). Shear strain index (SSI, a relative measure of excursion in flexion and extension) and maximum velocity ratio (MVR, the ratio of SSCT versus tendon during flexion and extension) were used to represent shear. A linear effect of exertion time was significant and corresponded with larger tendon shear in differential motion. The flexion SSI increased 20.4% from the first to the 30th minute, while MVR decreased 8.9% in flexion and 8.7% in extension. No significant changes were found during concurrent motion. These results suggest that exposure to repetitive differential finger tasks may increase the risk of shear injury in the carpal tunnel.

  7. Assessment and management of connective tissue disease-associated interstitial lung disease.

    PubMed

    Fischer, Aryeh; Chartrand, Sandra

    2015-01-01

    The intersection of the connective tissue diseases (CTD) and the interstitial lung diseases (ILD) is complex. Although often considered as a single entity, "CTD-ILD" actually reflects a heterogeneous spectrum of diverse CTDs and a variety of patterns of interstitial pneumonia. The evaluation of patients with CTD that develop ILD, or the assessment for underlying CTD in those presenting with presumed "idiopathic" ILD can be challenging and these evaluations can be optimized by effective multidisciplinary collaboration. When a diagnosis of CTD-ILD is confirmed, careful and thorough assessments to determine extra- versus intra-thoracic disease activity, and degrees of impairment are needed. Pharmacologic intervention with immunosuppression is the mainstay of therapy for all forms of CTD-ILD, but should be reserved only for those that demonstrate clinically significant and/or progressive disease. The management of CTD-ILD is not yet evidence based and there is a desperate need for controlled trials across the spectrum of CTD-ILD. Non-pharmacologic management strategies and addressing comorbidities or aggravating factors should be part of a comprehensive treatment plan for individuals with CTD-ILD.

  8. Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease.

    PubMed

    Toyoda, Yuko; Hanibuchi, Masaki; Kishi, Jun; Kawano, Hiroshi; Morizumi, Shun; Sato, Seidai; Kondo, Mayo; Takikura, Terumi; Tezuka, Toshifumi; Goto, Hisatsugu; Nishioka, Yasuhiko

    2016-01-01

    Acute exacerbation (AE) of interstitial lung disease is reported to be developed in not only idiopathic pulmonary fibrosis but also connective tissue disease-associated interstitial pneumonia (CTD-IP). As the significance of AE of CTD-IP has not been so widely recognized, its clinical feature is not fully elucidated. In the present study, we investigated the incidence, clinical features and outcome of AE of CTD-IP. We retrospectively reviewed admitted cases in our department with medical record from 2011 to 2015. Among 155 patients with CTD-IP, 10 (6.5%) cases developed AE (6 rheumatoid arthritis, 2 polymyositis/dermatomyositis, 1 systemic lupus erythematosus, 1 Sjögren syndrome), and one died of AE within 30 days. Median survival time after the onset of AE was 169 days in all 10 patients. The treatment with immunosuppressant just before AE onset might improve the prognosis of AE. The median survival time after the onset of AE was significantly longer in patients showing good response to corticosteroid compared with those with poor response to corticosteroid (805 days and 45 days, respectively) (p <0.05), suggesting that there are some cases in CTD-IP, showing the good response to corticosteroid even when AE was complicated. J. Med. Invest. 63: 294-299, August, 2016. PMID:27644575

  9. Direct determination of fatty acids in fish tissues: quantifying top predator trophic connections.

    PubMed

    Parrish, Christopher C; Nichols, Peter D; Pethybridge, Heidi; Young, Jock W

    2015-01-01

    Fatty acids are a valuable tool in ecological studies because of the large number of unique structures synthesized. They provide versatile signatures that are being increasingly employed to delineate the transfer of dietary material through marine and terrestrial food webs. The standard procedure for determining fatty acids generally involves lipid extraction followed by methanolysis to produce methyl esters for analysis by gas chromatography. By directly transmethylating ~50 mg wet samples and adding an internal standard it was possible to greatly simplify the analytical methodology to enable rapid throughput of 20-40 fish tissue fatty acid analyses a day including instrumental analysis. This method was verified against the more traditional lipid methods using albacore tuna and great white shark muscle and liver samples, and it was shown to provide an estimate of sample dry mass, total lipid content, and a condition index. When large fatty acid data sets are generated in this way, multidimensional scaling, analysis of similarities, and similarity of percentages analysis can be used to define trophic connections among samples and to quantify them. These routines were used on albacore and skipjack tuna fatty acid data obtained by direct methylation coupled with literature values for krill. There were clear differences in fatty acid profiles among the species as well as spatial differences among albacore tuna sampled from different locations. PMID:25376156

  10. [INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

    PubMed

    Nagornaya, A A; Magomedov, S; Gorchakova, N A; Belenichev, I F; Ghekman, I S; Kuzub, T A

    2015-01-01

    One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals.

  11. [INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

    PubMed

    Nagornaya, A A; Magomedov, S; Gorchakova, N A; Belenichev, I F; Ghekman, I S; Kuzub, T A

    2015-01-01

    One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals. PMID:27089728

  12. A bioreactor test system to mimic the biological and mechanical environment of oral soft tissues and to evaluate substitutes for connective tissue grafts.

    PubMed

    Mathes, Stephanie H; Wohlwend, Lorenz; Uebersax, Lorenz; von Mentlen, Roger; Thoma, Daniel S; Jung, Ronald E; Görlach, Christoph; Graf-Hausner, Ursula

    2010-12-15

    Gingival cells of the oral connective tissue are exposed to complex mechanical forces during mastication, speech, tooth movement and orthodontic treatments. Especially during wound healing following surgical procedures, internal and external forces may occur, creating pressure upon the newly formed tissue. This clinical situation has to be considered when developing biomaterials to augment soft tissue in the oral cavity. In order to pre-evaluate a collagen sponge intended to serve as a substitute for autogenous connective tissue grafts (CTGs), a dynamic bioreactor system was developed. Pressure and shear forces can be applied in this bioreactor in addition to a constant medium perfusion to cell-material constructs. Three-dimensional volume changes and stiffness of the matrices were analyzed. In addition, cell responses such as cell vitality and extracellular matrix (ECM) production were investigated. The number of metabolic active cells constantly increased under fully dynamic culture conditions. The sponges remained elastic even after mechanical forces were applied for 14 days. Analysis of collagen type I and fibronectin revealed a statistically significant accumulation of these ECM molecules (P < 0.05-0.001) when compared to static cultures. An increased expression of tenascin-c, indicating tissue remodeling processes, was observed under dynamic conditions only. The results indicate that the tested in vitro cell culture system was able to mimic both the biological and mechanical environments of the clinical situation in a healing wound.

  13. Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors

    PubMed Central

    Zhao, Hai-yang; Wu, Jiang; Zhu, Jing-jing; Xiao, Ze-cong; He, Chao-chao; Shi, Hong-xue; Li, Xiao-kun; Yang, Shu-lin; Xiao, Jian

    2015-01-01

    Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches. PMID:26347885

  14. Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors.

    PubMed

    Zhao, Hai-yang; Wu, Jiang; Zhu, Jing-jing; Xiao, Ze-cong; He, Chao-chao; Shi, Hong-xue; Li, Xiao-kun; Yang, Shu-lin; Xiao, Jian

    2015-01-01

    Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches.

  15. βig-h3 potentiates the profibrogenic effect of TGFβ signaling on connective tissue progenitor cells through the negative regulation of master chondrogenic genes.

