Human cartilage glycoprotein 39 (HC-gp39) is a glycoprotein secreted by articular chondrocytes, synoviocytes and macrophages. Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. The increased secretion of HC-gp39 under physiological and pathological conditions with elevated connective-tissue turnover suggests its involvement in the homoeostasis of these tissues. We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1. At suboptimal concentrations, the two growth factors work in a synergistic fashion. The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39. Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39. Activation of these signalling pathways could also be demonstrated in human chondrocytes. Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis.
Elevated levels of CHI3L1 (chitinase-3-like protein 1) are associated with disorders exhibiting increased connective tissue turnover, such as rheumatoid arthritis, osteoarthritis, scleroderma, and cirrhosis of the liver. This secreted protein is not synthesized in young healthy cartilage, but is produced in cartilage from old donors or patients with osteoarthritis. The molecular processes governing the induction of CHI3L1 are currently unknown. To elucidate the molecular events involved in CHI3L1 synthesis, we investigated two models of articular chondrocytes: neonatal rat chondrocytes, which do not express CHI3L1, and human chondrocytes, which express CHI3L1 constitutively. In neonatal rat chondrocytes, the inflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1 potently induced steady-state levels of CHI3L1 mRNA and protein secretion. Treatment of chondrocytes with TNF-␣ for as little as 1 h was sufficient for sustained induction up to 72 h afterward. Using inhibitors selective for the major signaling pathways implicated in mediating the effects of TNF-␣ and interleukin-1, only inhibition of NF-B activation was effective in curtailing cytokine-induced expression, including after removal of the cytokine, indicating that induction and continued production of CHI3L1 are controlled mainly by this transcription factor. Inhibition of NF-B signaling also abolished constitutive expression by human chondrocytes. Thus, induction and continued secretion of CHI3L1 in chondrocytes require sustained activation of NF-B. Selective induction of CHI3L1 by cytokines acting through NF-B coupled with the known restriction of the catabolic responses by CHI3L1 in response to these inflammatory cytokines represents a key regulatory feedback process in controlling connective tissue turnover.
Objective. Cartilage oligomeric matrix protein (COMPj is a component of the extracellular matrix of articular cartilage. Its increased presence in synovial fluid and serum has been associated with accelerated joint damage in patients with rheumatoid arthritis (RA) and osteoarthritis. To fully understand the reasons for fluctuations of COMP levels, we studied the biosynthe-sis of this molecule in cells derived from joint tissues. Methods. Synovial cells were derived from syno-vial tissues of patients with RA, and human articular chondrocytes were prepared from normal articular cartilage. Analysis by Northern blotting was used to evaluate steady-state levels of COMP messenger RNA (mRNAj, while secretion of the protein into culture media was analyzed by Western blotting. Expression of COMP in synovial tissues was studied by reverse transcriptase-polymerase chain reaction analysis and by in situ hybridization. Results. COMP was synthesized and secreted by synovial cells as well as by articular chondrocytes in culture. The basal rate of synthesis was very low; however, COMP biosynthesis in both cell populations was induced very strongly by transforming growth factor p 1 (TGFPl). Interleukin-lp counteracted COMP induction by TGF-P1. COMP was not detected in culture media of skin or fetal lung fibroblasts, either in the absence or the presence of TGFP1. COMP mRNA was also present in fresh synovial tissue specimens obtained from patients with RA. Conclusion. COMP is synthesized and secreted not only by articular chondrocytes, but also by synovial fibroblasts. The demonstration of COMP expression in surgical specimens of synovial tissues suggests that the inflamed synovium may provide an additional source for the elevated levels of COMP observed in arthritis. Thus, increased COMP levels in body fluids may he indicative of active synovitis as well as of accelerated joint erosion. Cartilage oligomeric matrix protein (COMP) is a component of the extracellular matrix of articular cartilage (1). Based on amino acid sequence homology, COMP belongs to the thrombospondin (TSP) protein family (2) and is sometimes referred to as TSP-5 (3). Similar to its 2 closest rclatives, TSP-3 and TSP-4 (4), native COMP is a pentameric complex of identical subunits with a molecular size of-120 kd, depending on the degree of glycosylation of the individual subunits (2,5). The COMP subunit consists of an N-terminal domain, which mediates the association of individual subunits into the oligomeric form. followed by 4 epider-mal growth factor-like repeats and 7 TSP-3 repeats, which contain calmodulin-like calcium-binding motifs, and finally a C-terminal globular domain (2.5). The function of COMP in the extracellular milieu of the chondrocyte is not precisely understood. Extraction of COMP from cartilage matrix is facilitated by the divalent metal chelator EDTA (6). Considering the presence of calcium-binding domains in the COMP molecule, this would suggest that calcium may be involved in the interaction of COMP with other matrix components. Intact...
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