Osteoarthritis (OA) is a highly prevalent, disabling joint disease with no existing therapies to slow or halt its progression. Cartilage degeneration hallmarks OA pathogenesis, and pannexin 3 (Panx3), a member of a novel family of channel proteins, is upregulated during this process. The function of Panx3 remains poorly understood, but we consistently observed a strong increase in Panx3 immunostaining in OA lesions in both mice and humans. Here, we developed and characterized the first global and conditional Panx3 knockout mice to investigate the role of Panx3 in OA. Interestingly, global Panx3 deletion produced no overt phenotype and had no obvious effect on early skeletal development. Mice lacking Panx3 specifically in the cartilage and global Panx3 knockout mice were markedly resistant to the development of OA following destabilization of medial meniscus surgery. These data indicate a specific catabolic role of Panx3 in articular cartilage and identify Panx3 as a potential therapeutic target for OA. Lastly, while Panx1 has been linked to over a dozen human pathologies, this is the first in vivo evidence for a role of Panx3 in disease.

F-spondin is a pericellular matrix protein upregulated in developing growth plate cartilage and articular cartilage during osteoarthritis. To address its function in bone and cartilage in vivo, we generated mice that were deficient for the F-spondin gene, Spon1. Spon1 − /− mice were viable and developed normally to adulthood with no major skeletal abnormalities. At 6 months, femurs and tibiae of Spon1 − /− mice exhibited increased bone mass, evidenced by histological staining and micro CT analyses, which persisted up to 12 months. In contrast, no major abnormalities were observed in articular cartilage at any age group. Immunohistochemical staining of femurs and tibiae revealed increased levels of periostin, alkaline phosphate and tartrate resistant acid phosphatase (TRAP) activity in the growth plate region of Spon1 − /− mice, suggesting elevated bone synthesis and turnover. However, there were no differences in serum levels of TRAP, the bone resorption marker, CTX-1, or osteoclast differentiation potential between genotypes. Knockout mice also exhibited reduced levels of TGF-β1 in serum and cultured costal chondrocytes relative to wild type. This was accompanied by increased levels of the BMP-regulatory SMADs, P-SMAD1/5 in tibiae and chondrocytes. Our findings indicate a previously unrecognized role for Spon1 as a negative regulator of bone mass. We speculate that Spon1 deletion leads to a local and systemic reduction of TGF-β levels resulting in increased BMP signaling and increased bone deposition in adult mice.

Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years.

Objective Osteoarthritis (OA) results in pathologic changes in the joint tissue. The mechanisms driving disease progression remain largely unclear, and thus disease‐modifying treatments are lacking. Pannexin 3 (Panx3) was identified as a potential mediator of cartilage degeneration in OA, and our previous study in mice indicated that deletion of the Panx3 gene delayed surgically induced cartilage degeneration. This study was undertaken to examine the role of Panx3 in other OA subtypes, particularly primary OA during aging, in a mouse model of aging‐induced OA. Methods Wild‐type (WT) and Panx3−/− C57BL/6J (Black‐6) mice, ages 18–24 months, were analyzed by micro–computed tomography to investigate bone mineral density and body composition. Joints were harvested from the mice, and histopathologic analysis of the joint tissue for OA development was conducted with a specific focus on changes in articular cartilage, subchondral bone, and synovial tissue. Results Global loss of Panx3 in aging mice was not associated with increased mortality or changes in body composition. Mice lacking Panx3 had shorter appendicular skeletons than WT mice, but overall the body compositions appeared quite similar. Panx3 deletion dramatically accelerated cartilage degeneration and subchondral bone thickening with aging in both 18‐month‐old and 24‐month‐old mice, while promoting synovitis in 18‐month‐old mice. Conclusion These observations in a mouse model of OA suggest that Panx3 has a protective role against the development of primary aging‐associated OA. It appears that Panx3 has opposing context‐specific roles in joint health following traumatic injury versus that associated with aging. These data strongly suggest that there are differences in the molecular pathways driving different subtypes of OA, and therefore a detailed understanding of these pathways could directly improve strategies for OA diagnosis, therapy, and research.

Pannexin 3 (Panx3) is a mechanosensitive, channel-forming glycoprotein implicated in the progression of post-traumatic osteoarthritis. Despite evidence for Panx3 expression in the intervertebral disc (IVD), its function in this cartilaginous joint structure remained unknown. Using Panx3 knockout mice, this study investigated the role of Panx3 in age-associated IVD degeneration and degeneration induced by annulus fibrosus (AF) needle puncture. Loss of Panx3 did not significantly impact the progression of age-associated histopathological IVD degeneration; however, loss of Panx3 was associated with decreased gene expression of Acan, Col1a1, Mmp13 and Runx2 and altered localization of COLX in the IVD at 19 months-of-age. Following IVD injury in the caudal spine, histological analysis of wild-type mice revealed clusters of hypertrophic cells in the AF associated with increased pericellular proteoglycan accumulation, disruptions in lamellar organization and increased lamellar thickness. In Panx3 knockout mice, hypertrophic AF cells were rarely detected and AF structure was largely preserved post-injury. Interestingly, uninjured IVDs adjacent to the site of injury more frequently showed evidence of early nucleus pulposus degeneration in Panx3 knockout mice but remained healthy in wild-type mice. These findings suggest a role for Panx3 in mediating the adaptive cellular responses to altered mechanical stress in the IVD, which may buffer aberrant loads transferred to adjacent motion segments.