title: ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. This mutation aberrantly activates the BMP-Smad1/5/8 signaling pathway and leads to HEO in FOP patients. Here we report development of a soluble recombinant ACVR1-Fc fusion protein by combining the extracellular domain of human wild type ACVR1 and the Fc portion of human immunoglobulin gamma 1 (IgG1). The ACVR1-Fc fusion protein significantly down-regulated the dysregulated BMP signaling caused by the FOP ACVR1 mutation and effectively suppressed chondro-osseous differentiation in a previously described cellular FOP model, human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus-ACVR1R206H(HUVECR206H). This ACVR1-Fc fusion protein holds great promise for prevention and treatment of HEO in FOP and related diseases.
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Jing
authors: J
authors: Pang
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Yue
authors: Y
authors: Zuo
authors: Kanda Biotech Company, Shanghai, China.
authors: Yi
authors: Y
authors: Chen
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Lige
authors: L
authors: Song
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Qi
authors: Q
authors: Zhu
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Jing
authors: J
authors: Yu
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
authors: Chang
authors: C
authors: Shan
authors: Kanda Biotech Company, Shanghai, China.
authors: Zeling
authors: Z
authors: Cai
authors: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA.
authors: Jijun
authors: J
authors: Hao
authors: Departments of Orthopaedic Surgery (FSK & EMS), Medicine (FSK), and Genetics (EMS) and the Center for Research in FOP and Related Disorders (FSK & EMS), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Frederick S
authors: FS
authors: Kaplan
authors: Departments of Orthopaedic Surgery (FSK & EMS), Medicine (FSK), and Genetics (EMS) and the Center for Research in FOP and Related Disorders (FSK & EMS), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Eileen M
authors: EM
authors: Shore
authors: Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China. Electronic address: keqzhang2007@126.com.
authors: Keqin
authors: K
authors: Zhang
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009221:Myositis Ossificans / Q000188:drug therapy / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
keywords: ACVR1; ALK2; BMP signaling; Fibrodysplasia ossificans progressiva; Heterotopic ossification