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CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion

, : CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion. Biochimica et Biophysica Acta 1833(5): 966-975

CCN4 is a cysteine-rich protein that belongs to the Cyr61, CTGF, Nov family of matricellular proteins. Here, we investigated the intracellular signaling pathways involved in CCN4-induced vascular cell adhesion molecule-1 expression in human osteoarthritis synovial fibroblasts. Stimulation of OASFs with CCN4 induced VCAM-1 expression. CCN4-induced VCAM-1 expression was attenuated by ?v?5 or ?6?1 integrin antibody, Syk inhibitor, PKC? inhibitor (rottlerin), JNK inhibitor (SP600125), and AP-1 inhibitors (curcumin and tanshinone). Stimulation of cells with CCN4 increased Syk, PKC?, and JNK activation. Treatment of OASFs with CCN4 also increased c-Jun phosphorylation, AP-1-luciferase activity, and c-Jun binding to the AP-1 element in the VCAM-1 promoter. Moreover, up-regulation of VCAM-1 increased the adhesion of monocytes to OASF monolayers, and this adhesion was attenuated by transfection with a VCAM-1 siRNA. Our results suggest that CCN4 increases VCAM-1 expression in human OASFs via the Syk, PKC?, JNK, c-Jun, and AP-1 signaling pathways. The CCN4-induced VCAM-1 expression promoted monocyte adhesion to human OASFs. CCN4 was highly expressed in OA synovial fibroblasts as compared to normal SFs. CCN4 induces the monocyte adhesion in OASFs by up-regulation of VCAM-1 expression. CCN4 acts through the ?v?5/?6?1 integrin, Syk, PKC?, and JNK pathways to induce VCAM-AP-1 is key transcription factor of CCN4-induced VCAM-1 expression.


PMID: 23313051

DOI: 10.1016/j.bbamcr.2012.12.023

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