Double‐knockout of ADAMTS‐4 and ADAMTS‐5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis

Objective To phenotypically characterize ADAMTS‐4– and ADAMTS‐5–double‐knockout mice, and to determine the effect of deletion of ADAMTS‐4 and ADAMTS‐5 on the progression of osteoarthritis (OA) in mice. Methods Mice lacking the catalytic domain of ADAMTS‐4 and ADAMTS‐5 were crossed to generate ADAMTS‐4/5–double‐knockout animals. Twelve‐week‐old and 1‐year‐old male and female ADAMTS‐4/5–double‐knockout mice were compared with age‐ and sex‐matched wild‐type (WT) mice by evaluating terminal body weights, organ weights, clinical pathology parameters, PIXImus mouse densitometry findings, and macroscopic and microscopic observations. ADAMTS‐4/5–double‐knockout mice were challenged by surgical induction of joint instability to determine the importance of these genes in the progression of OA. Articular and nonarticular cartilage explants from WT and ADAMTS‐4/5–double‐knockout mice were treated with interleukin‐1 (IL‐1) plus retinoic acid ex vivo, to examine proteoglycan degradation. Results There were no genotype‐related phenotype differences between ADAMTS‐4/5–double‐knockout and WT mice through 1 year of age, with the exception that female ADAMTS‐4/5–double‐knockout mice had a lower mean terminal body weight at the 12‐week time point. Eight weeks after surgical induction of joint instability, OA was significantly less severe in ADAMTS‐4/5–double‐knockout mice compared with WT mice. Following stimulation of cartilage explants with IL‐1 plus retinoic acid, aggrecanase‐mediated degradation in ADAMTS‐4/5–double‐knockout mice was ablated, to a level comparable with that in ADAMTS‐5–knockout mice. Conclusion Dual deletion of ADAMTS‐4 and ADAMTS‐5 generated mice that were phenotypically indistinguishable from WT mice. Deletion of ADAMTS‐4/5 provided significant protection against proteoglycan degradation ex vivo and decreased the severity of murine OA. These effects in the ADAMTS‐4/5–double‐knockout mice were comparable with those observed with deletion of ADAMTS‐5 alone.