Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes

Objective: Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions. Methods: Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopepticles of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [110 ng/ml], with salmon calcitonin [0.0001-1 mu M]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin) for 9 weeks. Results: The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P< 0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P < 0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P< 0.001) decrease in CTX-II levels. Conclusion: These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.