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Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil
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Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil
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Journal Article
Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil
2017
Overview
Growth factor-based therapeutics using bone morphogenetic protein 2 (BMP-2) presents a promising strategy to reconstruct craniofacial bone defects such as mandible. However, clinical applications require supraphysiological BMP doses that often increase inappropriate adipogenesis, resulting in well-documented, cyst-like bone formation. Here we reported a novel complementary strategy to enhance osteogenesis and mandibular bone repair by using small-molecule phenamil that has been shown to be a strong activator of BMP signaling. Phenamil synergistically induced osteogenic differentiation of human bone marrow mesenchymal stem cells with BMP-2 while suppressing their adipogenic differentiation induced by BMP-2 in vitro. The observed pro-osteogenic and antiadipogenic activity of phenamil was mediated by expression of tribbles homolog 3 (Trb3) that enhanced BMP-smad signaling and inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipogenesis. The synergistic effect of BMP-2+phenamil on bone regeneration was further confirmed in a critical-sized rat mandibular bone defect by implanting polymer scaffolds designed to slowly release the therapeutic molecules. These findings indicate a new complementary osteoinductive strategy to improve clinical efficacy and safety of current BMP-based therapeutics.
Publisher
SAGE Publications,Mary Ann Liebert, Inc
Subject
Amiloride - analogs & derivatives
/ Amiloride - pharmacokinetics
/ Animals
/ Bone Morphogenetic Protein 2 - pharmacokinetics
/ Bone Morphogenetic Protein 2 - pharmacology
/ Bones
/ Drug Implants - pharmacokinetics
/ Drug Implants - pharmacology
/ Humans
/ Mandibular Injuries - drug therapy
/ Mandibular Injuries - metabolism
/ Mandibular Injuries - pathology
/ Mesenchymal Stromal Cells - metabolism
/ Mesenchymal Stromal Cells - pathology
/ Original
