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Historically, OA research focused on joint tissues, but our studies highlight adipose (fat) tissue and fat\u2010secreted factors as critical contributors to OA development and pain. Using diet\u2010induced obesity models in rats, we demonstrated that fat mass and adipose\u2010derived 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\u2010free 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\u2010secreted 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\u2010related lipid mediators) and identifying other fat\u2010derived molecules driving OA. Using advanced spatial multi\u2010omics 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\u2010derived mediators that drive pain and joint damage.<\/jats:p>","DOI":"10.1002\/jor.70168","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T02:00:46Z","timestamp":1773021646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Fat in Osteoarthritis"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7348-7348","authenticated-orcid":false,"given":"Kelsey H.","family":"Collins","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery and Department of Anatomy  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"issue":"107","key":"e_1_2_10_2_1","first-page":"37","article-title":"Why We Should Study Pain in Animal Models of Rheumatic Diseases","volume":"35","author":"Malfait A. 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