    PubMed

    Lorda-Diez, Carlos I; Montero, Juan A; Diaz-Mendoza, Manuel J; Garcia-Porrero, Juan A; Hurle, Juan M

    2013-02-01

    Tendons and cartilage are specialized forms of connective tissues originated from common progenitor cells. Initial stages of differentiation of these tissues are characterized by the formation of cell aggregates, which share many molecular markers. Once differentiated, these cells retain considerable plasticity, and chondral metaplasia of tendon and fibrous connective tissues and eventual ossification often accompany degenerative diseases in the adult musculoskeletal system. While this fact is of great relevance for regenerative medicine and aging biology, its molecular basis remains to be elucidated. Gene expression analysis in several physiological and experimental paradigms suggests that differentiation of tendon and cartilage is regulated by a balance in the expression of chondrogenic versus tenogenic genes in the connective tissue cell precursors. Transforming growth factor β (TGFβ) may function both as a profibrogenic or as a prochondrogenic factor for embryonic limb mesoderm and mesenchymal stem cell cultures, but mice that are null for TGFβ 2 and 3 lack tendons. Here, we identify βig-h3 as a factor downstream TGFβ signaling regulated by Smad 2 and 3, which is highly expressed in the differentiating tendons and joint capsules. Furthermore, gain- and loss-of-function experiments using limb mesoderm micromass cultures show that βig-h3 downregulates the expression of cartilage master genes, including Sox9, type II collagen, and Hif-1α. Positive regulation of Sox9 and type II Collagen observed in micromass cultures grown under hypoxic conditions is prevented by exogenous administration of βIG-H3, and the antichondrogenic influence of βIG-H3 is lost after Hif-1α silencing with shRNA. Collectively, our findings indicate that βig-h3 promotes the fibrogenic influence of TGFβ signaling, neutralizing the prochondrogenic influence of the hypoxic-inducible factor 1 activated by the hypoxic microenvironment characteristic of limb mesenchymal aggregates.

  16. βig-h3 Potentiates the Profibrogenic Effect of TGFβ Signaling on Connective Tissue Progenitor Cells Through the Negative Regulation of Master Chondrogenic Genes

    PubMed Central

    Lorda-Diez, Carlos I.; Montero, Juan A.; Diaz-Mendoza, Manuel J.; Garcia-Porrero, Juan A.

    2013-01-01

    Tendons and cartilage are specialized forms of connective tissues originated from common progenitor cells. Initial stages of differentiation of these tissues are characterized by the formation of cell aggregates, which share many molecular markers. Once differentiated, these cells retain considerable plasticity, and chondral metaplasia of tendon and fibrous connective tissues and eventual ossification often accompany degenerative diseases in the adult musculoskeletal system. While this fact is of great relevance for regenerative medicine and aging biology, its molecular basis remains to be elucidated. Gene expression analysis in several physiological and experimental paradigms suggests that differentiation of tendon and cartilage is regulated by a balance in the expression of chondrogenic versus tenogenic genes in the connective tissue cell precursors. Transforming growth factor β (TGFβ) may function both as a profibrogenic or as a prochondrogenic factor for embryonic limb mesoderm and mesenchymal stem cell cultures, but mice that are null for TGFβ 2 and 3 lack tendons. Here, we identify βig-h3 as a factor downstream TGFβ signaling regulated by Smad 2 and 3, which is highly expressed in the differentiating tendons and joint capsules. Furthermore, gain- and loss-of-function experiments using limb mesoderm micromass cultures show that βig-h3 downregulates the expression of cartilage master genes, including Sox9, type II collagen, and Hif-1α. Positive regulation of Sox9 and type II Collagen observed in micromass cultures grown under hypoxic conditions is prevented by exogenous administration of βIG-H3, and the antichondrogenic influence of βIG-H3 is lost after Hif-1α silencing with shRNA. Collectively, our findings indicate that βig-h3 promotes the fibrogenic influence of TGFβ signaling, neutralizing the prochondrogenic influence of the hypoxic-inducible factor 1 activated by the hypoxic microenvironment characteristic of limb mesenchymal aggregates. PMID

  17. [The connective tissues, from the origin of the concept to its "Maturation" to extracellular matrix. Application to ocular tissues. Contribution to the history of medical sciences].

    PubMed

    Labat-Robert, J; Robert, L; Pouliquen, Y

    2011-06-01

    The "Tissue" concept emerged apparently in the medical literature at about the French revolution, during the second half of the 18(th) century. It was found in the texts written by the physicians of Béarn and Montpellier, the Bordeu-s and also by the famous physician, Felix Vicq d'Azyr, the last attending physician of the queen Marie-Antoinette, "Bordeu et al. (1775) et Pouliquen (2009)". It was elaborated into a coherent doctrine somewhat later by Xavier Bichat, considered as the founder of modern pathological anatomy, Bichat. With the advent of histochemistry, from the beginning of the 20(th) century, several of the principal macromolecular components of connective tissues, collagens, elastin, "acid mucopolysaccharides" (later glycosaminoglycans and proteoglycans) and finally structural glycoproteins were characterized. These constituents of connective tissues were then designated as components of the extracellular matrix (ECM), closely associated to the cellular components of these tissues by adhesive (structural) glycoproteins as fibronectin, several others and cell receptors, "recognising" ECM-components as integrins, the elastin-receptor and others. This molecular arrangement fastens cells to the ECM-components they synthesize and mediates the exchange of informations between the cells to the ECM (inside-out) and also from the ECM-components to the cells (outside-in). This macromolecular arrangement is specific for each tissue as a result of the differentiation of their cellular components. It is also the basis and condition of the fulfillment of the specific functions of differentiated tissues. This is a short description of the passage of the "tissue" concept from its vague origin towards its precise identification at the cellular and molecular level up to the recognition of its functional importance and its establishment as an autonomous science. This can be considered as a new example of the importance of metaphors for the progress of science, Keller

  18. Dynamic culture induces a cell type-dependent response impacting on the thickness of engineered connective tissues.

    PubMed

    Fortier, Guillaume Marceau; Gauvin, Robert; Proulx, Maryse; Vallée, Maud; Fradette, Julie

    2013-04-01

    Mesenchymal cells are central to connective tissue homeostasis and are widely used for tissue-engineering applications. Dermal fibroblasts and adipose-derived stromal cells (ASCs) allow successful tissue reconstruction by the self-assembly approach of tissue engineering. This method leads to the production of multilayered tissues, devoid of exogenous biomaterials, that can be used as stromal compartments for skin or vesical reconstruction. These tissues are formed by combining cell sheets, generated through cell stimulation with ascorbic acid, which favours the cell-derived production/organization of matrix components. Since media motion can impact on cell behaviour, we investigated the effect of dynamic culture on mesenchymal cells during tissue reconstruction, using the self-assembly method. Tissues produced using ASCs in the presence of a wave-like movement were nearly twice thicker than under standard conditions, while no difference was observed for tissues produced from dermal fibroblasts. The increased matrix deposition was not correlated with an increased proliferation of ASCs, or by higher transcript levels of fibronectin or collagens I and III. A 30% increase of type V collagen mRNA was observed. Interestingly, tissues engineered from dermal fibroblasts featured a four-fold higher level of MMP-1 transcripts under dynamic conditions. Mechanical properties were similar for tissues reconstructed using dynamic or static conditions. Finally, cell sheets produced using ASCs under dynamic conditions could readily be manipulated, resulting in a 2 week reduction of the production time (from 5 to 3 weeks). Our results describe a distinctive property of ASCs' response to media motion, indicating that their culture under dynamic conditions leads to optimized tissue engineering.

