Dietary omega-6 lipids promote post-injury aberrant bone formation in obesity

Obesity is associated with impaired wound healing, but the mechanisms linking excess adiposity to aberrant tissue repair remain unresolved. Heterotopic ossification (HO) is a severe example of pathologic tissue repair in which mesenchymal progenitor cells (MPCs) undergo aberrant osteochondral differentiation within soft tissue, leading to joint contractures and pain. Here, we show that injury site accumulation of dietary omega-6 (ω-6) lipids is a key mechanism linking obesity to heterotopic ossification. Specifically, in mice fed a high-fat diet (HFD), injured tissues are enriched in linoleic and arachidonic acids, providing substrate for myeloid cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production. PGE2 then drives a transcriptional program in mesenchymal progenitor cells that promotes osteochondral differentiation. An isocaloric, low linoleic acid HFD reduces HO despite comparable obesity, demonstrating that dietary lipid composition, rather than adiposity alone, drives pathological repair. Clinical data mirror these findings, showing that obesity confers increased HO risk, and COX-2 inhibition reduces HO exclusively in obese patients. Together, these findings identify injury site ω-6 lipid enrichment as the key signal linking the diet to MPC reprogramming, pointing to dietary lipid modulation as an actionable strategy to limit HO in obesity.