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At least 217 records · Page 12Linked to original sources
PubMed2004

Activated human platelets release connective tissue growth factor.

Connective tissue growth factor (CTGF) is overexpressed in wound healing, fibrosis and advanced atherosclerotic lesions. Platelets adhere to CTGF, suggesting that this protein may be involved in the formation of platelet-rich thrombi at the sites of tissue injury or atherosclerotic plaque rupture. Since platelets contain a wide array of biologically active proteins, we investigated the presence, localization and release of CTGF from these cells. For this purpose, human platelets from healthy donors were washed and stimulated with thrombin or ADP. Following incubation, proteins from unstimulated and stimulated cell lysates and the supernatants were analysed by Western blotting. The experiments showed that unstimulated platelets contain considerable amounts of CTGF, whereas no CTGF was detectable in platelet-poor plasma. To elucidate the origin of CTGF in platelets, we performed immunohistochemical analysis of human bone marrow sections. The analysis showed that although CTGF protein is widely expressed in bone marrow cells, it is not expressed by platelet-producing megakaryocytes, suggesting that CTGF presence in platelets is a result of endocytosis from extracellular environment in bone marrow. Agonist-stimulation of platelets resulted in a significant release of CTGF from the storage granules, with thrombin at 0.1 U/mL being a more potent activator than ADP at 20 micro mol/L. The agonist-dependent CTGF secretion was significantly inhibited by aspirin. In conclusion, CTGF is stored in normal human platelets, and can be released upon platelet activation. Aspirin treatment prevents CTGF release, suggesting that clinical benefits of this drug may involve the inhibition of CTGF secretion.

Adenosine Diphosphate↗
PubMed2006

Mixed connective tissue disease.

Mixed connective tissue disease (MCTD) was first described in 1972 as a disease syndrome with overlapping features of systemic sclerosis, systemic lupus erythematosus (SLE) and polymyositis associated with antibodies to RNAse sensitive extractable nuclear antigen. When the antigen was subsequently characterized as polypeptides on the U1 ribonuclear protein component of the splicesosome (U1RNP), MCTD became the first rheumatic disease syndrome to be defined by a serologic test. Clinical features include a high frequency of Raynaud's syndrome, swollen hands, sclerodactyly, arthritis, polymyositis and interstitial lung disease. Over the last 30 years there has been a continuing debate as to whether MCTD constitutes a 'distinct clinical entity'. Here, I will review the pathological, immunogenetic and clinical features of MCTD and conclude that the debate remains unresolved. The early misconception that it has a relatively good prognosis has not stood the test of time with long-term follow-up studies. These have identified a tendency for MCTD to evolve into SLE or systemic sclerosis and highlighted pulmonary hypertension and scleroderma renal crisis as important causes of death. Providing it is realized that our appreciation of the clinical features associated with anti-U1RNP have evolved over time, MCTD remains a useful concept in clinical practice. Whether it can be credited with the term 'disease' awaits the demonstration of common etiopathological events underlying the development of antibodies to U1 RNP and their associated clinical features.

Humans↗
PubMed2001

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

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.

Amino Acid Sequence↗
PubMed2005

Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor.

Connective tissue growth factor (CTGF) plays an important role in pathways leading to lung fibrosis via the mitogenic action of CTGF on fibroblasts. Studies have shown that lipoxin A4 (LXA4) inhibits proliferation of renal mesangial cells induced by leukotriene D4 or platelet-derived growth factor. This study investigates the regulatory role of LXA4 on proliferation of human lung fibroblasts (HLF) induced by CTGF and mechanisms of LXA4 action. CTGF induced HLF proliferation; enhanced the expression of cyclin D1; phosphorylated extracellular signal-regulated kinase (ERK)1/2, phosphoinositide 3-kinase (PI3-K), protein kinase B (PKB), and DNA-binding activity of signal transducers and activators of transcription-3 (STAT3); and inhibited expression of p27(kip1). LXA4 downregulated the CTGF-stimulated HLF proliferation and expression of cyclin D1; and phosphorylated ERK1/2, PI3-K, PKB, and DNA-binding activity of STAT3. CTGF-induced decrement in expression of p27(kip1) was ameliorated by LXA4. PI3-K or STAT blockade but not ERK1/2 blockade partially inhibited the CTGF-activated proliferation of HLF. Transfection of the human LXA4 receptor gene into HLF intensified the inhibition of LXA4 on CTGF-induced cell proliferation. These results demonstrate that CTGF induces proliferation of HLF via upregulation of PI3-K/PKB, STAT3, and cyclin D1, and downregulation of p27(kip1). LXA4 inhibits these effects of CTGF on HLF.

