TMEM2 maintains hyaluronan turnover and cartilage homeostasis during early osteoarthritis progression

Osteoarthritis (OA) is characterized by progressive cartilage degeneration, yet the initiating molecular events remain incompletely understood. Transmembrane protein 2 (TMEM2), a cell-surface hyaluronidase that degrades hyaluronan (HA), has been implicated in extracellular matrix homeostasis. Here, we delineate the spatiotemporal expression pattern of TMEM2 in mouse knee joints and assess its functional role during OA development. Single-cell RNA sequencing and histological analyses of normal joints revealed predominant Tmem2 expression in non-calcified articular chondrocytes and synovial cells. Following destabilization of the medial meniscus (DMM), Tmem2 was transiently upregulated during early OA, particularly within the non-calcified cartilage zone, coinciding with a pronounced reduction in HA content indicative of accelerated HA turnover. In contrast, Tmem2 expression declined at later stages, suggesting a temporally restricted activation phase. Functionally, Tmem2 deficiency exacerbated DMM-induced OA, leading to more severe structural deterioration, increased chondrocyte apoptosis, reduced proliferation, and elevated type X collagen, consistent with impaired cartilage homeostasis. Collectively, these findings identify TMEM2 as a key regulator of HA metabolism and a context-dependent modulator of OA progression. We propose that early, transient TMEM2 upregulation represents an adaptive remodeling response, whereas dysregulated or prolonged activity may contribute to HA depletion and cartilage breakdown.