Joint tissues are exquisitely sensitive to their mechanical environment. Indeed, mechanical loading may be the most important external factor regulating the development and long-term maintenance of joint tissues. Moderate mechanical loading maintains the integrity of articular cartilage, and under these conditions of homeostasis, matrix metalloproteinases (MMPs) are expressed at modest levels. However, both disuse and overuse can result in altered likely high levels of MMP expression, leading to cartilage degradation. The transcriptional regulator ED-rich tail 2 (CITED2) is expressed in chondrocytes in a load-dependent manner but in a pattern inversely related to that of MMPs. CITED2 mediates the moderate load-induced suppression of MMPs, possibly by competing with Ets-1, a known MMP transactivator, for binding to the co-activator p300, suggesting a mechanism for transcriptional suppression by CITED2. These findings suggest that CITED2 may act as a mechanosensitive molecular switch regulating cartilage matrix breakdown. This regulatory pathway could be exploited clinically to limit pathologic cartilage degradation.