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Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.
Mol Ther. 2017 08 02; 25(8):1974-1987.MT

Abstract

Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).

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ncbi.nlm.nih.gov
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Authors+Show Affiliations

Agarwal S
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Loder SJ
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Breuler C
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Li J
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cholok D
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Brownley C
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Peterson J
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Hsieh HH
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Drake J
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ranganathan K
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Niknafs YS
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Xiao W
Stanford University, Palo Alto, CA 94305, USA.
Li S
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kumar R
Acceleron Pharma, Cambridge, MA 02139, USA.
Tompkins R
Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Longaker MT
Hagey Research Laboratory, Department of Surgery, Stanford University, Palo Alto, CA 94305, USA.
Davis TA
Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD 20910, USA.
Yu PB
Department of Medicine, Harvard University, Boston, MA 02115, USA.
Mishina Y
Department of Biological and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Levi B
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: blevi@umich.edu.

MeSH

Activin Receptors, Type IAnimalsAnti-Inflammatory AgentsBiomarkersBone Morphogenetic Protein ReceptorsBone Morphogenetic Protein Receptors, Type IGene Knockout TechniquesGene TargetingGenetic Predisposition to DiseaseHumansLigandsMacrophagesMiceMice, KnockoutNeutrophilsOssification, HeterotopicProtein Kinase InhibitorsWounds and Injuries

Pub Type(s)

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

Language

eng

PubMed ID

28716575

Citation

Agarwal, Shailesh, et al. "Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 25, no. 8, 2017, pp. 1974-1987.
Agarwal S, Loder SJ, Breuler C, et al. Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Mol Ther. 2017;25(8):1974-1987.
Agarwal, S., Loder, S. J., Breuler, C., Li, J., Cholok, D., Brownley, C., Peterson, J., Hsieh, H. H., Drake, J., Ranganathan, K., Niknafs, Y. S., Xiao, W., Li, S., Kumar, R., Tompkins, R., Longaker, M. T., Davis, T. A., Yu, P. B., Mishina, Y., & Levi, B. (2017). Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Molecular Therapy : the Journal of the American Society of Gene Therapy, 25(8), 1974-1987. https://doi.org/10.1016/j.ymthe.2017.01.008
Agarwal S, et al. Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. Mol Ther. 2017 08 2;25(8):1974-1987. PubMed PMID: 28716575.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. AU - Agarwal,Shailesh, AU - Loder,Shawn J, AU - Breuler,Christopher, AU - Li,John, AU - Cholok,David, AU - Brownley,Cameron, AU - Peterson,Jonathan, AU - Hsieh,Hsiao H, AU - Drake,James, AU - Ranganathan,Kavitha, AU - Niknafs,Yashar S, AU - Xiao,Wenzhong, AU - Li,Shuli, AU - Kumar,Ravindra, AU - Tompkins,Ronald, AU - Longaker,Michael T, AU - Davis,Thomas A, AU - Yu,Paul B, AU - Mishina,Yuji, AU - Levi,Benjamin, Y1 - 2017/07/15/ PY - 2016/09/15/received PY - 2017/01/09/revised PY - 2017/01/11/accepted PY - 2017/7/19/pubmed PY - 2018/4/24/medline PY - 2017/7/19/entrez KW - BMP receptors KW - BMP signaling KW - stem cells SP - 1974 EP - 1987 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol Ther VL - 25 IS - 8 N2 - Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854). SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/28716575/Strategic_Targeting_of_Multiple_BMP_Receptors_Prevents_Trauma_Induced_Heterotopic_Ossification_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(17)30014-X DB - PRIME DP - Unbound Medicine ER -