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ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva.
Bone. 2016 11; 92:29-36.BONE

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+Show Affiliations

Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Kanda Biotech Company, Shanghai, China.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China.Kanda Biotech Company, Shanghai, China.College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA.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.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.Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine Shanghai, China. Electronic address: keqzhang2007@126.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27492611

Citation

Pang, Jing, et al. "ACVR1-Fc Suppresses BMP Signaling and Chondro-osseous Differentiation in an in Vitro Model of Fibrodysplasia Ossificans Progressiva." Bone, vol. 92, 2016, pp. 29-36.
Pang J, Zuo Y, Chen Y, et al. ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva. Bone. 2016;92:29-36.
Pang, J., Zuo, Y., Chen, Y., Song, L., Zhu, Q., Yu, J., Shan, C., Cai, Z., Hao, J., Kaplan, F. S., Shore, E. M., & Zhang, K. (2016). ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva. Bone, 92, 29-36. https://doi.org/10.1016/j.bone.2016.07.023
Pang J, et al. ACVR1-Fc Suppresses BMP Signaling and Chondro-osseous Differentiation in an in Vitro Model of Fibrodysplasia Ossificans Progressiva. Bone. 2016;92:29-36. PubMed PMID: 27492611.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva. AU - Pang,Jing, AU - Zuo,Yue, AU - Chen,Yi, AU - Song,Lige, AU - Zhu,Qi, AU - Yu,Jing, AU - Shan,Chang, AU - Cai,Zeling, AU - Hao,Jijun, AU - Kaplan,Frederick S, AU - Shore,Eileen M, AU - Zhang,Keqin, Y1 - 2016/08/02/ PY - 2015/10/18/received PY - 2016/04/22/revised PY - 2016/07/30/accepted PY - 2016/8/6/pubmed PY - 2018/1/4/medline PY - 2016/8/6/entrez KW - ACVR1 KW - ALK2 KW - BMP signaling KW - Fibrodysplasia ossificans progressiva KW - Heterotopic ossification SP - 29 EP - 36 JF - Bone JO - Bone VL - 92 N2 - 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. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/27492611/ACVR1_Fc_suppresses_BMP_signaling_and_chondro_osseous_differentiation_in_an_in_vitro_model_of_Fibrodysplasia_ossificans_progressiva_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(16)30211-3 DB - PRIME DP - Unbound Medicine ER -