| Summary: | Wntl Inducible Secreted Protein 3 (WISP-3/CCN6) is a member of the CCN (Cysteine rich 61/Connective tissue Growth Factor/Nephroblastoma Overexpressed) family of matricellular proteins. WISP-3/CCN6 is mutated in Progressive Pseudorheumatoid Dysplasia (pPRD), a rare disease of articular cartilage degeneration. The expression of WISP-3/CCN6 in osteoarthritis at the mRNA and protein level was investigated. To determine the role of WISP-3/CCN6 in chondrocyte biology the WISP-3/CCN6 gene was stably transfected into immortalised chondrocytic (C-281I2) cells. The effect of stable WISP-3/CCN6 over-expression on metalloproteinase gene expression was investigated.. The expression of WISP-3/CCN6 mRNA was significantly up-regulated in osteoarthritic cartilage extracts compared to post.-mortem .controls. Immunohistochemistry of osteoarthritic cartilage sections revealed that WISP-3/CCN6 protein expression was upregulated in areas of cartilage damage and was often localised to the pericellular matrix surrounding chondrocytes. The steady state mRNA levels for the aggrecanases ADAMTSI, ADAMTS4 and in particular, ADAMTS5 were significantly lower in clonal C-28/I2 cell lines stably over-expressing WISP-3/CCN6 compared to controls, while MMPIO mRNA was significantly up-regulated. Treatment with lithium chloride, which can mimic activation of canonical \Vnt signalling, led to a de-repression of ADAMTS5 mRNA and enhanced up-regulation ofMMPIO in the WISP-3/CCN6 clones. Treatment with the cytokines Interleukin In and Oncostatin M up-regulated ADAMTS5 mRNA and .down-regulated MMPI0 mRNA in the WISP-3/CCN6 clones. These data demonstrate that WISP-3/CCN6 may repress ADAMTS5 mRNA expression in chondrocytic cells by inhibiting canonical Wnt signalling. In addition, inflammatory pathways may oppose WISP-3/CCN6 activity. WISP-3/CCN6 may therefore be protective against cartilage degradation and could be up-regulated in osteoarthritis as a protective or reparative response. The WISP-3/CCN6 mediated up-regulation ofMMPlO also apparently involves Wnt signalling suggesting alternative mechanisms of WISP3/ CCN6 interaction with this signalling pathway. These divergent responses suggest that the role ofWISP-3/CCN6 is context dependent.
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