  19. Comparison of different test systems for simultaneous autoantibody detection in connective tissue diseases.

    PubMed

    Eissfeller, Petra; Sticherling, Michael; Scholz, Dietmar; Hennig, Kirsten; Lüttich, Tanja; Motz, Manfred; Kromminga, Arno

    2005-06-01

    The serological diagnosis of connective tissue diseases (CTDs) is based on the analysis of circulating autoantibodies to cytoplasmic and nuclear proteins (extractable nuclear antigens [ENAs]). The determination of autoantibody specificities supports the clinical diagnosis of the type of CTD and also often the prognosis of the disease. The former indirect immunofluorescence (IIF) technique still provides a useful screening method that currently is supplemented by a range of different techniques allowing the exact determination of single autoantibody specificities. These ENA profiling techniques include ELISA, immunoblotting, line-blot assays, and flow cytometric bead-based multiplex assays. The novel line immunoassay (LIA) from Mikrogen has been introduced in a recent study as a suitable technique for the simultaneous detection of autoantibodies in a routine clinical laboratory, providing comparable results as ELISA and ELiA (both from Pharmacia Diagnostics) (see Damoiseaux et al., this volume). In this study, LIAs from three different manufacturers were performed in 30 serum samples from patients with dermatological manifestations and 27 samples from SLE patients with renal involvement. The line assays from Mikrogen (recomLine ANA/ENA), Innogenetics (Inno-Lia ANA Update), and Imtec (ANA-LIA) were compared for antigen composition, handling, and statistical analysis including sensitivity and concordance. Autoantibody frequencies detected by the Mikrogen, Innogenetics, and Imtec line assays were 14.0%, 19.3%, and 15.8% for RNP; 14.0%, 22.8%, and 14.0% for Sm; 26.3%, 31.6%, and 40.3% for SSA; 3.5%, 12.3%, and 14.0% for SSB; and 3.5%, 14.0%, and 10.5% for histones. Our studies show that the line assay format is an easy-to-use, sensitive, and specific method for ENA antibody detection in human sera.

  20. [The clinical immunology laboratory in diagnosis and monitoring of systemic lupus erythematosus and connective tissue diseases].

    PubMed

    Sinico, R A; Radice, A

    2005-01-01

    The laboratory and particularly clinical immunology laboratories have an essential role in diagnosing and monitoring systemic lupus erythematosus (SLE), as well as other connective tissue diseases. The role of the clinical immunology laboratory in these diseases is to confirm or exclude diagnosis, to monitor disease activity, and to identify subgroup of patients. To obtain the best results in terms of diagnostic performance and clinical usefulness, the following recommendations should be fulfilled: anti-nuclear antibodies (ANA) determination by indirect immunofluorescence on Hep-2 cells is an effective screening assay in patients with clinical features of SLE. A negative ANA test makes the diagnosis of SLE unlikely. Anti-dsDNA antibodies are highly specific for SLE and are associated with renal involvement. The method of choice for anti-dsDNA is the Farr assay; however, the necessity of using radioactive materials reduces its applicability. As an alternative, immunofluorescence on Crithidia Luciliae can be used in the diagnostic phase due to its high specificity. The detection of antibodies to extractable nuclear antigens (ENA) and to phospholipids (lupus anticoagulant and anti-cardiolipin antibodies) is useful in identifying subgroups of patients at risk for some clinical manifestations. Anti-dsDNA measurement with a quantitative assay (the Farr assay or ELISA) is currently the best method to monitor disease activity along with complement levels. New assays (anti-C1q and anti-nucleosome antibodies) have been recently proposed for the diagnosis (anti-nucleosome) and monitoring of SLE patients (anti-C1q and anti-nucleosome antibodies), with promising results.

  1. Reduced-fat bologna manufactured with poultry skin connective tissue gel.

    PubMed

    Osburn, W N; Mandigo, R W

    1998-10-01

    The objectives of this study were to determine temperature (50, 60, 70, and 80 C) and time (0.5, 1.0, 1.5, and 2.0 h) effects on the water binding ability of chicken skin connective tissue (CCT) and its ability to form model gels; to develop and determine the functionality of added water (AW, 100, 200, and 300%) CCT gels; and to evaluate the attributes of reduced-fat bologna containing 10 to 30% addition of 100 to 300% AW CCT gels. Determination of water binding and holding capacities, and objective textural and color attributes provided data suggesting the practicality of developing and incorporating AW CCT gels as water binders in reduced-fat bologna. Processing qualities, and textural and sensory attributes were analyzed to assess the feasibility of manufacturing a reduced-fat processed poultry product containing a modified poultry by-product. Heating (60 C) CCT for 0.5 h allowed the formation of model CCT gels containing 100 to 300% AW. Added water decreased CCT gel fat, protein, collagen content, and hardness due to a protein (collagen) dilution. Hydration values were sufficient to allow CCT to bind up to 300% AW. Gel fragility and syneresis were observed in higher AW CCT gels due to protein dilution, a result of the high fat content of raw CCT (approximately 40%) and added water. Percentage gel addition and AW decreased (P < 0.05) the hardness of reduced-fat CCT gel bologna. All bologna treatments exhibited acceptable sensory attributes. This study indicated the feasibility of using lower AW CCT gels as texture-modifying agents in reduced-fat comminuted meat products.

  2. Efficacy and Safety of Grapefruit Juice Intake Accompanying Tacrolimus Treatment in Connective Tissue Disease Patients.

    PubMed

    Tsuji, Hideaki; Ohmura, Koichiro; Nakashima, Ran; Hashimoto, Motomu; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Fujii, Takao; Mimori, Tsuneyo

    2016-01-01

    Objective It is well known that grapefruit juice (GFJ) elevates the blood tacrolimus (TAC) concentration. We investigated the efficacy and safety of GFJ intake with TAC in cases of connective tissue diseases in which the TAC blood concentration was insufficiently high for clinical improvement, even when 3 mg/day or more of TAC was administered. Methods Seven patients took 200 mL of GFJ every day. The trough levels of the TAC blood concentration were measured before and after GFJ intake and the clinical courses were monitored thereafter. Results First, we surveyed the blood TAC trough levels of 30 recent patients who took 3 mg/day of TAC, and found that 21 patients (70%) did not achieve the minimum target TAC concentration (>5 ng/mL). Seven patients took GFJ due to a lack of efficacy and a relatively low TAC blood concentration. GFJ increased the TAC level from 4.3±2.4 ng/mL to 13.8±6.9 ng/mL (average increase: 3.3-fold). GFJ was also effective in achieving a clinical improvement in most cases without causing any severe adverse events, and it helped to decrease the dosages of glucocorticoid and TAC. In some cases, the blood TAC concentration fluctuated for no apparent reason. Conclusion GFJ intake was effective for the elevation of TAC concentration by approximately three fold and clinical improvement, but special care is required for monitoring its influence on concomitantly used drugs as well as TAC concentration. The addition of GFJ to TAC treatment could be an efficacious treatment option, when the plasma TAC concentration does not reach the minimal target concentration. PMID:27301503

  3. Volumetric imaging of oral epithelial neoplasia by MPM-SHGM: epithelial connective tissue interface (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Pal, Rahul; Yang, Jinping; Qiu, Suimin; Resto, Vicente; McCammon, Susan; Vargas, Gracie

    2016-03-01

    The majority of oral cancers are comprised of oral squamous cell carcinoma in which neoplastic epithelial cells invade across the epithelial connective tissue interface (ECTI). Invasion is preceded by a multi-component process including epithelial hyperproliferation, loss of cell polarity, and remodeling of the extracellular matrix. Multiphoton Autofluorescence Microscopy (MPAM) and Second Harmonic Generation Microscopy (SHGM) show promise for revealing indicators of neoplasia. In particular, volumetric imaging by these methods can reveal aspects of the 3D microstructure that are not possible by other methods and which could both further our understanding of neoplastic transformation and be explored for development of diagnostic approaches in this disease having only 55% 5-year survival rate. MPAM-SHG were applied to reveal the 3D structure of the critical ECTI interface that plays an integral part toward invasion. Epithelial dysplasia was induced in an established hamster model. MPAM-SHGM was applied to lesion sites, using 780 nm excitation (450-600nm emission) for autofluroescence of cellular and extracellular components; 840 nm using 420 nm bandpass filter for SHG. The ECTI surface was identified as the interface at which SHG signal began following the epithelium and was modeled as a 3D surface using Matlab. ECTI surface area and cell features at sites of epithelial expansion where ECTI was altered were measured; Imaged sites were biopsied and processed for histology. ROC analysis using ECTI image metrics indicated the ability to delineate normal from neoplasia with high sensitivity and specificity and it is noteworthy that inflammation did not significantly alter diagnostic potential of MPAM-SHGM .

