ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva

  • Bone. 2016 Nov;92:29-36. doi: 10.1016/j.bone.2016.07.023.
Jing Pang  1 ,  Yue Zuo  1 ,  Yi Chen  2 ,  Lige Song  1 ,  Qi Zhu  1 ,  Jing Yu  1 ,  Chang Shan  1 ,  Zeling Cai  2 ,  Jijun Hao  3 ,  Frederick S Kaplan  4 ,  Eileen M Shore  4 ,  Keqin Zhang  5
Affiliations
  • 1. Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.
  • 2. Kanda Biotech Company, Shanghai, China.
  • 3. College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA.
  • 4. 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.
  • 5. Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China. Electronic address: [email protected].
PMID: 27492611 DOI: 10.1016/j.bone.2016.07.023
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.

Keywords
ACVR1; ALK2; BMP signaling; Fibrodysplasia ossificans progressiva; Heterotopic ossification.
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