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Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity
- Source :
- eLife, Vol 7 (2018)
- Publication Year :
- 2018
- Publisher :
- eLife Sciences Publications, Ltd, 2018.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Agonist
medicine.medical_specialty
QH301-705.5
medicine.drug_class
Science
ACVR1
Palovarotene
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
fibro/adipogenic progenitor
fibrodysplasia ossificans progressiva
Internal medicine
medicine
Biology (General)
Progenitor cell
General Immunology and Microbiology
business.industry
General Neuroscience
General Medicine
Retinoic acid receptor gamma
Chondrogenesis
medicine.disease
palovarotene
030104 developmental biology
Endocrinology
heterotopic ossification
Fibrodysplasia ossificans progressiva
Medicine
activin A
Heterotopic ossification
business
Subjects
Details
- ISSN :
- 2050084X
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....55b09e074a37833a54fd47482dd8cc1c