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

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 Acvr1 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 Acvr1 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 Acvr1, expression of the man-made, ligand-independent ACVR1 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 Acvr1 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.

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

“…The specific localization of ScxGFP re-expression and aberrant cartilage formation to the tendon stubs suggest that these events may be interrelated, and indeed we found Scx lin cells within the cartilage masses, consistent with two recent studies that also show a contribution of tenocytes to heterotopic ossification, either in the context of injury or via constitutive activation of the BMP receptor, ACVR13233. During embryonic development, an early pool of bipotent Scx + / Sox9 + progenitors give rise to either the cartilage or tendon components of the skeletal enthesis3435.…”

Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva

“…In FOP, however, we found what we believe to be a new signaling pathway for Activin-A that initiates HO formation by mistransducing BMP signaling. MSCs, which are cells of origin of HO in FOP (67,68), respond abnormally to an Activin-A-evoked signal by taking on an osteo/chondrogenic lineage that is consistent with the response to bone fracture. Because Activin-A activates mTOR signaling in FOP, this response by MSCs could be related to the alert state.…”

Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up‐regulation

“…Very recently, two seminal works have demonstrated that these mutations cause a modification of ACVR1 ligand binding properties, by conferring to the mutated receptor the ability to respond to Activin-A, a molecule that normally transduces TGF-b signaling through the Smad2/3 cascade (13,14). In FOP, the binding of Activin A to the mutated receptor, improperly induces the activation of the canonical, ACVR1-mediated, Smad1/5/8 pathway thus committing resident, tissue-specific, multipotent progenitors to the formation of ectopic bone (15). The analysis of early FOP lesions, in biopsies of undiagnosed patients or obtained from mouse models of HO and FOP, has shown that the endochondral ossification process is preceded by an important, local, inflammatory reaction with tissue invasion by lymphocytes, mast cells and macrophages.…”