  4. Undiagnosed connective tissue diseases: High prevalence in pulmonary arterial hypertension patients.

    PubMed

    Cavagna, Lorenzo; Codullo, Veronica; Ghio, Stefano; Scirè, Carlo Alberto; Guzzafame, Eleonora; Scelsi, Laura; Rossi, Silvia; Montecucco, Carlomaurizio; Caporali, Roberto

    2016-09-01

    Among different subgroups of pulmonary arterial hypertension (PAH), those associated with connective tissue diseases (CTDs) have distinct hemodynamic and prognostic features; a correct etiologic diagnosis is thus mandatory.To estimate frequency and prognosis of previously undiagnosed CTDs in a suspect idiopathic (i) PAH cohort.Consecutive patients with PAH confirmed by right heart catheterization referred at the Cardiology Division of our Hospital without a previous rheumatological assessment or the occurrence of other conditions explaining PAH were checked for CTD by a clinical, laboratory, and instrumental evaluation. Survival in each group has also been analyzed.In our study 17 of 49 patients were classified as CTD-PAH, corresponding to a prevalence (95% CI) of 34.7% (21.7-49.6%). ANA positivity had 94% (71.3-99.9%) sensitivity and 78.1% (60-90.7%) specificity for a diagnosis of CTD-PAH; Raynaud phenomenon (RP) showed 83.3% (51.6-97.9%) sensitivity and 100% (90.5-100%) specificity for the diagnosis of Systemic Sclerosis (SSc)-PAH. At diagnosis, SSc patients were older and had a lower creatinine clearance compared with iPAH and other CTD-PAH. After a median follow-up of 44 (2-132) months, 18 of 49 (36.7%) patients died: 31.2% in the iPAH group, 20% in the CTD-, and 58.3% in the SSc-PAH group. Mortality was significantly higher in SSc-PAH (HR 3.32, 1.11-9.95, P <0.05) versus iPAH.We show a high prevalence of undiagnosed CTDs in patients with iPAH without a previous rheumatological assessment. All patients with RP were diagnosed with SSc. Our data stress the importance of a rheumatological assessment in PAH, especially because of the unfavorable prognostic impact of an associated SSc. PMID:27684814

  5. Brachial Neuritis With Phrenic Nerve Involvement in a Patient With a Possible Connective Tissue Disease

    PubMed Central

    Subash, Meera; Patel, Gaurav; Welker, John

    2014-01-01

    Background. Brachial neuritis (BN) is a rare inflammatory condition of peripheral nerves, usually involving the cervicobrachial plexus. These patients present with sudden onset of shoulder and arm pain that evolves into muscle weakness and atrophy.. Case Report. A 33-year-old woman presented with a 1-month history of diffuse pain in her thorax. She had no trauma or inciting incident prior to the onset of this pain and was initially treated for muscle spasms. The patient was seen in the emergency room multiple times and was treated with several courses of antibiotics for pneumonia on the basis of clinical symptoms and abnormal x-rays. The pleuritic chest pain persisted for at least 4 months, and the patient was eventually admitted for worsening pain and dyspnea. On physical examination, crackles were heard at both lung bases, and chest inspection revealed increased expansion in the upper thorax but poor expansion of the lower thorax and mild paradoxical respiration. “Sniff” test revealed no motion of the left hemidiaphragm and reduced motion on the right hemidiaphragm. Her computed tomography scan revealed bilateral atelectasis, more severe at the left base. She reported no symptoms involving her joints or skin or abdomen. Her presentation and clinical course are best explained by BN with a bilateral diaphragmatic weakness. However, she had a positive ANA, RF, anti-RNP antibody, and anti SS-A. Conclusion. Patients with BN can present with diffuse thoracic pain, pleuritic chest pain, and diaphragmatic weakness. Our patient may represent a case of connective tissue disease presenting with brachial plexus neuritis. PMID:26425609

  6. [Three dimensional structure of the connective tissue papillae of the tongue in Suncus murinus].

    PubMed

    Kobayashi, K; Miyata, K; Iwasaki, S; Takahashi, K

    1989-08-01

    The surface structure of the connective tissue papillae (CP) of Suncus murinus tongue was observed by SEM after fixing with Karnovsky's fixative and removal of the epithelial cell layer with 3N or 8N HCl. On the surface of the slender conical tongue, there are densely distributed filiform papillae among which fungiform papillae are seen sporadically. A pair of vallate papillae are situated in the posterior region of the tongue. Filiform papillae appear somewhat different externally depending on the dorsal surface of the anterior tongue. At the tip of the tongue, filiform papillae are of a slender conical shape and have a slight depression in the anterior basal portion. The CP of these is seen as a spherical protrusion on which a shallow groove runs in the anteroposterior direction. In the middle region, somewhat large filiform papillae contain CP having one or two small round head-like structures on each spherical protrusion. These head-like structures are increased in number in the posterior region. In the most posterior region of the anterior tongue, there are distributed large filiform papillae having several slender protrusions that surround a basal anterior depression. These large branched filiform papillae have a glove finger like CP. Small conical filiform papillae are distributed in the posterior marginal region of the anterior tongue which have CP of a horse-shoe like protrusion that opens in the anterior direction. Spherical fungiform papillae have CP which are thick columnar in shape with many lateral thin folds running vertically and having a round depression on the top of each. CP of the vallate papillae appear as a beehive like structure.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Comparative morphological study on the lingual papillae and their connective tissue cores in rabbits.

    PubMed

    Nonaka, Kouji; Zheng, Jin Hua; Kobayashi, Kan

    2008-08-01

    The morphological structure of the lingual papillae and their connective tissue cores (CTC) in a rabbit were studied using LM and SEM and were compared to that of other animal species. Externally, the filiform papillae distributed on the anterior surface of the dorsal tongue were short and conical with a round base and had a flat area on their anterior upper half. The CTC of the conical filiform papillae had a roughly triangular plate-like structure with a round top. Several small round protrusions were found on both inclined planes of the triangle. Spearhead-like filiform papillae were distributed on the anterior edge of the lingual prominence and branched filiform papillae were on the posteriorly wide area of the prominence. These papillae on the prominence had a slightly ramified CTC that differed from that of the CTC of the conical filiform papillae distributed on the anterior tongue. Dome-like fungiform papillae were distributed among the conical filiform papillae of the anterior tongue and had a CTC with a roundish structure that was almost but, not quite spherical in appearance with 1 to 10 small round concave indentations for taste buds on their upper surface. The foliate papillae had approximately 15 parallel ridges separated by grooves. These ridges contained a parallel thin plate-like CTC exhibited after removal of the epithelium. The vallate papilla was comprised of a spherical central papilla and had a circular wall with a flower-like CTC almost resembling a carnation. The stereostructure of the rabbit's filiform CTC are comparatively described as being morphologically in between those of rodents and those of the guinea pig and Japanese serow. Such evolution has probably occurred due to the species unique masticatory and gustatory needs and functions. PMID:18975613

  8. Basement membrane and connective tissue proteins in intestinal mucosa of patients with coeliac disease

    PubMed Central

    Verbeke, S; Gotteland, M; Fernández, M; Bremer, J; Ríos, G; Brunser, O

    2002-01-01

    Aims: Gluten ingestion in coeliac disease is associated with alterations of the intestinal mucosa, especially the expansion of the lamina propria. Antiendomysium and antireticulin antibodies may result from interactions between gliadin and extracellular matrix components. By behaving as autoantigens, connective tissue proteins could initiate mucosal damage. This study evaluates changes in the distribution of laminin, type IV collagen, and fibronectin in the mucosa of patients with coeliac disease in an attempt to explain the alterations of mucosal morphology. Methods: Intestinal biopsies were obtained from patients with coeliac disease on admission and while on a gluten free diet. The distribution of type IV collagen, laminin, fibronectin, and α-smooth muscle actin was evaluated by immunofluorescence and by immunogold labelling and electron microscopy. Results: In patients with coeliac disease, the intensity of type IV collagen, laminin, and fibronectin immunofluorescent staining was decreased and less well defined than in controls, with frequent breaches in the basement membrane; fibronectin staining was weak in the distal third of the elongated crypts and absent under the flat surface. The distribution of smooth muscle fibre in the distal lamina propria of flat mucosae was altered. The distribution of these proteins was normal as assessed by immunoelectron microscopy. Conclusions: The intensity of staining of some components of the basement membrane is decreased in coeliac disease and the distribution of smooth muscle fibres is altered. These changes may result from interactions between gliadin and components of the extracellular matrix and may play a role in the genesis of mucosal lesions and in the damage to the epithelium. PMID:12037027

