Activation of PPARγ redirects fibro-adipogenic progenitors to replace ectopic bone with fat in models of fibrodysplasia ossificans progressiva and trauma-induced heterotopic ossification

Koirala, P.; Chen, Z.; Hanumantharao, S. N.; Siegel, A. E.; Liu, C.; Williams, Z.; Sekhon, H.; Maridas, D.; Mishina, Y.; Rosen, V.; Agarwal, S.

doi:10.64898/2026.02.26.708276

bioRxiv · 10.64898/2026.02.26.708276

Activation of PPARγ redirects fibro-adipogenic progenitors to replace ectopic bone with fat in models of fibrodysplasia ossificans progressiva and trauma-induced heterotopic ossification

Koirala, P.·Chen, Z.·Hanumantharao, S. N.·Siegel, A. E.·Liu, C.·Williams, Z.·Sekhon, H.·Maridas, D.·Mishina, Y.·Rosen, V.·Agarwal, S.

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Abstract

The pathologic, osteogenic differentiation of fibroadipogenic progenitor cells (FAPs) is the primary recognized contributor to ectopic bone formation in fibrodysplasia ossificans progressiva (FOP) and trauma-induced heterotopic ossification (HO). Both conditions are characterized by up-regulated BMP signaling - the former by a gene mutation rendering the BMP receptor ACVR1 susceptible to activation by inflammatory ligands (Activin A), and the latter by up-regulated presence of BMP2 ligand in the setting of unmutated BMP receptor. We performed an unbiased assessment of FDA-approved therapies which would optimally target the transcriptional aberrations observed in developing FOP and HO lesions based on publicly-available datasets. This analysis uncovered rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist as the highest scoring therapeutic option across three data sets for both conditions. Rosiglitazone treatment eliminated ectopic bone lesions in a mouse model of FOP, and replaced these lesions with ectopic adipose tissue; similarly, systemic and local rosiglitazone treatment eliminated ectopic bone lesions in a mouse model of trauma-induced HO and replaced these lesions with ectopic adipose tissue. Our findings were corroborated by a single case report from 2010 showing positive results with rosiglitazone in a non-diabetic patient with FOP, with no subsequent studies. Overall, our findings suggest that a previously FDA-approved therapeutic is likely to be a successful therapeutic agent for both FOP and trauma-induced HO, both conditions for which current therapeutic options remain inadequate. One Sentence SummaryWe show that a previously FDA-approved therapeutic known to induce adipogenesis reduces ectopic bone and induces ectopic fat formation in diseases of heterotopic ossification.

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Koirala, P., Chen, Z., Hanumantharao, S. N., Siegel, A. E., Liu, C., Williams, Z., Sekhon, H., Maridas, D., Mishina, Y., Rosen, V., Agarwal, S.. 2026-03-02. Activation of PPARγ redirects fibro-adipogenic progenitors to replace ectopic bone with fat in models of fibrodysplasia ossificans progressiva and trauma-induced heterotopic ossification. https://doi.org/10.64898/2026.02.26.708276

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