title: Enhanced Mandibular Bone Repair by Combined Treatment of Bone Morphogenetic Protein 2 and Small-Molecule Phenamil.
abstract: 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.
authors: 1 Division of Advanced Prosthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors: Jiabing
authors: J
authors: Fan
authors: 2 Department of Neurosurgery, The 2nd Affiliated Hospital of Harbin Medical University , Harbin, China .
authors: Mian
authors: M
authors: Guo
authors: 1 Division of Advanced Prosthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors: Choong Sung
authors: CS
authors: Im
authors: 3 Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors: Joan
authors: J
authors: Pi-Anfruns
authors: 1 Division of Advanced Prosthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors: Zhong-Kai
authors: ZK
authors: Cui
authors: 4 Department of Bioengineering, University of California , Los Angeles, Los Angeles, California.
authors: Soyon
authors: S
authors: Kim
authors: 1 Division of Advanced Prosthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.|4 Department of Bioengineering, University of California , Los Angeles, Los Angeles, California.
authors: Benjamin M
authors: BM
authors: Wu
authors: 3 Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California , Los Angeles, Los Angeles, California.
authors: Tara L
authors: TL
authors: Aghaloo
authors: 1 Division of Advanced Prosthodontics, School of Dentistry, University of California , Los Angeles, Los Angeles, California.|4 Department of Bioengineering, University of California , Los Angeles, Los Angeles, California.
authors: Min
authors: M
authors: Lee
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000493:pharmacokinetics / Q000494:pharmacology; D004343:Drug Implants / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008334:Mandible / Q000378:metabolism* / Q000473:pathology; D008338:Mandibular Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; C047088:phenylamil; D000584:Amiloride
keywords: BMP-2; adipogenesis; hBMSCs; mandible; osteogenesis; phenamil