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BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints.
Dev Biol. 2015 Apr 15; 400(2):202-9.DB

Abstract

BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre(+) transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints - tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration.

Authors+Show Affiliations

University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA.University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA.University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA.University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA.University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA.University of Michigan, School of Dentistry, Department of Biologic and Materials Sciences, Ann Arbor, MI, USA.Albert Einstein College of Medicine, Department of Genetics, Bronx, New York, USA.Albert Einstein College of Medicine, Department of Genetics, Bronx, New York, USA.University of Michigan, School of Dentistry, Department of Biologic and Materials Sciences, Ann Arbor, MI, USA.Johns Hopkins University, Department of Plastic Surgery, Baltimore, MD, USA.University of Michigan, School of Dentistry, Department of Biologic and Materials Sciences, Ann Arbor, MI, USA. Electronic address: mishina@umich.edu.University of Michigan Medical School, Department of Surgery, Ann Arbor, MI, USA. Electronic address: blevi@umich.edu.

Pub Type(s)

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

Language

eng

PubMed ID

25722188

Citation

Agarwal, Shailesh, et al. "BMP Signaling Mediated By Constitutively Active Activin Type 1 Receptor (ACVR1) Results in Ectopic Bone Formation Localized to Distal Extremity Joints." Developmental Biology, vol. 400, no. 2, 2015, pp. 202-9.
Agarwal S, Loder SJ, Brownley C, et al. BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. Dev Biol. 2015;400(2):202-9.
Agarwal, S., Loder, S. J., Brownley, C., Eboda, O., Peterson, J. R., Hayano, S., Wu, B., Zhao, B., Kaartinen, V., Wong, V. C., Mishina, Y., & Levi, B. (2015). BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. Developmental Biology, 400(2), 202-9. https://doi.org/10.1016/j.ydbio.2015.02.011
Agarwal S, et al. BMP Signaling Mediated By Constitutively Active Activin Type 1 Receptor (ACVR1) Results in Ectopic Bone Formation Localized to Distal Extremity Joints. Dev Biol. 2015 Apr 15;400(2):202-9. PubMed PMID: 25722188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. AU - Agarwal,Shailesh, AU - Loder,Shawn J, AU - Brownley,Cameron, AU - Eboda,Oluwatobi, AU - Peterson,Jonathan R, AU - Hayano,Satoru, AU - Wu,Bingrou, AU - Zhao,Bin, AU - Kaartinen,Vesa, AU - Wong,Victor C, AU - Mishina,Yuji, AU - Levi,Benjamin, Y1 - 2015/02/23/ PY - 2014/11/20/received PY - 2015/02/11/revised PY - 2015/02/15/accepted PY - 2015/2/28/entrez PY - 2015/2/28/pubmed PY - 2015/5/30/medline KW - ALK2 KW - Acvr1 KW - BMP receptor KW - Bone KW - Cartilage KW - Endochondral ossification KW - FOP KW - Fibrodysplasia ossificans progressive KW - Heterotopic ossification KW - Nfatc1 SP - 202 EP - 9 JF - Developmental biology JO - Dev Biol VL - 400 IS - 2 N2 - BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre(+) transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints - tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration. SN - 1095-564X UR - https://www.unboundmedicine.com/medline/citation/25722188/BMP_signaling_mediated_by_constitutively_active_Activin_type_1_receptor__ACVR1__results_in_ectopic_bone_formation_localized_to_distal_extremity_joints_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(15)00069-X DB - PRIME DP - Unbound Medicine ER -