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Review
. 2018 Apr:109:210-217.
doi: 10.1016/j.bone.2017.06.011. Epub 2017 Jun 16.

The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva

Dana M Alessi Wolken  1 , Vincent Idone  1 , Sarah J Hatsell  1 , Paul B Yu  2 , Aris N Economides  3
Affiliations
Review

The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva

Dana M Alessi Wolken et al. Bone. 2018 Apr.

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.

Keywords: ACVR1; Activin A; Anti-Activin antibody; Fibrodysplasia Ossificans Progressiva; Heterotopic Ossification; Progenitor cells.

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Figures

Fig. 1.
Fig. 1.
A genetically accurate and physiologically relevant mouse model of FOP. (A) Acvr1[R206H]FlEx (Acvr1tm2.1Vlcg; MGI:5763014) [1] is a conditional-on knock-in allele of ACVR1[R206H]. It was generated by introducing the R206H variant in exon 5 of mouse Acvr1, and then placing this mutant exon in the antisense orientation within intron 5 of Acvr1. In order to restore the function of Acvr1, a wild type exon 5 from human ACVR1 was placed upstream of the mutant exon (but in the sense strand), thereby preserving the structure of the resulting Acvr1 transcript. These elements – wild type exon 5 and mutant exon 5 – were flanked by FlEx arrays [29] in a manner such that upon action of Cre, the wild type exon is deleted and mutant exon 5 is placed into the sense strand. Thereby, Cre effectively converts the Acvr1[R206H]FlEx allele to Acvr1[R206H], and hence recreates – in mice – the genotype found in ACVR1R206H FOP patients. (B) HO (pseudocolored yellow) develops as early as 2 weeks post model initiation by tamoxifen administration in locations such as the back. This HO can expand over time and new lesions can form in close proximity, mirroring the expansions of the heterotopic bone field seen in human FOP. (C) In addition to the back, HO develops in other locations seen in FOP such as the limbs, sternum, ribcage, jaw, and hip. The location of each lesion is pinpointed by yellow arrows.
Fig. 2.
Fig. 2.
ACVR1[R206H] has gained the ability to recognize Activin A as an agonist. (A) Activin A signals via the type I receptors ACVR1B/1C, inducing phosphorylation of Smad2/3, yet shares type II receptors (ACVR2A, ACVR2B, and BMPR2) with BMPs. (B) BMPs do not utilize ACVR1B/1C as type I receptors; they signal through ACVR1 in complex with ACVR2A, ACVR2B, and BMPR2 to induce phosphorylation of Smad1/5/8. (Note that BMPs also form complexes with other type I receptors - in our Review we focusing mainly on ACVR1.) (C) ACVR1, in conjunction with the type II receptors, binds Activin but the resulting complex does not stimulate phosphorylation of Smad1/5/8; instead, Activin acts as a competitive inhibitor of canonical BMP-mediated signaling through ACVR1. (D) In FOP, when ACVR1[R206H] is engaged by Activin (in the context of the type II receptors), the resulting receptor complexes induce Smad1/5/8 phosphorylation. Hence, ACVR1[R206H] recognizes Activin A just like a BMP, effectively converting the typeII•ACVR1•Activin complex from a ‘dead end’ complex into a signaling complex. These results have been extended to all of the FOP-causing ACVR1 variants described to date [2] (unpublished results). Neither ACVR1[R206H] nor any of the other FOP-causing ACVR1 variants lose their ability to respond to canonical BMPs. (Note: The type II•ACVR1•Activin complex shown here comprises a heterodimer of ACVR1•ACVR1[R206H]; however, this is not an obligate arrangement – homodimers of ACVR1[R206H] also transduce signal.) (E) An artificially generated variant commonly used in experiments – ACVR1[Q207D] – is constitutively active, and hence turns on Smad1/5/8 phosphorylation in the absence of engagement by ligands [51]. Activin A is not able to inhibit ACVR1[Q207D] from signaling nor can it stimulate it further (unpublished results).
Fig. 3.
Fig. 3.
Activin A activates ACVR1[R206H] signals through Smad1/5/8 in human and mouse cells, and hence acts much like a BMP. (A, B, C) The responsiveness of ACVR1 or ACVR1[R206H] to different BMP family ligands was tested in HEK293 cells overexpressing either ACVR1 or ACVR1[R206H] and the Smad1/5/8 reporter BRE-luciferase [1]. (A) ACVR1[R206H] and ACVR1 respond equally to some BMPs, including BMP2/7. (B) ACVR1[R206H] displays an enhanced response to some ligands, e.g. BMP7. (C) ACVR1[R206H] responds to Activin A just like it does to a BMP, whereas ACVR1 does not recognize Activin A as an agonistic ligand. (D) Identical results were obtained in the mouse bone marrow stromal cell line W20, expressing either endogenous ACVR1 or overexpressing ACVR1[R206H] and using alkaline phosphatase (ALP) as a readout for activation of Smad1/5/8 signaling. (E) The same pattern is observed in a non-overexpressing system, i.e. mouse embryonic stem (ES) cells, in which the R206H variant has been knocked in (as described in Fig. 1A). Mouse ES cell line Acvr1[R206H]FlEx/+; Gt(ROSA26)SorCreERT2/+ (FlEx/WT) and its post-Cre counterpart, ES line Acvr1[R206H]/+; Gt(ROSA26)SorCreERT2/+ (R206H/WT) were treated with 6 nM BMP7 or 6 nM Activin A for 1 h prior to protein lysate collection. pSmad1/5/8 was measured by Western blotting using beta-tubulin as a loading control. Mirroring results obtained in HEK293 cells and W20 cells, R206H/WT ES cells recognize Activin A as an agonistic ligand, whereas FlEx/WT cells do not. In contrast, both lines respond to BMP7. A more detailed presentation of the responsiveness of ACVR1[R206H] to BMP family ligands can be found in Hatsell, Idone et al. [1] and Dey et al. [3]. The responsiveness of other FOP-causing variants of ACVR1 to Activin A and other BMP family ligands has been examined in detail by Hino et al. [2]. The data presented here was generated as described [1].
Fig. 4.
Fig. 4.
A working model for the formation of heterotopic bone in FOP. Tissue damage to skeletal muscles, ligaments, and tendons as a result of injury or regular use results in the recruitment of immune system cells into the area in need of repair. In addition, tissue damage provides a yet-to-be-identified signal that enables tissue-resident progenitor cells to become competent to give rise to the chondrocytes that form the initial cartilage anlagen that will give rise to the heterotopic bone. Activin A, secreted by the immune system cells at the site of tissue damage, is perceived as a pro-osteogenic signal by the tissue-resident progenitor cells. (Alternatively, the immune system cells may instruct other cells in the area of the future heterotopic bone lesion to express Activin A.) These progenitor cells, in response to Activin A, differentiate into chondrocytes and proceed to form heterotopic bone lesions.
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