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 2nM, 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.
- growth factor
- mitogen-activated protein kinase (MAP kinase)
- synovial cell
Abbreviations used: bpV, potassium bisperoxo (1,10-phenanthroline)oxovanadate; HC-gp39, human cartilage glycoprotein 39; HFL, human fetal lung fibroblast; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; MEK, MAP kinase and ERK kinase; PI-3K, phosphoinositide 3-kinase; AKT, protein kinase B; IGF-1, insulin-like growth factor-1; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum.
- The Biochemical Society, London ©2002