Tags

Type your tag names separated by a space and hit enter

Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP).
Dev Biol. 2021 02; 470:136-146.DB

Abstract

The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP.

Authors+Show Affiliations

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, Philadelphia, PA 19104, United States; Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, Clinical Research Building, Philadelphia, PA 19104, United States; Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. Electronic address: shore@pennmedicine.upenn.edu.

Pub Type(s)

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

Language

eng

PubMed ID

33217406

Citation

Towler, O Will, et al. "Dysregulated BMP Signaling Through ACVR1 Impairs Digit Joint Development in Fibrodysplasia Ossificans Progressiva (FOP)." Developmental Biology, vol. 470, 2021, pp. 136-146.
Towler OW, Peck SH, Kaplan FS, et al. Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Dev Biol. 2021;470:136-146.
Towler, O. W., Peck, S. H., Kaplan, F. S., & Shore, E. M. (2021). Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). Developmental Biology, 470, 136-146. https://doi.org/10.1016/j.ydbio.2020.11.004
Towler OW, et al. Dysregulated BMP Signaling Through ACVR1 Impairs Digit Joint Development in Fibrodysplasia Ossificans Progressiva (FOP). Dev Biol. 2021;470:136-146. PubMed PMID: 33217406.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP). AU - Towler,O Will, AU - Peck,Sun H, AU - Kaplan,Frederick S, AU - Shore,Eileen M, Y1 - 2020/11/17/ PY - 2019/10/23/received PY - 2020/11/01/revised PY - 2020/11/10/accepted PY - 2022/02/01/pmc-release PY - 2020/11/21/pubmed PY - 2021/4/20/medline PY - 2020/11/20/entrez KW - ACVR1 KW - Bone morphogenetic protein KW - Chondrogenesis KW - Digit KW - Fibrodysplasia ossificans progressiva KW - Joint SP - 136 EP - 146 JF - Developmental biology JO - Dev Biol VL - 470 N2 - The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP. SN - 1095-564X UR - https://www.unboundmedicine.com/medline/citation/33217406/Dysregulated_BMP_signaling_through_ACVR1_impairs_digit_joint_development_in_fibrodysplasia_ossificans_progressiva__FOP__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(20)30296-7 DB - PRIME DP - Unbound Medicine ER -