Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Osteoarthritis is the most prevalent chronic joint disease, affecting millions globally, and is a leading cause of pain and disability. With the rising incidence of obesity and an aging population, the societal impact of osteoarthritis is expected to grow. Currently, there are no drugs that can address both the structural damage to joints and the associated pain. Growing evidence suggests that the Wnt signaling pathway plays a critical role in the disease. Genetic and functional studies indicate that precise regulation of Wnt signaling in cartilage is crucial for maintaining joint health. In this review, we explore the evolution of this concept, delve into the regulation of Wnt signaling—particularly through Wnt modulators like frizzled-related protein and DOT1-like histone lysine methyltransferase—and summarize the preclinical data and molecular mechanisms of lorecivivint, the first Wnt antagonist in clinical SM04690 development for osteoarthritis.