The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator

Abstract

Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene ALK2 in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.

Keywords: ALK2; Activin A; FOP; Heterotopic ossification.

Figure 1. Schematic diagram of the BMP/Activin A signaling network in normal and FOP patients

BMP signals via the BMP type I receptor ALK2, inducing phosphorylation of Smad1/5, whereas Activin A induces the phosphorylation of Smad2/3 via ALK4/7. It also binds to ALK2, but it does not activate Smad1/5 phosphorylation and inhibits BMP signaling. BMP and Activin A share type II receptors (ACVR2A, ACVR2B). However, in FOP, Activin A leads to activation of Smad1/5 phosphorylation via mutant ALK2 and triggers HO formation. The star: classic mutation site of ALK2 R206H. Abbreviation: P, phosphorylation.

Figure 2. Schematic diagram showing the numbers and locations of ALK2 mutations associated with FOP

*R206H is the most common mutation in FOP. Abbreviations: LBD, ligand binding domain; SP, signal peptide; TM, transmembrane.

Figure 3. Schematic presentation of Activin A and its involvement in the formation of heterotopic bone in FOP

HO formation involves inflammation and the destruction of connective tissues followed by bone formation. After various triggers, such as injury, abundant perivascular lymphocytes are present in damaged tissue. Activin A is secreted by the lymphocytes and induced by inflammation, then activates ALK2 R206H signaling as an osteogenic ligand. Some progenitor cells are recruited and differentiate into chondrocytes and osteoblasts, eventually forming heterotopic bones in soft tissues. However, the previous studies do not indicate the involvement of Activin A in the exact stages of HO formation. In addition, targets and strategies for the prevention and treatment of FOP presents : inhibition of Activin A and block mutant ALK2 activity. See the text for details. The star: classic mutation site of ALK2 R206H.