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.
Highlights
Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder, which is characterized by progressive heterotopic ossification (HO) of muscle, tendon, and ligamentous tissues throughout the body
FOP is caused by gain-of-function mutations in activin receptor-like kinase 2 (ALK2, known as ACVR1), a bone morphogenetic protein (BMP) type I receptor [4,5]
Recent studies have revealed that mutant ALK2 activated Smad1/5 signaling in response to Activin A, whereas Activin A acts as an inhibitor of BMP signaling through wild-type ALK2 [6,10,38]
Summary
Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder, which is characterized by progressive heterotopic ossification (HO) of muscle, tendon, and ligamentous tissues throughout the body. Activin A has been reported to trigger heterotopic bone formation, while inhibition of Activin A blocks the progression of spontaneous or trauma-induced HO in a mouse model of FOP [10,12]. Recent studies have revealed that mutant ALK2 activated Smad1/5 signaling in response to Activin A, whereas Activin A acts as an inhibitor of BMP signaling through wild-type ALK2 [6,10,38].
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