Severe Osteoarthritis in Aged PANX3 Knockout Mice: Implications for a Novel Primary Osteoarthritis Model

Abstract

Osteoarthritis (OA) is a multi-factorial disease associated with aging. As the molecular mechanisms underpinning the pathogenesis of this disease are unclear, there are no disease-modifying drugs to combat OA. Pannexin 3 (PANX3) has been shown to promote cartilage loss during posttraumatic OA. In contrast, the ablation of Panx3 in male mice results in spontaneous full-thickness cartilage lesions at 24 months of age. While protected from traumatic intervertebral disc (IVD) degeneration, Panx3 knockout (KO) mice show signs of IVD disease with altered disc mechanics. Whether the deleterious effects of ablating Panx3 in aging is the result from accumulated mechanical damage is unknown. We used male and female wildtype (WT) and global Panx3 KO C57Bl6 mice aged to 18 months of age. Mice were then randomized to sedentary (SED) or forced treadmill running (FEX) for 6 weeks. Knee joint tissues including patellar tendon, quadriceps and distal patellar enthesis, and synovium were analyzed histologically and through micro-CT, along with lumbar spine IVDs. Half of male and female sedentary Panx3 KO mice developed full-thickness cartilage lesions, severe synovitis, and ectopic fibrocartilage deposition and calcification of the knee joints in comparison to all other conditions. Panx3 KO mice with severe OA show signs of quadriceps and patellar enthesitis, characterized by bone and marrow formation. Forced treadmill running did not seem to exacerbate these phenotypes in male or female Panx3 KO mice; however, it may have contributed to the development of lateral compartment OA. The IVDs of aged Panx3 KO mice displayed no apparent differences to control mice, and forced treadmill running had no further effects in either genotype. We conclude that aged Panx3 KO mice show features of late-stage primary OA including full-thickness cartilage erosion, severe synovitis, and enthesitis. These data suggest that the deletion of Panx3 is deleterious to synovial joint health in aging.