  9. A multiscale analysis of nutrient transport and biological tissue growth in vitro.

    PubMed

    O'Dea, R D; Nelson, M R; El Haj, A J; Waters, S L; Byrne, H M

    2015-09-01

    In this paper, we consider the derivation of macroscopic equations appropriate to describe the growth of biological tissue, employing a multiple-scale homogenization method to accommodate explicitly the influence of the underlying microscale structure of the material, and its evolution, on the macroscale dynamics. Such methods have been widely used to study porous and poroelastic materials; however, a distinguishing feature of biological tissue is its ability to remodel continuously in response to local environmental cues. Here, we present the derivation of a model broadly applicable to tissue engineering applications, characterized by cell proliferation and extracellular matrix deposition in porous scaffolds used within tissue culture systems, which we use to study coupling between fluid flow, nutrient transport, and microscale tissue growth. Attention is restricted to surface accretion within a rigid porous medium saturated with a Newtonian fluid; coupling between the various dynamics is achieved by specifying the rate of microscale growth to be dependent upon the uptake of a generic diffusible nutrient. The resulting macroscale model comprises a Darcy-type equation governing fluid flow, with flow characteristics dictated by the assumed periodic microstructure and surface growth rate of the porous medium, coupled to an advection-reaction equation specifying the nutrient concentration. Illustrative numerical simulations are presented to indicate the influence of microscale growth on macroscale dynamics, and to highlight the importance of including experimentally relevant microstructural information to correctly determine flow dynamics and nutrient delivery in tissue engineering applications.

  10. Changes in pulmonary connective tissue proteins after a single intratracheal instillation of cadmium chloride in the rat

    SciTech Connect

    Kobrle, V.; Mirejovska, E.; Holusa, R.; Hurych, J.

    1986-06-01

    Changes of soluble and insoluble fractions of pulmonary connective tissue proteins were studied in rats for 2-84 days following a single intratracheal instillation of cadmium chloride (10 micrograms Cd/sup 2 +//lung). A transient decrease in body weight and an immediate increase in lung wet weight (200% of control value, P less than 0.01) were observed. Incorporation of (/sup 14/C)proline and its conversion to (/sup 14/C)hydroxyproline in vivo into different soluble and insoluble fractions of connective tissue revealed an increased metabolic turnover elicited by cadmium intoxication. A lag in the maturation of collagen into higher functional forms in the early phase of the process was demonstrated. A striking decrease in elastin was found in first 7 days (40-50%). However, this acute damage of pulmonary connective tissue was followed by a permanent increase of collagen and elastin concentration in the later phase of recovery. Histopathologic examination 14-84 days after cadmium instillation confirmed the presence of lesions in pulmonary tissue with an initial inflammation followed by reparatory changes.

  11. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity.

    PubMed

    Unhavaithaya, Yingdee; Orr-Weaver, Terry L

    2012-01-01

    Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood-brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples.

  12. Therapeutic ultrasound applications in craniofacial growth, healing and tissue engineering.

    PubMed

    El-Bialy, Tarek

    2007-09-01

    Previous reports have shown that therapeutic ultrasound enhances healing of fractured bone as well as cut tendons. Moreover, it has been shown that therapeutic ultrasound enhances bone formation during distraction osteogenesis that is also known as Ilizarove technique. It has been recently reported that therapeutic ultrasound enhances tooth formation and eruption during mandible distraction osteogenesis in rabbits. This enhanced tooth formation and eruption was caused by new dental tissue formation, known as dentin and cementum. This led to a clinical trial in human that showed that therapeutic ultrasound can enhance repairing tooth root resorption caused by orthodontic treatment. This discovery can lead to many applications of ultrasound in the dental as well as in the craniofacial reconstructions. This paper provides an overview of the molecular basis of the achieved clinical results. Moreover, potential future application will be elaborated.

  13. A dp53-Dependent Mechanism Involved in Coordinating Tissue Growth in Drosophila

    PubMed Central

    Milán, Marco

    2010-01-01

    Coordination of growth between and within organs contributes to the generation of well-proportioned organs and functionally integrated adults. The mechanisms that help to coordinate the growth between different organs start to be unravelled. However, whether an organ is able to respond in a coordinated manner to local variations in growth caused by developmental or environmental stress and the nature of the underlying molecular mechanisms that contribute to generating well-proportioned adult organs under these circumstances remain largely unknown. By reducing the growth rates of defined territories in the developing wing primordium of Drosophila, we present evidence that the tissue responds as a whole and the adjacent cell populations decrease their growth and proliferation rates. This non-autonomous response occurs independently of where growth is affected, and it is functional all throughout development and contributes to generate well-proportioned adult structures. Strikingly, we underscore a central role of Drosophila p53 (dp53) and the apoptotic machinery in these processes. While activation of dp53 in the growth-depleted territory mediates the non-autonomous regulation of growth and proliferation rates, effector caspases have a unique role, downstream of dp53, in reducing proliferation rates in adjacent cell populations. These new findings indicate the existence of a stress response mechanism involved in the coordination of tissue growth between adjacent cell populations and that tissue size and cell cycle proliferation can be uncoupled and are independently and non-autonomously regulated by dp53. PMID:21179433

  14. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. Purpose: The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, medial gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  15. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  16. A functional connection between pRB and transforming growth factor beta in growth inhibition and mammary gland development.

    PubMed

    Francis, Sarah M; Bergsied, Jacqueline; Isaac, Christian E; Coschi, Courtney H; Martens, Alison L; Hojilla, Carlo V; Chakrabarti, Subrata; Dimattia, Gabriel E; Khoka, Rama; Wang, Jean Y J; Dick, Frederick A

    2009-08-01

    Transforming growth factor beta (TGF-beta) is a crucial mediator of breast development, and loss of TGF-beta-induced growth arrest is a hallmark of breast cancer. TGF-beta has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-beta cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1(DeltaL) and Rb1(NF)), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-beta growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-beta signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-beta cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-beta in growth control and mammary gland development.

  17. Developmental delay and connective tissue disorder in four patients sharing a common microdeletion at 6q13-14.

    PubMed

    Van Esch, Hilde; Rosser, Elisabeth M; Janssens, Sandra; Van Ingelghem, Ingrid; Loeys, Bart; Menten, Bjorn

    2010-10-01

    Interstitial deletions of the long arm of chromosome 6 are rare, and most reported cases represent large, cytogenetically detectable deletions. The implementation of array comparative genome hybridisation in the diagnostic work-up of patients presenting with congenital disorders, including developmental delay, has enabled identification of many patients with smaller chromosomal imbalances. In this report, the cases are presented of four patients with a de novo interstitial deletion of chromosome 6q13-14, resulting in a common microdeletion of 3.7 Mb. All presented with developmental delay, mild dysmorphism and signs of lax connective tissue. Interestingly, the common deleted region harbours 16 genes, of which COL12A1 is a good candidate for the connective tissue pathology.

