2. Academic Validation
  3. ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva

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

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: keqzhang2007@126.com.
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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