biostudies-literatureAgarwal SACS Clowes AwardCalifornia Institute for Regenerative Medicine (CIRM) Clinical FellowNIH, NIGMSAAS Roslyn AwardNIDCR NIH HHSHoward Hughes Medical InstituteHagey Laboratory for Pediatric Regenerative MedicineNHLBI NIH HHSAmerican Society of Maxillofacial Surgeons (ASMS)/Maxillofacial Surgeons Foundation (MSF) Research Grant AwardNIH Loan Repayment ProgramDefense Medical Research and Development ProgramHoward Hughes Medical Institute (HHMI) Medical Fellows ProgramNIHAmerican Association of Plastic Surgery Research FellowshipPlastic Surgery Foundation National Endowment AwardGunn/Olivier fundPlastic Surgery Foundation/AAPS Pilot Research AwardThe Oak FoundationInternational Fibrodysplasia Ossificans Progressiva Association Research AwardNIAMS NIH HHSNIGMS NIH HHS1974-1987https://www.ebi.ac.uk/biostudies/studies/S-EPMC5542633biostudies-literatureUnknown25(8)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).Molecular therapy : the journal of the American Society of Gene TherapyStrategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.PMC5542633R01DE020843R01 AR057374TG2-01159K08 GM109105R01 DE020843F32 AR068902AR057374K08GM109105T32 GM007863U01 HL099776CDMRP: W81XWH-14-2-0010F32 AR066499Longaker MTTompkins RLi JCholok DAgarwal SRanganathan KXiao WBrownley CYu PBDrake JKumar RDavis TAPeterson JHsieh HHBreuler CLi SMishina YLevi BLoder SJNiknafs YSfalseStrategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.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).2017-01-01T00:00:00Z2017 Aug2024-11-14T05:18:46.844Z2019-03-26T23:48:38ZS-EPMC55426332871657510.1016/j.ymthe.2017.01.008