Dietary omega-6 lipids promote postinjury 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 accumulation of dietary omega-6 (ω-6) lipids in the injury site is a key mechanism linking obesity to HO. Specifically, in mice fed a high-fat diet (HFD), injured tissues were enriched in linoleic and arachidonic acids, providing substrate for myeloid COX-2-dependent prostaglandin E2 (PGE2) production. PGE2 then drove a transcriptional program in MPCs that promoted osteochondral differentiation. An isocaloric, low linoleic acid HFD reduced HO despite comparable obesity, demonstrating that dietary lipid composition, rather than adiposity alone, drove pathological repair. Clinical data mirrored these findings, showing that obesity conferred increased HO risk, and COX-2 inhibition reduced 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.