The Type I BMP Receptor ACVR1/ALK2 is Required for Chondrogenesis During Development

Abstract

Bone morphogenetic proteins (BMPs) are crucial regulators of chondrogenesis. BMPs transduce their signals through three type I receptors: BMPR1A, BMPR1B, and ACVR1/ALK2. Fibrodysplasia ossificans progressiva (FOP), a rare disorder characterized by progressive ossification of connective tissue, is caused by an activating mutation in Acvr1 (the gene that encodes ACVR1/ALK2). However, there are few developmental defects associated with FOP. Thus, the role of ACVR1 in chondrogenesis during development is unknown. Here we report the phenotype of mice lacking ACVR1 in cartilage. Acvr1CKO mice are viable but exhibit defects in the development of cranial and axial structures. Mutants exhibit a shortened cranial base, and cervical vertebrae are hypoplastic. Acvr1CKO adult mice develop progressive kyphosis. These morphological defects were associated with decreased levels of Smad1/5 and p38 activation, and with reduced rates of chondrocyte proliferation in vertebral cartilage. We also tested whether ACVR1 exerts coordinated functions with BMPR1A and BMPR1B through analysis of double mutants. Acvr1/Bmpr1a and Acvr1/Bmpr1b mutant mice exhibited generalized perinatal lethal chondrodysplasia that was much more severe than in any of the corresponding mutant strains. These findings demonstrate that ACVR1 is required for chondrocyte proliferation and differentiation, particularly in craniofacial and axial elements, but exerts coordinated functions with both BMPR1A and BMPR1B throughout the developing endochondral skeleton.

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

“…Previous in vitro data indicate that the ACVR1 receptor plays a key role in early steps of chondrocyte differentiation and commitment (12) . Acvr1 was recently shown to be expressed in growth plates, and its conditional ablation in cartilage was found to cause growth plate dysfunction and reduced chondrocyte proliferation (43) . Consistently, we observe greater proliferation in the Acvr1 R206H growth plates, with failure or significant delay in hypertrophic chondrocyte differentiation.…”

Bmpr1a Signaling in Cartilage Development and Endochondral Bone Formation

“…Acvr1/Bmpr1a and Acvr1/Bmpr1b mutant mice exhibited generalized perinatal lethal chondrodysplasia that was much more severe than in any of the corresponding mutant strains. ACVR1 is required for chondrocyte proliferation and differentiation, particularly in craniofacial and axial elements, but exerts coordinated functions with both BMPR1A and BMPR1B throughout the developing endochondral skeleton (Rigueur et al, 2015).…”

Signaling pathways regulating cartilage growth plate formation and activity

“…The activating mutations in ACVR1/ALK2 cause Fibrodysplasia Ossificans Progressiva (FOP), a rare and devastating genetic disorder characterized by endochondral ossification occurring at extra-skeletal sites, such as muscle and ligaments [24] [25]. Human mesenchymal stem cells overexpressing the ACVR1 activating mutation R206H, which occurs in 98% of FOP patients, were shown to cause ectopic bone formation in nude mice [26], and mice lacking Acvr1 in chondrocytes had significantly reduced BMP signaling, as well as craniofacial defects, axial skeleton defects, and thoracic kyphosis [27] [28]. …”