We report that the chitinase-like protein, human cartilage glycoprotein 39 (HC-gp39) is a growth and survival factor. It promotes connective tissue cell survival and growth, and counteracts catabolic processes. Dose-dependent growth stimulation was observed when human synoviocytes and fibroblasts were exposed to HC-gp39. Both the ERK1/2 MAP kinase and the PI3 kinase pathways were activated by HC-gp39. Thus HC-gp39 elicits a signaling cascade leading to increased connective tissue cell proliferation, suggesting that HC-gp39 may play a major role in the pathological conditions leading to tissue fibrosis. In addition to acting as a mitogen, HC-gp39 also reduces stress-induced apoptosis in human connective tissue cells. HC-gp39 significantly inhibited H2 O2 activation of SAPK/JNK and p38 in chondrocytes. A reduction of caspase-3 activation, poly(ADP-ribose) polymerase (PARP) cleavage and apoptotic cell number was also seen. These results suggest that HC-gp39 plays an important role in the survival of connective tissue cells. The protective effect is further illustrated by the ability of HC-gp39 to reduce cellular responses to inflammatory cytokines. IL-1 or TNF-alpha stimulated phosphorylation of SAPK/JNK and p38 were greatly reduced by HC-gp39. Signalling through the NF-kappab pathway was unaffected. These actions resulted in a significant reduction of MMP1, MMP3, MMP13 and IL-8 production, suggesting that HC-gp39 can participate in the catabolic aspects of tissue remodelling as a repair or protecting factor counteracting the catabolic processes. Although HC-gp39 affected the response to IL-1 and TNF-alpha, these cytokines had no effect on the high expression level of HC-gp39 in chondrocytes cultures. However, inhibition of the NF-B signalling pathway, which has been implicated as a major effectory mechanism for TNF-alpha, significantly decreased HC-gp39 protein and mRNA levels in a concentration and time dependent manner. Increased NF-kappaB / Therefore, this work demonstrated that expression of HC-gp39 at inflammation sites is part of the reaction chain in the pathogenesis of joint degeneration and/or inflammation. The activity of the elements regulating the expression of HC-gp39 suggests that it could serve as a negative feedback regulator for the inflammatory cytokines.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85567 |
| Date | January 2004 |
| Creators | Ling, Hua, 1963- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Surgical Research.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002201588, proquestno: AAINR12885, Theses scanned by UMI/ProQuest. |
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