Animals↗
PubMed1994

Increased frequency of mutations in the hprt gene of T cells isolated from patients with anti-U1-70kD-autoantibody-positive connective tissue disease.

Mixed connective tissue disease (MCTD) is characterized by the presence of high titers of anti-U1-70kD autoantibodies which are the result of substantial B cell activation. The hprt gene encodes the constitutively expressed enzyme hypoxanthine-guanine phosphoribosyl transferase which is active in the purine salvage pathway. Rapidly dividing cells randomly accumulate gene mutations, including mutations in the hprt gene. These mutations may be used to identify activated cells. If activated T cells play a role in the pathogenesis of MCTD, an increased frequency of mutations in the hprt gene might be expected among T cells isolated from such patients. To examine this hypothesis, we isolated and cloned T cells from 10 anti-U1-70kD-autoantibody-positive MCTD patients and determined the precursor frequencies of cells possessing mutations in hprt by comparing the frequency of cells grown in the presence and absence of the purine analogue 6-thioguanine. We found that the frequency of 6-thioguanine-resistant hprt-negative T cells was significantly increased among MCTD patients (mean 566/10(6); range 122-2,845/10(6)) versus age- and sex-matched controls (mean 42/10(6); range 21-78/10(6); p < 0.003). These results demonstrate that there is an increase in the measured mutant frequency of T cells from MCTD patients. Such T cells may play a role in the pathogenesis of this disease.

Adult↗
PubMed2006

Intrinsic biological activity of the thrombospondin structural homology repeat in connective tissue growth factor.

Connective tissue growth factor (CCN2) is a 349-residue mosaic protein that contains four structural modules (modules 1-4), which are presumptive domains for interactions with regulatory binding proteins and receptors. Module 3, corresponding to residues 199-243, is a thrombospondin structural homology repeat (TSR) and is flanked by regions that are highly susceptible to proteolytic cleavage. To test whether CCN2 module 3 (CCN2(3)) has intrinsic biological properties, it was produced recombinantly in Escherichia coli (E. coli) and examined for its effects on the function of hepatic stellate cells (HSC), the principal fibrogenic cell type in the liver. CCN2(3) stimulated dose-dependent HSC adhesion and activity of p42/p44 mitogen activated protein kinase, the latter of which was antagonized by blocking the activity of focal adhesion kinase. HSC adhesion to immobilized CCN2(3) was attributed to binding interactions with cell surface integrin alpha6beta1. As assessed by RT-PCR or Western blotting, CCN2(3) stimulated production of fibronectin and pro-collagen type IV(alpha5), both of which are downstream components of HSC-mediated fibrogenesis and which are constituents of high density matrix in fibrotic lesions. These data show that while the full length CCN2 protein is strongly associated with fibrosis and stellate cell function, key integrinbinding properties, signaling, and fibrogenic pathways are exhibited by module 3 alone. These data indicate that module 3 of CCN2 is intrinsically active and suggest that liberation of module 3 following CCN2 proteolysis may contribute to HSC-mediated fibrogenesis, as well as other CCN2-dependent processes.

Animals↗
PubMed1996

Neutralization of HIV type 1 infectivity by serum antibodies from a subset of autoimmune patients with mixed connective tissue disease.

Mixed connective tissue disease (MCTD) is a rheumatic disorder with clinical similarities to HIV-1 infection, and with characteristic autoimmune anti-RNP antibodies specific for the U1 snRNP splicing complex. Anti-RNP antibodies cross-react with the HIV-1 surface, owing to multiple homologies between the gp120/41 envelope complex and the 70K protein of U1 snRNP. A key epitope of 70K, its RNA-binding site, is homologous to a dominant B and T cell epitope in the third variable loop (V3) of gp120. In this study, we tested the ability of anti-RNP sera to inhibit HIV-1 infectivity in vitro. Of nine sera tested, five were 70-99% effective in neutralizing one or more HIV-1 strains. One serum was > 99% effective in neutralizing HIV-1MN, and 86 and 77% effective against the primary isolates HIV-1(CO) and HIV-1(JR-FL), respectively, an efficacy equal to that of a pool of broadly neutralizing antibodies from HIV-1-infected subjects (HIVIG). The mean neutralizing titer of anti-RNP sera against HIV-1(JR-FL) was 3.9-fold higher than that of HIVIG. Neutralizing potency was associated with high reactivity to gp120 by ELISA, and with the presence of serum rheumatoid factor, known to enhance antibody neutralization of other viruses. The current findings provide further evidence that individuals unexposed to HIV-1 may develop immunologic resistance by alternative mechanisms, possibly including molecular mimicry, or exposure to as yet unidentified retroviruses. Thus MCTD, which involves both B and T cell reactivity to self-epitopes homologous to HIV-1, may elucidate new strategies for generating protective immunity to this virus.

