Lubricin in osteoarthritis: functions and therapeutic prospects

Osteoarthritis (OA) represents a major global public health challenge, characterized by chronic pain and progressive loss of joint function. As the leading cause of disability among the elderly, it imposes a substantial socioeconomic burden worldwide. Pathologically, OA is increasingly understood as a systemic joint disorder that encompasses not only cartilage and subchondral bone, but also periarticular soft tissues and changes within the intra-articular microenvironment. Amid this complex, multi-tissue pathological milieu, lubricin(PRG4)-also known as superficial zone protein (SZP) or proteoglycan 4 (PRG4)-plays a critical chondroprotective role. Secreted predominantly by the superficial zone of articular cartilage and synovial fibroblasts, PRG4 contributes not only to boundary lubrication and the reduction of mechanical wear, but also to the maintenance of chondrocyte metabolic homeostasis, suppression of inflammatory signaling, modulation of immune cell polarization, and attenuation of synovial fibrosis. This review provides a comprehensive overview of the biological properties of PRG4 and elucidates its multifaceted protective mechanisms in joint homeostasis, including lubrication, metabolic regulation, immunomodulation, and antifibrotic activity-particularly through the CD44/TLR/NF-κB signaling pathway. Additionally, the therapeutic potential of PRG4 as a disease-modifying OA drug (DMOAD) is critically evaluated. Key translational challenges, such as issues related to interfacial adsorption stability and delivery system design, are also discussed. Collectively, this review aims to establish a theoretical framework and propose future research directions for developing novel biological therapies targeting OA.