  18. Temperature responses of substrate carbon conversion efficiencies and growth rates of plant tissues.

    PubMed

    Hansen, Lee D; Thomas, Nathan R; Arnholdt-Schmitt, Birgit

    2009-12-01

    Growth rates of plant tissues depend on both the respiration rate and the efficiency with which carbon is incorporated into new structural biomass. Calorespirometric measurement of respiratory heat and CO2 rates, from which both efficiency and growth rate can be calculated, is a well established method for determining the effects of rapid temperature changes on the respiratory and growth properties of plant tissues. The effect of the alternative oxidase/cytochrome oxidase activity ratio on efficiency is calculated from first principles. Data on the temperature dependence of the substrate carbon conversion efficiency are tabulated. These data show that epsilon is maximum and approximately constant through the optimum growth temperature range and decreases rapidly as temperatures approach temperature limits to growth. The width of the maximum and the slopes of decreasing epsilon at high and low temperatures vary greatly with species, cultivars and accessions.

  19. Structural changes in connective tissues caused by a moderate laser heating

    SciTech Connect

    Bagratashvili, Viktor N; Bagratashvili, N V; Sviridov, A P; Shakh, G Sh; Ignat'eva, Natalia Yu; Lunin, Valery V; Grokhovskaya, T E; Averkiev, S V

    2002-10-31

    The structural changes in adipose and fibrous tissues caused by 2- and 3-W IR laser irradiation are studied by the methods of IR and Raman spectroscopy and differential scanning calorimetry. It is shown that heating of fibrous tissue samples to 50 {sup 0}C and adipose tissue samples to 75 {sup 0}C by IR laser radiation changes the supramolecular structure of their proteins and triacylglycerides, respectively, without the intramolecular bond breaking. Heating of fibrous tissue to 70 {sup 0}C and adipose tissue to 90 - 110 {sup 0}C leads to a partial reversible denaturation of proteins and to oxidation of fats.

  20. 3D bone tissue growth in hollow fibre membrane bioreactor: implications of various process parameters on tissue nutrition.

    PubMed

    Abdullah, N S; Das, D B; Ye, H; Cui, Z F

    2006-09-01

    New experimental evidence shows that hollow fibre membrane bioreactor (HFMB) may be applied to grow bulky bone tissues which may then be implanted into patients to repair skeletal defects. To design effective bone tissue engineering protocols, it is necessary to determine the quantitative relationships between the cell environment and tissue behaviour in HFMBs and their relationship with nutrient supply. It is also necessary to determine under what conditions nutritional limitations may occur and, hence, may cause cell death. These require that the appropriate bioreactor conditions for generating neotissues, and the nutrient transfer behaviour and chemical reaction during cell growth and extracellular matrix formation are studied thoroughly. In this paper, we aim to use an existing mathematical framework to analyse the influence of various relevant parameters on nutrient supply for bone tissue growth in HFMB. We adopt the well-known Krogh cylinder approximation of the HFMB. The model parameters (e.g., cell metabolic rates) and operating conditions for the mathematical model have been obtained from, or correspond to, in-house experiments with the exception of a few variables which have been taken from the literature. The framework is then used to study oxygen and glucose transport behaviour in the HFMB. Influence of a number of important process parameters, e.g., reaction kinetics, cell density, inlet concentration of nutrients, etc, on the nutrient distributions have been systematically analysed. The work presented in this paper provides insights on unfavourable system designs and specifications which may be avoided to prevent mass transfer limitations for growing bone tissues in HFMB.

  1. Optical coherence tomography investigation of growth cycles of engineered skin tissue

    NASA Astrophysics Data System (ADS)

    Schmitt, Robert; Marx, Ulrich; Walles, Heike; Heymer, Andrea

    2010-02-01

    Engineered skin tissues are widely used in dermatological, pharmacological and toxicological studies and as autologous transplants in wound healing. Due to the high demand for artificial skin equivalents, there is a need for an automation of the manual production process to achieve a high-grade product. Thus, non-invasive monitoring of engineered tissue during the growth cycles is of major significance to understand and consequently improve the growth characteristics of in vitro tissue. Prior to the framework of the automation of artificial humanoid 3d-skin tissue engineering, optimal growth parameters need to be determined. The successful engineering of humanoid tissue is strongly coupled to the composition and structure of the upper epidermal and dermal skin layers. The layers are based on primary humanoid keratinocytes and a collagen - fibroblasts matrix. We applied optical coherence tomography as tissue imaging technology, which offers great potential to detect and characterize the differentiation processes of engineered skin. OCT provides a high resolution in the micron range with an imaging depth of about 1.5mm in semitransparent tissue. Due to a high quality signal to noise ratio, even small changes in signal at the boundary of the skin layers are detectable. In a study, OCT tomograms were taken after each production step of the skin equivalents and compared to the images of histologies.

  2. Coordination between catch connective tissue and muscles through nerves in the spine joint of the sea urchin Diadema setosum.

    PubMed

    Motokawa, Tatsuo; Fuchigami, Yoshiro

    2015-03-01

    Echinoderms have catch connective tissues that change their stiffness as a result of nervous control. The coordination between catch connective tissue and muscles was studied in the spine joint of the sea urchin Diadema setosum. Spine joints are equipped with two kinds of effector: spine muscles and a kind of catch connective tissue, which is called the catch apparatus (CA). The former is responsible for spine movements and the latter for maintenance of spine posture. Diadema show a shadow reaction in which they wave spines when a shadow falls on them, which is a reflex involving the radial nerves. Dynamic mechanical tests were performed on the CA in a joint at which the muscles were severed so as not to interfere with the mechanical measurements. The joint was on a piece of the test that contained other spines and a radial nerve. Darkening of the preparation invoked softening of the CA and spine waving (the shadow reaction). Electrical stimulation of the radial nerve invoked a similar response. These responses were abolished after the nerve pathways from the radial nerve to spines had been cut. A touch applied to the CA stiffened it and the adjacent spines inclined toward the touched CA. A touch to the base of the adjacent spine softened the CA and the spines around the touched spine inclined towards it. The softening of the CA can be interpreted as a response that reduces the resistance of the ligaments to spine movements. Our results clearly show coordination between catch connective tissue and muscles through nerves.

  3. A case of mixed connective tissue disease with pseudo-pseudo Meigs' syndrome (PPMS)-like features.

    PubMed

    Cheah, C K; Ramanujam, S; Mohd Noor, N; Gandhi, C; D Souza, Beryl A; Gun, S C

    2016-02-01

    Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy.

  4. Surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft

    PubMed Central

    Bellver-Fernández, Ricardo; Martínez-Rodriguez, Ana-María; Gioia-Palavecino, Claudio; Caffesse, Raul-Guillermo

    2016-01-01

    Background A coronally advanced flap with subepithelial connective tissue graft is the gold standard surgical treatment of gingival recessions, since it offers a higher probability of achieving complete root coverage compared with other techniques. However, optimum short- and middle-term clinical results have also been obtained with coronally advanced flaps alone. The aim of the present study was to evaluate the results obtained by the surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft. Material and Methods The reduction of recession height was assessed, together with the gain in gingival attachment apical to the recession, and total reduction of recession, in a comparative study of two techniques. Twenty-two gingival recessions were operated upon: 13 in the control group (coronally advanced flap) and 9 in the test group (coronally advanced flap associated to subepithelial connective tissue graft). Results After 18 months, the mean reduction of recession height was 2.2 ± 0.8 mm in the control group and 2.3 ± 0.7 mm in the test group, with a mean gain in gingival attachment of 1.3 ± 0.9 mm and 2.3 ± 1.3 mm, respectively. In percentage terms, the mean reduction of recession height was 84.6 ± 19.6% in the control group and 81.7 ± 17.8% in the test group, with a mean gain in gingival attachment of 20.5 ± 37.4% and 184.4 ± 135.5%, respectively. Conclusions Significant reduction of gingival recession was achieved with both techniques, though the mean gain in gingival attachment (in mm and as a %) was greater in test group. Key words:Gingival recession, coronally advanced flap, subepthelial connective tissue graft. PMID:26595836

  5. Repair of full-thickness tendon injury using connective tissue progenitors efficiently derived from human embryonic stem cells and fetal tissues.