Antibodies, Antinuclear↗
PubMed1998

Effects of pre- and postnatal protein deprivation on rat's hard palatine mucosae: a scanning electron microscopic study of the connective tissue papillae.

The primary (connective tissue papillae) and secondary projections of the subepithelial connective tissue of the lamina propria were studied in the hard palate of normal (control group), and in protein-deficient pups (experimental group) obtained through maternal protein deprivation during pregnancy and lactation. At birth, the primary projections in the control group are more developed in width whereas in the experimental group they are thin with a crest-like shape. On day 7 of lactation, the primary projections are abundant, well developed and regularly arranged in the control group. They are few in number and are irregular in shape and disposition in the experimental group. The secondary projections are located posterior to the primary ones in the control group and are intercalated with them in the experimental group. On day 21 of lactation, the characteristic foliate aspect of the primary projections are noted in the control group. In the experimental group they remain thin with a crest-like aspect.

Animals↗
PubMed1998

Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue.

The degradation of soft connective tissue collagen is considered to depend on the activity of various proteolytic enzymes, particularly those belonging to the group of matrix metalloproteinases and cysteine proteinases. In the present study, we investigated the contribution of these enzymes to this process. Using a general inhibitor of MMPs (SC44463), collagen degradation was strongly inhibited, by about 40% after 24 h and up to 80% after 72 h of culturing. Blockage of cysteine proteinase activity (with leupeptin or E-64) reduced breakdown at these time intervals by 50% and 20%, respectively. Given the abundant presence of gelatinases--in particular gelatinase A (MMP-2)--in the tissue, the effect of an inhibitor selective for gelatinases (CT1166) was studied. Gelatinase inhibition resulted in a dose-dependent decrease of collagen breakdown up to 90% after 48 h. The ability of gelatinase A to degrade collagens was demonstrated by the induction of breakdown in devitalized explants by addition of activated gelatinase A, or by activation of endogenous enzyme with 4-aminophenylmercuric acetate. This latter effect was not found with plasmin, an activator of MMPs other than gelatinase A. Finally, the relevance of gelatinase A to the in vivo degradation of soft connective tissue collagen was implicated by the significant correlation found between its activity and the collagen turnover rates of four soft connective tissues (tooth pulp, periodontal ligament, molar gingiva and skin). We conclude that collagen degradation in soft connective tissue is mediated by MMPs and to a lesser extent by cysteine proteinases. Our data are the first to attach a key role to gelatinase A in this process.

Animals↗
PubMed1998

The relation between nailfold bleeding and capillary microscopic abnormality in patients with connective tissue diseases.

BACKGROUND: Patients with connective tissue diseases, mainly scleroderma, show nailfold bleeding and nailfold capillary abnormality. An attempt was made to determine the possible relation between nailfold bleeding and nailfold capillary abnormality. METHODS: The correlation between nailfold bleeding and nailfold capillary abnormality was studied using quantitative nailfold capillary microscopy. RESULTS: The frequencies of nailfold bleeding in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, and secondary Raynaud's phenomenon were significantly higher than those of normal controls. The distributions of abnormal values of capillary parameters in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, secondary Raynaud's phenomenon, primary Raynaud's phenomenon, and diabetes mellitus were significantly higher than those of normal controls. In normal controls, scleroderma, mixed connective tissue diseases, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, primary Raynaud's phenomenon, and diabetes mellitus, all nailfold bleeding was observed in subjects with nailfold capillary abnormality. The distribution of nailfold bleeding in secondary Raynaud's phenomenon with abnormal values of capillary parameters was significantly higher than that with normal values. CONCLUSIONS: There is a close relationship between nailfold bleeding and nailfold capillary abnormality.

Adolescent↗
PubMedDate not supplied

Joint hypermobility and skin elasticity: the hereditary disorders of connective tissue.

The hereditary disorders of connective tissues (HDCTs) encompass a spectrum of conditions linked pathophysiologically by abnormalities of collagen, fibrillin, and matrix proteins. The clinical picture ranges from morbidity because of musculoskeletal, skin, ocular and visceral pathologies to mortality from acute vascular collapse. For many of the conditions, there is a considerable overlap in clinical features, although severity varies; appreciating the subtle differences in presentation is vital to the clinician in determining the diagnosis. Though conditions associated with severe vascular pathology are rare, other hereditary disorders of connective tissues such as the joint hypermobility syndrome and Stickler's disease are common and probably underrecognized. Abnormal skin elasticity and scaring, joint hypermobility, and chronic arthralgia are important clues that should trigger the clinician to search for underlying hereditary disorders of connective tissues. In this article, we discuss the spectrum of clinical findings, management, and genetic screening of the more common hereditary disorders of connective tissues, highlighting their diagnostic criteria and their differences.

