Enhanced Expression of Tissue Inhibitor of Metalloproteinases-4 Gene in Human Osteoarthritic Synovial Membranes and Its Differential Regulation by Cytokines in Chondrocytes

Wensheng Huang, Mohammed El Mabrouk, Judith Sylvester, Faramaze Dehnade , Muhammad Zafarullah*
Department of Medicine, University of Montreal and Research Center of CHUM (CRCHUM) Notre-Dame Hospital, Montreal, Quebec, H2L 4M1, Canada

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© Huang et al.; Licensee Bentham Open.

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* Address correspondence to this author at the K-5255 Mailloux, Hôpital Notre-Dame du CHUM, 1560 Sherbrooke est, Montréal, Québec, H2L 4M1, Canada; Tel: 1-514-890-8000, Ext. 25690; Fax: 1-514-412-7612; E-mail:



Tissue inhibitors of metalloproteinases (TIMPs) are multi-functional proteins with matrix metalloproteinases-inhibiting activities. We studied expression of anti-inflammatory, TIMP-4 gene in human joint tissues and its regulation by arthritis-associated cytokines.


TIMP-4 RNA expression originating from synovial fibroblasts was significantly (2.4 fold; p<0.001) elevated in 8 osteoarthritic (OA) versus 7 non-arthritic synovial membranes. Non-arthritic and OA femoral head and knee chondrocytes displayed substantial but variably constitutive expression of the TIMP-4 mRNA. In articular chondrocytes, transforming growth factor beta (TGF-β1) and oncostatin M (OSM) upregulated TIMP-4 RNA and protein expression while interleukin-1 (IL-1β) and tumor necrosis factor alpha (TNF-α) did not, suggesting differential regulation by arthritis-associated cytokines. Interleukin 17 (IL-17) mildly induced TIMP-4 mRNA. TGF-β1 induction of TIMP-4 expression was partly inhibited by ERK pathway and Sp1 transcription factor inhibitors.


Enhanced TIMP-4 gene expression in OA synovial membranes and cartilage may be due to induction by TGF-β1, OSM and IL-17, suggesting its pathophysiological role in tissue remodeling in human joints. TGF-β1 induction of TIMP-4 expression is mediated partly by ERK pathway and Sp1 transcription factor.

Keywords: Osteoarthritis, synovium, chondrocytes, TIMP-4, cytokines..