Our work challenges the traditional view of osteoarthritis (OA) as a wear-and-tear disease of aging, proposing a paradigm shift toward understanding OA as a systemic condition influenced by metabolic and immune factors. Historically, OA research focused on joint tissues, but our studies highlight adipose (fat) tissue and fat-secreted factors as critical contributors to OA development and pain. Using diet-induced obesity models in rats, we demonstrated that fat mass and adipose-derived factors, rather than body weight alone, strongly correlate with OA severity. Clinical studies in humans further validated this, showing body fat percentage predicts OA incidence more accurately than body mass index (BMI), even in individuals with normal or overweight BMI. In addition, a fat-free mouse model revealed that the absence of fat protects against OA regardless of diet or sex, emphasizing adipose interorgan crosstalk as a key driver of OA. These findings confirmed leptin's role in OA and uncovered complement factor D (FD), a fat-secreted mediator modulated by leptin. FD unexpectedly influences OA structure and pain in distinct ways. Our current research focuses on understanding how FD drives pain through eicosanoids (pain-related lipid mediators) and identifying other fat-derived molecules driving OA. Using advanced spatial multi-omics and proximity labeling technologies, alongside bioengineering tools and translational pain testing strategies, our goal is to redefine OA as a systemic disease. Ultimately, we aim to transform personalized OA care by developing therapies targeting fat-derived mediators that drive pain and joint damage.
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