Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.
John B Lees-ShepardSarah-Anne E NicholasSean J StoesselParvathi M DevarakondaMichael J SchneiderMasakazu YamamotoDavid J GoldhamerPublished in: eLife (2018)
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs' skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.
Keyphrases
- wild type
- clinical trial
- pi k akt
- endothelial cells
- high fat diet induced
- signaling pathway
- high resolution
- bone mineral density
- quantum dots
- genome wide
- randomized controlled trial
- copy number
- skeletal muscle
- induced pluripotent stem cells
- dna methylation
- risk assessment
- binding protein
- bone loss
- pluripotent stem cells
- bone marrow
- radiofrequency ablation
- loop mediated isothermal amplification
- study protocol