期刊
TISSUE ENGINEERING PART A
卷 23, 期 5-6, 页码 195-207出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ten.tea.2016.0308
关键词
adipogenesis; BMP-2; hBMSCs; mandible; osteogenesis; phenamil
资金
- National Institutes of Health [R01 AR060213, R21 DE021819]
- International Association for Dental Research
- Academy of Osseointegration
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 (PPAR), 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.
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