Connective Tissue Diseases↗
PubMed1997

Report of a gingival "surgical cyst" developing secondarily to a subepithelial connective tissue graft.

The subepithelial connective tissue graft is a valuable technique used to cover exposed root surfaces or to increase the zone of attached gingiva. Cysts, such as the gingival cyst of the adult, are epithelial-lined cysts which may arise from heterotropic glandular tissue, a proliferating rete peg, remnants of the dental lamina, or traumatic implantation of epithelial tissue. In this paper, a case report is described of a "surgical cyst" or cystic morphogenesis of surgically implanted epithelium developing secondarily to a subepithelial connective tissue graft.

Aged↗
PubMedDate not supplied

Therapeutic effects of heat, cold, and stretch on connective tissue.

The anatomic architecture of connective tissue is dependent on the stresses associated with motion. Immobilization results in stress deprivation, causing structural changes in the tissue matrix. The structural changes that occur are due to the remodeling of tissue to its new resting length while being held immobile. The goal of remodeling stiffened, shortened tissues is to regain tissue length and promote unrestricted tissue gliding. The article reviews studies that examine the viscoelastic response of connective tissue to heat, cold, and stretch. An understanding of connective tissue response to these therapeutic interventions will enable clinicians to choose the appropriate modality and apply stretching techniques in a safe, efficient manner to enable patients to regain mobility.

Connective Tissue↗
PubMed1995

Morphology of the dorsal phalangeal connective tissue body.

BACKGROUND: The connective tissue body of the dorsal finger is partitioned by multiple horizontal lamellae derived from expansions of intercellular spaces. These connective fibres are involved in providing gliding spaces for the extensor apparatus, and they formed spreading rooms of infection processes. METHODS: In order to describe the topographical histological and histochemical behavior of cellular and intercellular elements of the border lamellae of the dorsal aponeurosis of the fingers, a modified method of Epoxid resin embedding technique without pre-infiltration is used. RESULTS: The bordering elements of the connective tissue lamellae described in this investigation are especially well defined in the region of the dorsal aponeurosis. The morphological examinations show that both the expansions of the intercellular space as well as defined fibrocytic cellular elements function in a manner equivalent to a synovial membrane of tendon sheaths. CONCLUSIONS: Saving or reconstructing these structures appears to be of importance in preventing for adhesive disorders of finger motion following surgical intervention in this region.

Aged↗
PubMed1985

Zosteriform connective-tissue nevus.

Zosteriform connective-tissue nevus, because of its distribution and histopathologic characteristics, is considered to be a separate entity. The only previous case of zosteriform connective-tissue nevus to be reported in the American literature was in 1944. We report and discuss a similar case.

Adult↗
PubMedDate not supplied

Differential regulation of collagen gene expression in granulation tissue and non-repair connective tissues in vitamin C-deficient guinea pigs.

Poor wound healing during vitamin C deficiency is thought to be due to decreased hydroxylation of proline residues in collagen. In non-repair connective tissues of guinea pigs, however, procollagen gene expression is not decreased until weight loss occurs during the third and fourth weeks of scurvy (phase II) with only a moderate decrease in proline hydroxylation. Decreased procollagen gene expression is related to the induction of insulin-like growth factor binding proteins 1 and 2 that inhibit insulin-like growth factor-I action. We examined wound healing and granulation tissue formation during phase I of vitamin C deficiency. Synthetic sponges were implanted on day 7 of vitamin C deficiency and analyzed at 6 and 10 days after surgery, when there was no weight loss or induction of insulin-like growth factor binding proteins. Healing of incisions was almost complete at 10 days after surgery in normal controls but not in scorbutic animals. The area around the incision and implant exhibited excessive angiogenesis and hemorrhaging of vessels in the scorbutic animals at 6 and 10 days after surgery. At 10 days after surgery, collagen synthesis in the implants of scorbutic guinea pigs was 36% lower than control values, with a normal extent of proline hydroxylation. Concentrations of messenger RNAs for types I and III procollagens were slightly increased by scurvy at 6 days after surgery but were decreased by 26% and 40%, respectively, at 10 days. Fibronectin mRNA levels were unaffected by scurvy at both time points. Our results suggest that poor wound healing in phase I of scurvy may be related to defective interstitial procollagen gene expression and defective blood vessel formation, but it does not involve inhibition of proline hydroxylation or induction of insulin-like growth factor binding proteins. mRNA for insulin-like growth factor-II, transforming growth factor-beta(1), and transforming growth factor-beta(2) were significantly expressed in implants, but their patterns of expression did not correlate with changes in procollagen gene expression.

Journal Article↗