Aged male and femalePanx3KO mice develop severe osteoarthritis independent of forced mechanical use

Abstract

ABSTRACTBackgroundOsteoarthritis (OA) is a multi-factorial disease that is strongly associated with aging. As the molecular mechanisms underpinning the pathogenesis of this disease are partially unclear, there are no disease-modifying drugs to combat OA. The mechanosensitive channel Pannexin 3 (PANX3) has been shown to promote cartilage loss during posttraumatic OA. In contrast, the ablation ofPanx3in male mice results in spontaneous full-thickness cartilage lesions at 24 months of age. Additionally, while protected from traumatic intervertebral disc (IVD) degeneration,Panx3knockout (KO) mice show signs of IVD disease with altered disc mechanics. Whether the deleterious effects of ablatingPanx3in aging is the result from accumulated mechanical damage is unknown.MethodsMale and female wildtype (WT) and globalPanx3KO C57Bl6 mice were aged to 18 months of age. Mice were then randomized to sedentary (SED) or forced treadmill running (FEX) for 6 weeks (N = 5-14). Knee joint tissues including patellar tendon, quadriceps and distal patellar enthesis, and synovium were analyzed histologically, along with lumbar spine IVDs.ResultsApproximately half of male and femalePanx3KO mice developed full-thickness cartilage lesions, severe synovitis, and ectopic fibrocartilage deposition and calcification of the knee joints. Additionally,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 femalePanx3KO mice; however, it may have contributed to the development of lateral compartment OA. The IVDs of agedPanx3KO mice displayed no apparent differences to control mice, and forced treadmill running had no overt effects in either genotype.ConclusionAgedPanx3KO mice show histological features of late-stage primary OA including full-thickness cartilage erosion, subchondral bone thickening, and severe synovitis. This data suggests the deletion ofPanx3is deleterious to synovial joint health in aging.