Betaine Downregulates RARRES1 to Alleviate Cartilage Fibrosis and Promote Hyaline Cartilage Repair

Cartilage degeneration is the hallmark pathological alteration in osteoarthritis (OA). The irreversible accumulation of fibrotic cartilage compromises joint function and accelerates disease progression. However, reliable biomarkers and therapeutic targets for cartilage fibrosis remain lacking. Through bioinformatic analysis of bulk RNA sequencing and single-cell RNA sequencing datasets, RARRES1 (retinoic acid receptor responder 1) was identified as a key biomarker associated with cartilage degeneration. The functional role of RARRES1 was investigated using a CTGF (Connective tissue growth factor) induced chondrocyte fibrosis model and siRNA-mediated gene knockdown. Subsequently, in vitro and in vivo experiments were conducted, including Western blotting, functional assays, flow cytometry, and pathological staining. RARRES1 was markedly upregulated in the damaged cartilage regions of patients with osteoarthritis, and this finding was confirmed in the chondrocyte fibrosis model. Betaine downregulates RARRES1 and promotes hyaline cartilage repair. Importantly, RGS2 was identified as a critical gene through which betaine exerts its effects on scavenging reactive oxygen species (ROS) accumulation. Our study demonstrates that betaine inhibits RARRES1, thereby appearing to upregulate RGS2 and promote ROS clearance to alleviate fibrotic changes in cartilage. RARRES1 may serve as a biomarker and a potential therapeutic target for cartilage fibrosis.