Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification

Abstract

Fibrodysplasia ossificans progressiva (FOP), a congenital HO syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of diverse tissues including skeletal muscles, tendons, ligaments, fascia and joints. HO can occur in discrete flares, often triggered by injury or inflammation, or may progress incrementally without identified triggers. Mice harboring an Acvr1R206H knock-in allele recapitulated the phenotypic spectrum of FOP, including injuryresponsive intramuscular HO, and spontaneous articular, tendon and ligament ossification. HO in these distinct sites was formed by two anatomically distinct progenitor lineages: A muscle-resident interstitial Mx1+Sca1+LinPDGFRα+ population which was sufficient to facilitate intramuscular, injury-dependent endochondral HO, and an Scx+Sca1+Lin-PDGFRα+tendon-derived progenitor which was sufficient to initiate ligament and articular endochondral HO without injury. The cell-autonomous effects of Acvr1R206H in both of these lineages promoted heterotopic chondrogenesis, and conferred to cells abnormal gain of BMP signaling and endochondral differentiation in response to Activin A. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1R206H knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. The diverse spatiotemporal manifestations of HO in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in multiple non-overlapping tissue-resident progenitors, with direct implications for therapies designed to modify their recruitment or plasticity.