Background: Osteoarthritis (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 of Panx3 in male mice results in spontaneous full-thickness cartilage lesions at 24 months of age. Additionally, 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. Methods: Male and female wildtype (WT) and global Panx3 KO 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. Results: Approximately half of male and female Panx3 KO mice developed full-thickness cartilage lesions, severe synovitis, and ectopic fibrocartilage deposition and calcification of the knee joints. Additionally, 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 overt effects in either genotype. Conclusion: Aged Panx3 KO 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 of Panx3 is deleterious to synovial joint health in aging.

Pannexin 3 (Panx3) is a glycoprotein that forms mechanosensitive channels expressed in chondrocytes and annulus fibrosus cells of the intervertebral disc (IVD). Evidence suggests Panx3 plays contrasting roles in traumatic versus aging osteoarthritis (OA) and intervertebral disc degeneration (IDD). However, whether its deletion influences the response of joint tissue to mechanical stress is unknown. The purpose of this study was to determine if Panx3 deletion in mice causes increased knee joint OA and IDD after forced treadmill running. Male and female wildtype (WT) and Panx3 knockout (KO) mice were randomized to either a no exercise group (sedentary; SED) or daily forced treadmill running (forced exercise; FEX) from 24 to 30 weeks of age. Knee cartilage, tibial subchondral bone and IVD histopathology were evaluated by histology. Both male and female Panx3 KO mice developed larger superficial defects of the tibial cartilage after forced treadmill running compared to SED WT mice. Additionally, both male and female Panx3 KO mice developed a sclerotic secondary ossification center of the tibia with running. In the lower lumbar spine, both male and female Panx3 KO mice developed histopathological features of IDD after running compared to SED WT mice. Clinical Significance: These findings suggest that the combination of deleting Panx3 and forced treadmill running induces OA and causes histopathological changes associated with degeneration of the IVDs in mice.