Abstract
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to normal tissue repair. FOP is caused by gain-of-function mutations in ACVR1, which encodes a type I BMP receptor. Initial studies on the pathogenic mechanism of FOP-causing mutations in ACVR1 focused on the enhanced function of this receptor in response to certain BMP ligands, or independently of ligands, but did not directly address the fact that HO in FOP is episodic and inflammation-driven. Recently, we and others demonstrated that Activin A is an obligate factor for the initiation of HO in FOP, signaling aberrantly via mutant ACVR1 to transduce osteogenic signals and trigger heterotopic bone formation (Hatsell et al., 2015; Hino et al., 2015). Subsequently, we identified distinct tissue-resident mesenchymal progenitor cells residing in muscles and tendons that recognize Activin A as a pro-osteogenic signal (solely in the context of FOP-causing mutant ACVR1), and give rise to the cartilaginous anlagen that form heterotopic bone (Dey et al., 2016). During the course of these studies, we also found that the activity of FOP-causing ACVR1 mutations does not by itself explain the triggered or inflammatory nature of HO in FOP, suggesting the importance of other, inflammation-introduced, factors or processes. This review presents a synthesis of these findings with a focus on the role of Activin A and inflammation in HO, and lays out perspectives for future research.
Highlights
Fibrodysplasia Ossificans Progressiva (FOP) (OMIM #135100) is a rare, mostly sporadic, autosomal-dominant disorder that is characterized by congenital skeletal dysplasias that are evident at birth or shortly thereafter [4,5,6,7,8], most notably malformation of the great toes [9]
In order to determine whether the ability of Activin A to activate FOPcausing variants of ACVR1 bears any relevance to the pathophysiology of FOP, and heterotopic ossification (HO), we tested whether Activin A can induce the formation of heterotopic bone in Acvr1[R206H]/+ mice, using a classic osteogenic assay wherein the ligand is adsorbed into collagen sponges, implanted intramuscularly, and the formation of bone within and around the implants is monitored [16]
The availability of an accurate mouse model of FOP facilitated the search for the progenitor cells that give rise to heterotopic bone in FOP. Such progenitors should have several properties: (a) They should reside in the tissues where heterotopic bone forms in FOP; (b) they should express ACVR1 and, as long they are ACVR1R206H/+, be able to respond to Activin A and turn on Smad1/5/8 signaling; and (c) when they respond to Activin A they should assume a chondrogenic fate
Summary
Fibrodysplasia Ossificans Progressiva (FOP) (OMIM #135100) is a rare, mostly sporadic, autosomal-dominant disorder that is characterized by congenital skeletal dysplasias that are evident at birth or shortly thereafter [4,5,6,7,8], most notably malformation of the great toes [9]. About half of the episodes of ossification are preceded by characteristic soft tissue swellings usually accompanied by pain and warmth, referred to as “flareups” [11] These episodes frequently occur following trauma, febrile illness, and other pro-inflammatory insults, suggesting that inflammation is a common trigger for HO [6,7,10,12]. The discovery of the causative gene, together with the fact that more than 95% of FOP cases arise from one variant – ACVR1[R206H] – set in motion a lot of research aimed at deciphering the molecular mechanisms by which this mutant receptor drives HO These studies postulated that ACVR1[R206H] brings about HO because it acts as a hyperactive receptor that exhibits both constitutive (i.e. ligand-independent) activity [19,24,25,26], as well as an enhanced response to ligands [25,27,28]. We hypothesized that the inflammation-introduced signal(s) must be received by cells that can give rise to heterotopic bone via an endochondral process
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