Severe Osteoarthritis in Aged PANX3 Knockout Mice: Implications for a Novel Primary Osteoarthritis Model
Authors: Wakefield Brent , Tang Justin , Melo Julián Balanta , Hutchinson Jeffrey L. , Kanji Rehanna , Herold Geneva , O’Donnell Brooke L. , Brooks Courtney , Kiser Patti , Grol Matthew W. , Séguin Cheryle A. , Plotkin Lilian I. , Beier Frank , Penuela Silvia 
Published: July 2023

ABSTRACTOsteoarthritis (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 ofPanx3in male mice results in spontaneous full-thickness cartilage lesions at 24 months of age. 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. We used male and female wildtype (WT) and globalPanx3KO 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 sedentaryPanx3KO 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 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 further effects in either genotype. We conclude that agedPanx3KO mice show features of late-stage primary OA including full-thickness cartilage erosion, severe synovitis, and enthesitis. These data suggest that the deletion ofPanx3is deleterious to synovial joint health in aging.LAY SUMMARYOsteoarthritis is a common joint disease, and its incidence can increase with aging. As such, no drugs are available to treat its progression. Recently, we discovered that cellular channels composed of Pannexin 3 (PANX3) proteins may contribute to the health of joint tissues. In this study, we propose a new model for age-related primary OA, using histology, microCT, and pathology assessments under sedentary and forced exercise conditions. We found that aged mice lacking the channel protein PANX3 developed late-stage OA, including severe cartilage loss, joint inflammation, and tendon attachment damage. Half of the sedentary PANX3-deficient mice showed these changes, along with abnormal bone growth. Treadmill running did not make the condition worse but may have caused additional joint damage in some areas. The spine, however, remained unaffected. These findings suggest that deletingPanx3harms joint health with aging. Importantly, this mouse model mimics human primary OA, even without added factors like diet changes or forced exercise.