Zhang, Qiang

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. © 2021 American Society for Bone and Mineral Research (ASBMR).

AbstractMuch of the similarities of the tissue characteristics, pathologies and mechanisms of heterotopic ossification (HO) formation are shared between HO of tendon and ligament (HOTL). Unmet need and no effective treatment has been developed for HOTL, primarily attributable to poor understanding of cellular and molecular mechanisms. HOTL forms via endochondral ossification, a common process of most kinds of HO. HOTL is a dynamic pathologic process that includes trauma/injury, inflammation, mesenchymal stromal cell (MSC) recruitment, chondrogenic differentiation and, finally, ossification. A variety of signal pathways involve HOTL with multiple roles in different stages of HO formation, and here in this review, we summarize the progress and provide an up‐to‐date understanding of HOTL.