Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification
| Autor: | Michael T. Longaker, Yuji Mishina, Yashar S. Niknafs, Hsiao H. Hsieh, Thomas A. Davis, Shuli Li, Kavitha Ranganathan, Cameron Brownley, Ravindra Kumar, John Li, David Cholok, Wenzhong Xiao, Shailesh Agarwal, Ronald G. Tompkins, Shawn Loder, James Drake, Jonathan R. Peterson, Christopher Breuler, Benjamin Levi, Paul B. Yu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neutrophils Anti-Inflammatory Agents ACVR1 Ligands Bioinformatics Gene Knockout Techniques Mice 03 medical and health sciences Drug Discovery Genetics medicine Animals Humans Genetic Predisposition to Disease Bone morphogenetic protein receptor Receptor Protein Kinase Inhibitors Molecular Biology Bone Morphogenetic Protein Receptors Type I Mice Knockout Pharmacology business.industry Macrophages Ossification Heterotopic Bone Morphogenetic Protein Receptors Anatomy medicine.disease BMPR1A BMPR1B 030104 developmental biology Fibrodysplasia ossificans progressiva Gene Targeting Wounds and Injuries Molecular Medicine Original Article Heterotopic ossification Stem cell business Activin Receptors Type I Biomarkers |
| Zdroj: | Molecular Therapy. 25:1974-1987 |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2017.01.008 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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