Research ArticleGENETIC DISORDERS

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

Science Translational Medicine  23 Nov 2016:
Vol. 8, Issue 366, pp. 366ra163
DOI: 10.1126/scitranslmed.aaf1090

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Boning up on stem cells

Fibrodysplasia ossificans progressiva is a rare genetic disorder of uncontrolled bone growth, which manifests as formation of bone in the muscles, ligaments, and joints triggered by inflammation or injury. Dey et al. used mouse models with disease-causing mutations in ACVR1 protein localized to specific types of progenitor cells in ligaments or in muscles to clarify the biology of this disease and determine which cells give rise to abnormal bone. In addition, the authors showed that the harmful manifestations of these mutations can be successfully controlled by a selective inhibitor of ACVR1.

Abstract

Fibrodysplasia ossificans progressiva (FOP), a congenital heterotopic ossification (HO) syndrome caused by gain-of-function mutations of bone morphogenetic protein (BMP) type I receptor ACVR1, manifests with progressive ossification of skeletal muscles, tendons, ligaments, and joints. In this disease, 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 recapitulate the phenotypic spectrum of FOP, including injury-responsive intramuscular HO and spontaneous articular, tendon, and ligament ossification. The cells that drive HO in these diverse tissues can be compartmentalized into two lineages: an Scx+ tendon-derived progenitor that mediates endochondral HO of ligaments and joints without exogenous injury, and a muscle-resident interstitial Mx1+ population that mediates intramuscular, injury-dependent endochondral HO. Expression of Acvr1R206H in either lineage confers aberrant gain of BMP signaling and chondrogenic differentiation in response to activin A and gives rise to mutation-expressing hypertrophic chondrocytes in HO lesions. Compared to Acvr1R206H, expression of the man-made, ligand-independent ACVR1Q207D mutation accelerates and increases the penetrance of all observed phenotypes, but does not abrogate the need for antecedent injury in muscle HO, demonstrating the need for an injury factor in addition to enhanced BMP signaling. Both injury-dependent intramuscular and spontaneous ligament HO in Acvr1R206H knock-in mice were effectively controlled by the selective ACVR1 inhibitor LDN-212854. Thus, diverse phenotypes of HO found in FOP are rooted in cell-autonomous effects of dysregulated ACVR1 signaling in nonoverlapping tissue-resident progenitor pools that may be addressed by systemic therapy or by modulating injury-mediated factors involved in their local recruitment.

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