The Notch signaling pathway in regulating bone and cartilage homeostasis: novel insights into the pathogenesis and therapeutics of osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by cartilage degradation, bone hyperplasia, and synovitis. It is a primary cause of joint pain and dysfunction globally. The increasing incidence of OA, driven by an aging population, profoundly impairs patients' quality of life while imposing a growing economic burden on societies and families. Thus, in-depth investigations into the pathogenesis of OA, along with the exploration of novel therapeutic targets and strategies, hold significant clinical implications and social value. The Notch signaling pathway, a highly conserved intercellular communication pathway, plays a pivotal regulatory role in cell proliferation, differentiation, apoptosis, and organogenesis. In recent years, a growing body of research has revealed that the Notch signaling pathway is crucial for maintaining bone and cartilage homeostasis, with its aberrant activation or inhibition being closely linked to the initiation and progression of OA. Therefore, this narrative review performed an extensive PubMed database search using keywords like "Notch", "osteoarthritis", "bone", "cartilage", "synovitis", "osteoblasts", "osteoclasts", and "chondrocytes", and reviewed all pertinent literature. It specifically focuses on the role of Notch signaling in the differentiation and function of osteoblasts, osteoclasts, and chondrocytes, shedding light on its mechanism in cartilage damage, subchondral bone dysfunction, and synovitis. It also explores evidence for targeted Notch pathway therapies in OA, aiming to illuminate the molecular mechanisms underlying OA pathogenesis and offer new theoretical insights and therapeutic targets for OA prevention and treatment. Additionally, this narrative review seeks to decipher the mechanisms underlying the context-dependent duality of Notch signaling in bone and cartilage, and provides a critical appraisal of the challenges confronting current targeted therapies.