Clearance of Senescent Cells From Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva

Haitao Wang, Qiang Zhang, Frederick S. Kaplan, Robert J. Pignolo

Research output: Contribution to journalArticlepeer-review

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in activin A receptor type I/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, resulting in the formation of extraskeletal or heterotopic ossification (HO) and other features consistent with premature aging. During the first decade of life, episodic bouts of inflammatory swellings (flare-ups) occur, which are typically triggered by soft tissue trauma. Through an endochondral process, these exacerbations ultimately result in skeletal muscles, tendons, ligaments, fascia, and aponeuroses transforming into ectopic bone, rendering movement impossible. We have previously shown that soft tissue injury causes early FOP lesions characterized by cellular hypoxia, cellular damage, and local inflammation. Here we show that muscle injury in FOP also results in senescent cell accumulation, and that senescence promotes tissue reprogramming toward a chondrogenic fate in FOP muscle but not wild-type (WT) muscle. Using a combination of senolytic drugs we show that senescent cell clearance and reduction in the senescence associated secretory phenotype (SASP) ameliorate HO in mouse models of FOP. We conclude that injury-induced senescent cell burden and the SASP contribute to FOP lesion formation and that tissue reprogramming in FOP is mediated by cellular senescence, altering myogenic cell fate toward a chondrogenic cell fate. Furthermore, pharmacological removal of senescent cells abrogates tissue reprogramming and HO formation. Here we provide proof-of-principle evidence for senolytic drugs as a future therapeutic strategy in FOP.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2021

Keywords

  • CELLULAR SENESCENCE
  • FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
  • HETEROTOPIC OSSIFICATION
  • MUSCLE INJURY
  • SENOLYTICS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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