Opposite roles of pannexins in post-traumatic versus aging associated osteoarthritis

Abstract

Purpose: Osteoarthritis (OA) is a highly disabling and common degenerative joint disease. OA results from pathological changes in all joint tissues during aging or following joint injury. The mechanisms driving disease progression remain unclear, thus resulting in a lack of disease modifying treatments. A hallmarking feature of OA is cartilage degeneration, and chondrocyte hypertrophy is an important driver of cartilage breakdown. Pannexin 3 (Panx3) has been identified as a novel mediator of this process, and our recent study has shown that deletion of the Panx3 gene delays surgically induced cartilage degeneration in the DMM model in mice. Panx1, another member in the pannexin family, shares 60% sequence amino acid homology with Panx3 and is found ubiquitously throughout the joint and the body. Hence, in this study, we examine the systemic effects of global Panx3 and Panx1/Panx3 deletion during aging, with a specific focus on joint and skeletal health. Methods: WT and Panx3-/- mice were aged to 18 and 24 months of age. In parallel, WT and Panx1-/-/Panx3-/- mice were also aged to 24 months of age. MicroCT analysis was used to investigate bone mineral density and body composition. Joints were harvested, and histopathological analysis of OA development was conducted. The modified OARSI scoring system was used to assess cartilage destruction during aging. OsteoMeasure software was used to analyze subchondral bone parameters including subchondral thickness and area. Synovial changes were assessed using a synovitis scoring system modified from Krenn et al. Results: Our data show that the global loss of Panx3 and Panx1/Panx3 is not associated with increased mortality or significant changes in body composition with aging. We found that bone mineral density changes associated with aging were reduced in Panx3-/- mice compared to WT, although there were no significant differences in absolute bone mineral density at 24 months. Mice lacking Panx3 and Panx1/Panx3 had shorter appendicular and axial skeletons compared to WT mice. Lastly, we showed that loss of Panx3 dramatically accelerated cartilage degeneration with aging, at both 18 and 24 months. This is in sharp contrast to the protective effect previously observed in young mice following joint surgery. At 24 months of age, mice lacking Panx1/Panx3 also showed increased cartilage degeneration compared to WT mice. Conclusions: These studies highlight a novel, OA subtype-specific role for Panx3 in the maintenance of joint health following traumatic injury and with aging. While our previous data shows loss of Panx3 protects against post-DMM OA progression, these data show that loss of Panx3 accelerates OA progression during aging. In conclusion, this study shows that Panx3 and likely Panx1 are essential for the maintenance of cartilage homeostasis in aging mice and reinforces the idea that molecular mechanisms driving post-trauamtic and primary aging associated OA are distinct.