TMEM2-mediated hyaluronan turnover maintains articular cartilage homeostasis during osteoarthritis progression

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive disruption of the cartilage extracellular matrix (ECM), yet the molecular mechanisms governing ECM turnover during disease initiation remain incompletely defined. Hyaluronan (HA) is a major structural component of articular cartilage, and its regulated turnover is essential for maintaining tissue integrity. Transmembrane protein 2 (TMEM2) is a cell-surface hyaluronidase capable of degrading high-molecular weight HA under physiological conditions, but its role in joint tissues has remained unclear. Here, we examine the spatiotemporal expression and functional contribution of TMEM2 in articular cartilage using single-cell transcriptomic analysis, histological approaches, and a chondrocyte-specific conditional knockout mouse model. Under physiological conditions, Tmem2 was predominantly expressed in non-calcified articular chondrocytes. Following joint destabilization, Tmem2 expression was transiently increased during early osteoarthritis, coinciding with reduced cartilage HA content, consistent with altered HA turnover. Importantly, genetic ablation of Tmem2 in chondrocytes markedly exacerbated osteoarthritis progression, resulting in accelerated cartilage delamination, increased chondrocyte apoptosis, reduced proliferative activity, and enhanced hypertrophic differentiation. These changes occurred without detectable abnormalities in the synovium, subchondral bone, or osteophyte formation, indicating a cartilage-intrinsic phenotype. Collectively, these findings identify TMEM2 as an important regulator of hyaluronan homeostasis within the cartilage ECM and provide in vivo genetic evidence that TMEM2- dependent HA turnover contributes to the maintenance of articular cartilage integrity during osteoarthritis progression.