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

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.