    PubMed

    Cohen, Shahar; Leshansky, Lucy; Zussman, Eyal; Burman, Michael; Srouji, Samer; Livne, Erella; Abramov, Natalie; Itskovitz-Eldor, Joseph

    2010-10-01

    The use of stem cells for tissue engineering (TE) encourages scientists to design new platforms in the field of regenerative and reconstructive medicine. Human embryonic stem cells (hESC) have been proposed to be an important cell source for cell-based TE applications as well as an exciting tool for investigating the fundamentals of human development. Here, we describe the efficient derivation of connective tissue progenitors (CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and induced to generate tendon tissues in vitro, with ultrastructural characteristics and biomechanical properties typical of mature tendons. We describe a simple method for engineering tendon grafts that can successfully repair injured Achilles tendons and restore the ankle joint extension movement in mice. We also show the CTP's ability to differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers evidence for the possibility of using stem cell-derived engineered grafts to replace missing tissues, and sets a basic platform for future cell-based TE applications in the fields of orthopedics and reconstructive surgery.

  6. Controlled Multiple Growth Factor Delivery from Bone Tissue Engineering Scaffolds via Designed Affinity

    PubMed Central

    Suárez-González, Darilis; Lee, Jae Sung; Diggs, Alisha; Lu, Yan; Nemke, Brett; Markel, Mark; Hollister, Scott J.

    2014-01-01

    It is known that angiogenesis plays an important role in bone regeneration and that release of angiogenic and osteogenic growth factors can enhance bone formation. Multiple growth factors play key roles in processes that lead to tissue formation/regeneration during natural tissue development and repair. Therefore, treatments aiming to mimic tissue regeneration can benefit from multiple growth factor release, and there remains a need for simple clinically relevant approaches for dual growth factor release. We hypothesized that mineral coatings could be used as a platform for controlled incorporation and release of multiple growth factors. Specifically, mineral-coated scaffolds were “dip coated” in multiple growth factor solutions, and growth factor binding and release were dictated by the growth factor-mineral binding affinity. Beta tricalcium phosphate (β-TCP) scaffolds were fabricated using indirect solid-free form fabrication techniques and coated with a thin conformal mineral layer. Mineral-coated β-TCP scaffolds were sequentially dipped in recombinant human vascular endothelial growth factor (rhVEGF) and a modular bone morphogenetic peptide, a mineral-binding version of bone morphogenetic protein 2 (BMP2), solutions to allow for the incorporation of each growth factor. The dual release profile showed sustained release of both growth factors for over more than 60 days. Scaffolds releasing either rhVEGF alone or the combination of growth factors showed an increase in blood vessel ingrowth in a dose-dependent manner in a sheep intramuscular implantation model. This approach demonstrates a “modular design” approach, in which a controllable biologics carrier is integrated into a structural scaffold as a thin surface coating. PMID:24350567

  7. Cardiovascular Involvement in Connective Tissue Disease: The Role of Interstitial Lung Disease

    PubMed Central

    Wang, XiaoBing; Lou, MeiNa; Li, Yongji; Ye, WenJing; Zhang, ZhiYong; Jia, Xiufen; Shi, HongYing; Zhu, XiaoChun; Wang, LiangXing

    2015-01-01

    Objective The aim of this study was to assess cardiovascular involvement in patients with connective tissue disease (CTD), and determine whether interstitial lung disease (ILD) in these patients is associated with elevated cardiovascular risk. Methods This study evaluated a retrospective cohort of 436 CTD patients admitted to a large teaching hospital in Zhejiang province, China, along with an additional 436 participants of an annual community health screening conducted in the physical examination center who served as age- and gender-matched controls. Demographic, clinical, serologic and imaging characteristics, as well as medications used by each participant were recorded. Cardiovascular involvement was defined by uniform criteria. Correlations between clinical/serologic factors and cardiovascular involvement were determined by univariate and multivariate analyses. Results CTD patients had a significantly higher cardiovascular involvement rate than controls (64.7% vs 23.4%), with higher rates of diabetes, hypertension, and hyperlipidemia, elevated systolic and diastolic pressures, C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol, and lower albumin and high-density lipoprotein cholesterol (all p < 0.05). Furthermore, CTP patients with cardiovascular involvement were significantly older, had higher systolic and diastolic pressures, C-reactive protein, glucose, and uric acid, higher rates of diabetes, hypertension, and use of moderate- to high-dose glucocorticoids, and longer disease duration compared to patients without involvement (all p < 0.05). Moreover, CTD in patients with cardiovascular involvement was more likely to be complicated by ILD (p < 0.01), which manifested as a higher alveolar inflammation score (p < 0.05). In the multivariate analysis, cardiovascular involvement in CTD patients was associated with age, systolic pressure, body mass index, uric acid, disease duration > 2 years, use of moderate- to high

  8. Adverse Events in Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

    PubMed Central

    Rhee, Rennie L.; Gabler, Nicole B.; Praestgaard, Amy; Merkel, Peter A.; Kawut, Steven M.

    2016-01-01

    Objective Patients with connective tissue disease (CTD)–associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences. Methods Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by-diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models. Results The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00–2.47 versus OR 0.94, 95% CI 0.69–1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27). Conclusion Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs. PMID:26016953

  9. Silica-associated connective tissue disease. A study of 24 cases.

    PubMed

    Koeger, A C; Lang, T; Alcaix, D; Milleron, B; Rozenberg, S; Chaibi, P; Arnaud, J; Mayaud, C; Camus, J P; Bourgeois, P

    1995-09-01

    We prospectively studied all patients hospitalized for connective tissue disease (CTD) in our French rheumatology clinic from January 1979 to December 1989. Our aims were 1) to determine if CTDs associated with occupational exposure to silica (Si) are currently observed in a rheumatology clinic, and, if so, 2) to describe the major features of Si-associated CTD, and 3) to specify which individuals are affected by Si-associated CTD. Patients were divided into 2 groups based on their responses to a questionnaire: those who had been exposed to Si, and those who had no occupational exposure to Si. Among the 764 patients with CTD studied, 24 (3%) were patients with Si-associated CTD and 740 (97%) were patients with non-Si-associated CTD. The sex ratio between the 2 groups was significantly different with a high frequency of men and of immigrants in the Si-associated CTD group. Two thirds of the patients exposed to Si were male miners or sandblasters, but the other third had more unusual exposures to Si, which may involve members of all socio-economics sectors and both sexes, such as sculpture or exposure to abrasive powders. Progressive systemic sclerosis (PSS) was significantly more prevalent in the Si-associated CTD group. This group also consisted of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis (DM), and other autoimmune diseases. Si-associated CTD was characterized by the frequency of radiologic lung fibrosis, impaired pulmonary function tests, secondary Sjögren syndrome, and antinuclear antibodies. The number of mineral particles and crystalline Si content were raised in all the bronchoalveolar lavage specimens of Si-exposed patients but in none of those of nonexposed patients. In some cases of Si-associated CTD, the disease was reversible after early cessation of Si exposure. Epidemiologic studies are required to confirm our hypothesis that not only PSS and RA but also SLE and DM are associated with occupational

  10. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

    PubMed

    Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

    2016-01-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD.

  11. Spatial arrangement of the heart muscle fascicles and intramyocardial connective tissue in the Spanish fighting bull (Bos taurus).

