Role of Notch signaling pathway in joint homeostasis and osteoarthritis

The Notch signaling pathway is pivotal in joint homeostasis and the pathogenesis of osteoarthritis (OA). Under physiological conditions, transient or physiological Notch signaling maintains cartilage matrix synthesis to preserve joint function. Under pathological conditions, persistent or excessive activation of Notch signaling suppresses the expression of chondrogenic genes and induces the production of catabolic factors, thereby driving OA progression. From a cellular perspective, the Notch signaling pathway exerts crucial regulatory role in the functions of various resident cell types within the joint. For instance, it regulates the differentiation and maturation of chondrocytes, influences the chondrogenic differentiation process of mesenchymal stem cells (MSCs), and modulates the phenotype of fibroblast-like synoviocytes (FLSs). At the level of the extracellular cartilage microenvironment, the Notch signaling pathway participates in extracellular matrix (ECM) homeostasis imbalance and inflammatory factor activation in OA by regulating the expression of downstream genes. Furthermore, Notch controls chondrocyte hypertrophic degeneration through extensive molecular crosstalk with the TGF-β/BMP, Wnt/β-catenin, NF-κB, and Hippo-YAP pathways. Beyond cartilage, Notch plays a crucial role in promoting neurovascular invasion at the osteochondral junction and abnormal subchondral bone remodeling, which directly contributes to joint pain and structural failure. Many Notch-targeted approaches, such as pharmacological inhibitors, RNA-based therapies, and molecular interventions targeting ligands and downstream effectors, have been investigated because existing treatments are unable to stop the progression of OA. Simultaneously, stem cell-based approaches use precise Notch modulation to improve cartilage repair and chondrogenic differentiation. However, systemic administration of small-molecule inhibitors raises concerns about off-target effects and delivery inefficiency in avascular cartilage, while conventional stem cell injections frequently encounter problems like phenotypic instability and limited durability. In conclusion, in-depth studies on the Notch signaling pathway in OA not only clarify the pathogenesis of OA but also lay a theoretical and experimental foundation for the development of innovative therapeutic strategies.