Osteoarthritis and Chondrocytes: On the Road from Mechanisms to Treatment

Osteoarthritis (OA) is a degenerative whole-joint disease affecting more than 500 million people worldwide, characterized by irreversible tissue loss, chronic pain, and physical disability. The pathogenesis of OA is complex, with risk factors such as age, obesity, and injury contributing to a disruption of cartilage homeostasis. Here we focus on the chondrocyte, the sole mature cell type in cartilage, as an active participant in mediating joint demise rather than a mere casualty. In a healthy joint, chondrocytes are quiescent, but in the OA environment, they transition to a dysfunctional, catabolic state, undergoing pathological changes such as hypertrophy and senescence that drive tissue degradation. The canonical Wnt signaling pathway is a critical regulator of cartilage maintenance, and its dysregulation is a key driver of OA progression, making it a prime therapeutic target. However, translating this knowledge into effective disease-modifying OA drugs (DMOADs) has been challenging. While experimental DMOADs have shown promise, many have faced setbacks in clinical trials. These trials underscore the complexity of OA and highlight the critical need for improved trial design that stratifies patients based on disease stage and structural characteristics. Comparing the pathobiology of different joints, such as the knee and temporomandibular joint (TMJ), further reveals how joint-specific differences in biomechanics and cellular composition can dictate therapeutic responses. Among emerging strategies, Wnt-targeted therapies that stabilize the joint microenvironment by suppressing inflammation and promoting chondrocyte survival hold significant promise. This review consolidates the evidence positioning the chondrocyte as an active driver of OA pathogenesis, rather than a passive casualty, to inform future therapeutic development.