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

Stefanie L. Moye; Monisha Mittal; Tarun Srinivasan; Sneha Korlakunta; Chase A. Pagani; Ayelet Dar; Oromo Geshow; Dylan Feist; Lauren G. Zacharias; Zhao Li; Aaron W. James; Gerta Hoxhaj; Andrew M. Smith; Katherine A. Gallagher; Thomas P. Mathews; Robert J. Tower; Benjamin Levi

doi:10.1172/JCI205829

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Mittal, M. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Srinivasan, T. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Korlakunta, S. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Pagani, C. in: PubMed | Google Scholar |

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Dar, A. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Li, Z. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by James, A. in: PubMed | Google Scholar |

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Smith, A. in: PubMed | Google Scholar |

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Gallagher, K. in: PubMed | Google Scholar |

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Mathews, T. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Tower, R. in: PubMed | Google Scholar

¹Department of Surgery, University of Texas Southwestern Medical Center, Dallas, United States of America

²Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, United States of America

³Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States of America

⁴Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States of America

⁵Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, United States of America

⁶Department of Surgery, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Levi, B. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI205829.
Copyright © 2026, Moye et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 11, 2026 - Version history

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 cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production. PGE2 then drove a transcriptional program in mesenchymal progenitor cells 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.

Version 1 (June 11, 2026): In-Press Preview

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

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

Stefanie L. Moye,1 Monisha Mittal,1 Tarun Srinivasan,2 Sneha Korlakunta,1 Chase A. Pagani,1 Ayelet Dar,1 Oromo Geshow,1 Dylan Feist,1 Lauren G. Zacharias,3 Zhao Li,4 Aaron W. James,4 Gerta Hoxhaj,3 Andrew M. Smith,5 Katherine A. Gallagher,6 Thomas P. Mathews,3 Robert J. Tower,1 and Benjamin Levi1

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