Severe osteoarthritis in aged PANX3 knockout mice: implications for a novel primary osteoarthritis model

Abstract

Osteoarthritis (OA) is a multifactorial 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 Panx3in male mice results in spontaneous full-thickness cartilage lesions at 24 mo of age. While protected from traumatic intervertebral disc (IVD) degeneration, Panx3KO mice show signs of IVD disease with altered disc mechanics. Whether the deleterious effects of ablating Panx3in aging are the result of accumulated mechanical damage is unknown. We used male and female WT and global Panx3KO C57Bl6 mice aged 18 mo of age. Mice were then randomized to sedentary (SED) or forced treadmill running (FEX) for 6 wk. Knee joint tissues, including the 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 SED Panx3KO mice developed full-thickness cartilage lesions, severe synovitis, and ectopic fibrocartilage deposition and calcification of the knee joints in comparison to all other conditions. Panx3KO 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 Panx3KO mice; however, it may have contributed to the development of lateral compartment OA. The IVDs of aged Panx3KO mice displayed no apparent differences to control mice, and forced treadmill running had no further effects in either genotype. We conclude that aged Panx3KO mice show features of late-stage primary OA, including full-thickness cartilage erosion, severe synovitis, and enthesitis. These data suggest that the deletion of Panx3is deleterious to synovial joint health in aging.