【Purpose】 Osteoarthritis (OA) is a musculoskeletal disorder characterized by articular cartilage degeneration, with increasing prevalence in aging societies. OA symptoms include arthritis due to cartilage wear, resulting in pain, swelling, and limited joint mobility. Current treatments, including pain medication, exercise therapy, and joint replacement surgery, only manage symptoms without providing fundamental cartilage repair.
Lubricin, a proteoglycan protein encoded by PRG4, is primarily expressed in joint surface chondrocytes and reduces cartilage friction through synovial fluid. Because the loss of Prg4 function in rodents leads to early onset osteoarthritis, characterized by the loss of SFZ cells and synovial hyperplasia, Prg4 is essential for maintaining articular cartilage homeostasis. In OA patients, lubricin expression is decreased, contributing to disease progression, but intra-articular injection of PRG4 reduces OA progression and pain. Therefore, increasing lubricin expression in OA patients may alleviate pain and prevent symptom worsening. Various signaling pathways have been implicated in lubricin expression regulation. Although these pathways include the CREB1 pathway mediated by TRPV2, which functions as a mechanosensor, the Wnt signaling pathway, and the EGFR pathway, their complete mechanisms remain unclear. In this study, we aim to identify compounds that can modulate lubricin expression, an essential component of cartilage lubrication, and to elucidate part of its regulatory mechanism.
【Methods】 Through single-cell RNA analysis, we identified an amino acid metabolism pathway enzyme among genes correlating with Prg4 expression in Superficial Zone cartilage cells and analyzed its contribution to Prg4 expression. 【Results】 Knockdown analysis of the amino acid metabolism enzyme demonstrated decreased Prg4 expression, while administration of its coenzyme increased Prg4 expression and showed therapeutic effects in OA mouse models.【Discussion/Conclusion】 This research provides novel insights into the relationship between amino acid metabolism and OA, suggesting potential therapeutic approaches through metabolic regulation.