    PubMed Central

    Sánchez-Quintana, D; Climent, V; Garcia-Martinez, V; Rojo, M; Hurlé, J M

    1994-01-01

    The spatial arrangement of the muscle fascicles and intramyocardial connective tissue was examined in the ventricles of the heart of the Spanish fighting bull (Bos taurus). In both ventricles, the muscle fascicles of the myocardium are arranged in 3 main directions, forming 3 muscle layers within the ventricular wall. The preferentially vertical arrangement of the muscle fascicles in the superficial and deep layers at the level of the fibrous aortic rings and the base of the semilunar valve leaflets suggests that these fascicles are actively involved in valvular dynamics. After controlled digestion of myocytes and elastic fibres with NaOH, a 3-dimensional arrangement of the scaffolding of connective tissue that supports the muscle fascicles and myocytes was observed. The arrangement and structure of this scaffolding may influence the order of contraction of muscle fascicles in different layers of the ventricle. In addition, differences were observed between the connective tissue scaffolding surrounding the myocytes of the 2 ventricles; these variations were correlated with the different biomechanical properties. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 8 Fig. 9 Fig. 10 PMID:8014119

  12. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

    PubMed

    Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

    2016-01-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD. PMID:26818120

  13. Purification and characterization of pepsin-solubilized collagen from skin and connective tissue of giant red sea cucumber (Parastichopus californicus).

    PubMed

    Liu, Zunying; Oliveira, Alexandra C M; Su, Yi-Cheng

    2010-01-27

    Pepsin-solubilized collagen (PSC) was extracted from giant red sea cucumbers ( Parastichopus californicus ) and characterized for denaturation temperature (T(d)), maximum transition temperature (T(m)), enzyme-digested peptide maps, and gel-forming capability. SDS-PAGE showed that PSCs from giant red sea cucumber skin and connective tissue were both type I collagens, consisting of three alpha(1) chains of approximately 138 kDa each. The amino acid composition and peptide maps of PSCs digested by V8 protease were different from those of calf skin type I collagen. The T(d) and T(m) are 18.5 and 33.2 degrees C, respectively, for skin PSC and are 17.9 and 32.7 degrees C, respectively, for connective tissue PSC. Both skin and connective tissue PSCs exhibited good gel-forming capability at pH 6.5 and at an ionic strength of 300 mM salt (NaCl). Collagen isolated from giant red sea cucumbers might be used as an alternative to mammalian collagen in the food and pharmaceutical industries.

  14. The skinny on Fat: an enormous cadherin that regulates cell adhesion, tissue growth, and planar cell polarity.

    PubMed

    Sopko, Richelle; McNeill, Helen

    2009-10-01

    Fat is an extremely large atypical cadherin involved in the regulation of cell adhesion, tissue growth, and planar cell polarity (PCP). Recent studies have begun to illuminate the mechanisms by which Fat performs these functions during development. Fat relays signals to the Hippo pathway to regulate tissue growth, and to PCP proteins to regulate tissue patterning. In this review we briefly cover the historical data demonstrating that Fat regulates tissue growth and tissue patterning, and then focus on advances in the past three years illuminating the mechanisms by which Fat controls growth and planar polarity in flies and mammals.

  15. New insights into the structure, assembly and biological roles of 10-12 nm connective tissue microfibrils from fibrillin-1 studies.

    PubMed

    Jensen, Sacha A; Handford, Penny A

    2016-04-01

    The 10-12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10-12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10-12 nm diameter microfibril and perform such diverse roles. PMID:27026396

  16. New insights into the structure, assembly and biological roles of 10-12 nm connective tissue microfibrils from fibrillin-1 studies.

    PubMed

    Jensen, Sacha A; Handford, Penny A

    2016-04-01

    The 10-12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10-12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10-12 nm diameter microfibril and perform such diverse roles.

  17. Clinical Comparison of Full and Partial Double Pedicle Flaps with Connective Tissue Grafts for Treatment of Gingival Recession

    PubMed Central

    Ranjbari, Ardeshir; Gholami, Gholam Ali; Amid, Reza; Kadkhodazadeh, Mahdi; Youssefi, Navid; Mehdizadeh, Amir Reza; Aghaloo, Maryam

    2016-01-01

    Statement of the Problem Gingival recession has been considered as the most challenging issue in the field of periodontal plastic surgery. Purpose The purpose of this study was to evaluate the clinical efficacy of root coverage procedures by using partial thickness double pedicle graft and compare it with full thickness double pedicle graft. Materials and Method Eight patients, aged 15 to 58 years including 6 females and 2 males with 20 paired (mirror image) defects with class I and II gingival recession were randomly assigned into two groups. Clinical parameters such as recession depth, recession width, clinical attachment level, probing depth, and width of keratinized tissue were measured at the baseline and 6 months post-surgery. A mucosal double papillary flap was elevated and the respective root was thoroughly planed. The connective tissue graft was harvested from the palate, and then adapted over the root. The pedicle flap was secured over the connective tissue graft and sutured. The surgical technique was similar in the control group except for the prepared double pedicle graft which was full thickness. Results The mean root coverage was 88.14% (2.83 mm) in the test group and 85.7% (2.75 mm) in the control group. No statistical differences were found in the mean reduction of vertical recession, width of recession, or probing depth between the test and control groups. In both procedures, the width of keratinized tissue increased after three months and the difference between the two groups was not statistically significant in this respect. Conclusion Connective tissue with partial and full thickness double pedicle grafts can be successfully used for treatment of marginal gingival recession.

  18. Clinical Comparison of Full and Partial Double Pedicle Flaps with Connective Tissue Grafts for Treatment of Gingival Recession

    PubMed Central

    Ranjbari, Ardeshir; Gholami, Gholam Ali; Amid, Reza; Kadkhodazadeh, Mahdi; Youssefi, Navid; Mehdizadeh, Amir Reza; Aghaloo, Maryam

    2016-01-01

    Statement of the Problem Gingival recession has been considered as the most challenging issue in the field of periodontal plastic surgery. Purpose The purpose of this study was to evaluate the clinical efficacy of root coverage procedures by using partial thickness double pedicle graft and compare it with full thickness double pedicle graft. Materials and Method Eight patients, aged 15 to 58 years including 6 females and 2 males with 20 paired (mirror image) defects with class I and II gingival recession were randomly assigned into two groups. Clinical parameters such as recession depth, recession width, clinical attachment level, probing depth, and width of keratinized tissue were measured at the baseline and 6 months post-surgery. A mucosal double papillary flap was elevated and the respective root was thoroughly planed. The connective tissue graft was harvested from the palate, and then adapted over the root. The pedicle flap was secured over the connective tissue graft and sutured. The surgical technique was similar in the control group except for the prepared double pedicle graft which was full thickness. Results The mean root coverage was 88.14% (2.83 mm) in the test group and 85.7% (2.75 mm) in the control group. No statistical differences were found in the mean reduction of vertical recession, width of recession, or probing depth between the test and control groups. In both procedures, the width of keratinized tissue increased after three months and the difference between the two groups was not statistically significant in this respect. Conclusion Connective tissue with partial and full thickness double pedicle grafts can be successfully used for treatment of marginal gingival recession. PMID:27602394

  19. Reactions of connective tissue to amalgam, intermediate restorative material, mineral trioxide aggregate, and mineral trioxide aggregate mixed with chlorhexidine.

    PubMed

    Sumer, Mahmut; Muglali, Mehtap; Bodrumlu, Emre; Guvenc, Tolga

    2006-11-01

    The aim of this study was to histopathologically examine the biocompatibility of the high-copper amalgam, intermediate restorative material (IRM), mineral trioxide aggregate (MTA), and MTA mixed with chlorhexidine (CHX). This study was conducted to observe the rat subcutaneous connective tissue reaction to the implanted tubes filled with amalgam, IRM, MTA, and MTA mixed with CHX. The animals were sacrificed 15, 30, and 60 days after the implantation procedure. The implant sites were excised and prepared for histological evaluation. Sections of 5 to 6 microm thickness were cut by a microtome and stained with hemotoxylin eosin and examined under a light microscope. The inflammatory reactions were categorized as weak (none or few inflammatory cells < or =25 cells), moderate (>25 cells), and severe (a lot of inflammatory cells not to be counted, giant cells, and granulation tissue). Thickness of fibrous capsules measured five different areas by the digital imaging and the mean values were scored. Amalgam, IRM, and MTA mixed with CHX caused a weak inflammatory response on days 15, 30, and 60. MTA provoked an initial severe inflammatory response that subsided at the 30 and 60 day study period. A clear fibrous capsule was observ