Deletion of Panx3 Prevents the Development of Surgically Induced Osteoarthritis

Abstract

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.

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

“…64) although the effect of injury or inflammatory mediators on pannexin-1 or pannexin-3 expression and function is less well established. Interestingly, loss of pannexin-3 is protective in murine models of OA suggesting that this protein is not involved in the phenomena studied here65. The observation that mice lacking expression of ANKH develop arthritis consistent with OA at an early age further supports the hypothesis that extracellular adenosine, derived from ATP, plays a homeostatic role in cartilage.…”

A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction

“…Consistent with severe hearing loss found in the proband, hearing loss was recently reported in a Panx1 conditional knock-out (KO) mouse from the cochlea (54,55). At present, there is evidence of Panx1 expression in osteoblasts (56), but because Panx3 has been the most studied pannexin in bone and cartilage (57), our knowledge of the role of Panx1 in skeletal development remains limited. Likewise, although Panx1 has been reported in the ovaries and male reproductive organs, its functional importance is poorly understood (50,58).…”

Next-Generation Connexin and Pannexin Cell Biology

“…Given that Panx1 phosphorylation by Src has recently been reported to induce channel opening, this particular peptide may also be a useful Panx1 channel inhibitor [122][123][124]. In another study, Panx3 ablation inhibited the onset of surgically induced osteoarthritis, raising the possibility that a peptide therapeutic specifically inhibiting Panx3 channels may provide treatment for a poorly controlled disease [125,126]. While these studies are encouraging, new and more specific inhibitors of pannexin channels are necessary.…”