Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR /Ort Mouse Model of Spontaneous Osteoarthritis

Objective Cartilage destruction in osteoarthritis ( OA ) is mediated mainly by matrix metalloproteinases ( MMP s) and ADAMTS . The therapeutic candidature of targeting aggrecanases has not yet been defined in joints in which spontaneous OA arises from genetic susceptibility, as in the case of the STR /Ort mouse, without a traumatic or load‐induced etiology. In addition, we do not know the long‐term effect of aggrecanase inhibition on bone. We undertook this study to assess the potential aggrecanase selectivity of a variant of tissue inhibitor of metalloproteinases 3 ( TIMP ‐3), called [‐1A] TIMP ‐3, on spontaneous OA development and bone formation in STR /Ort mice. Methods Using the background of STR /Ort mice, which develop spontaneous OA , we generated transgenic mice that overexpress [‐1A] TIMP ‐3, either ubiquitously or conditionally in chondrocytes. [‐1A] TIMP ‐3 has an extra alanine at the N‐terminus that selectively inhibits ADAMTS but not MMP s. We analyzed a range of OA ‐related measures in all mice at age 40 weeks. Results Mice expressing high levels of [‐1A] TIMP ‐3 were protected against development of OA , while those expressing low levels were not. Interestingly, we also found that high levels of [‐1A] TIMP ‐3 transgene overexpression resulted in increased bone mass, particularly in females. This regulation of bone mass was at least partly direct, as adult mouse primary osteoblasts infected with [‐1A] TIMP ‐3 in vitro showed elevated rates of mineralization. Conclusion The results provide evidence that [‐1A] TIMP ‐3–mediated inhibition of aggrecanases can protect against cartilage degradation in a naturally occurring mouse model of OA , and they highlight a novel role that aggrecanase inhibition may play in increased bone mass.