Significance: Obesity is a primary risk factor for osteoarthritis, involving complex interactions among the metabolic, biomechanical, and inflammatory factors caused by increased adiposity. Using a mouse model of lipodystrophy, we demonstrate that fat-free mice on either a chow or high-fat diet are protected from cartilage damage, despite demonstrating many factors previously associated with osteoarthritis. Furthermore, implantation of a small fat pad reverses cartilage protection in lipodystrophic mice, indicating a direct relationship between adipose tissue and cartilage damage, independent of body weight. This study provides evidence of adipose–cartilage signaling, indicating that tissues outside the joint can influence cartilage health. These findings support the notion that osteoarthritis involves a systemic component, providing insight into the development of new therapeutic targets for osteoarthritis.

PIEZO1 and PIEZO2 are mechanosensitive cation channels that are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in multiple organ systems. Within the musculoskeletal system, PIEZO1 functions to maintain muscle and bone mass, sense tendon stretch, and regulate senescence and apoptosis in response to mechanical stimuli within cartilage and the intervertebral disc. PIEZO2 is essential for transducing pain and touch sensations as well as proprioception in the nervous system, which can affect musculoskeletal health. PIEZO1 and PIEZO2 have been shown to act both independently as well as synergistically in different cell types. Conditions that alter PIEZO channel mechanosensitivity, such as inflammation or genetic mutations, can have drastic effects on these functions. For this reason, therapeutic approaches for PIEZO-related disease focus on altering PIEZO1 and/or PIEZO2 activity in a controlled manner, either through inhibition with small molecules, or through dietary control and supplementation to maintain a healthy cell membrane composition. Although many opportunities to better understand PIEZO1 and PIEZO2 remain, the studies summarized in this review highlight how crucial PIEZO channels are to musculoskeletal health and point to promising possible avenues for their modulation as a therapeutic target.

Follistatin gene therapy prevents obesity, metabolic disease, and post-traumatic osteoarthritis.

Genome editing of stem cells creates a living implant that can produce arthritis-fighting drugs in response to inflammation.

Obesity is a risk factor for osteoarthritis (OA), and leptin is among the adipokines implicated in obesity-induced OA. However, the specific role of leptin in OA severity and pain is not known. Using lipodystrophic (LD) mice, we show that fat-secreted factors are required for knee OA development, implicating a fat-cartilage cross-talk. Fat pad implantation or systemic leptin restoration in LD mice reintroduced structural OA and pain, whereas implantation of leptin-deficient fat pad did not change OA susceptibility. Isochronic parabiosis and spatial transcriptomics confirmed that a fat-joint cross-talk likely occurred via soluble mediators. Global unsupervised multiomics of conditioned media from fat implants revealed that leptin exerts a regulatory effect on adipsin (or complement factor D), the activity of which modulates the contrastive OA structural and pain phenotype. These findings suggest that adipokines influence OA pathogenesis, providing conclusive evidence of a fat-joint cross-talk and implicating OA as a systemic disease of adipose tissue.