title: Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects.
abstract: Bone morphogenetic proteins (BMPs) have been widely used for bone repair in the craniofacial region. However, its high dose requirement in clinical applications revealed adverse effects and inefficient bone formation, along with high cost. Here, we report a novel osteoinductive strategy to effectively complement the osteogenic activity of BMP-2 using phenamil, a small molecule that can induce osteogenic differentiation via stimulation of BMP signaling. Treatment of adipose-derived stem cells (ASCs) with BMP-2 in combination with phenamil significantly promoted the in vitro osteogenic differentiation of ASCs. The efficacy of the combination strategy of phenamil+BMP-2 was further confirmed in a mouse calvarial defect model using scaffolds consisting of poly(lactic-co-glycolic acid) and apatite layer on their surfaces designed to slowly release phenamil and BMP-2. Six weeks after implantation, the scaffolds treated with phenamil+BMP-2 significantly promoted mouse calvarial regeneration as demonstrated by micro-computerized tomography and histology, compared with the groups treated with phenamil or BMP-2 alone. Moreover, the combination treatment reduced the BMP-2 dose without compromising calvarial healing efficacy. These results suggest promising complementary therapeutic strategies for bone repair in more efficient and cost-effective manners.
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.
authors: Jiabing
authors: J
authors: Fan
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.
authors: Choong Sung
authors: CS
authors: Im
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.
authors: Zhong-Kai
authors: ZK
authors: Cui
authors: 2 Department of Neurosurgery, the 2nd Affiliated Hospital of Harbin Medical University , Harbin, China .
authors: Mian
authors: M
authors: Guo
authors: 3 Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry , Los Angeles, California.
authors: Olga
authors: O
authors: Bezouglaia
authors: 3 Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry , Los Angeles, California.
authors: Armita
authors: A
authors: Fartash
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.
authors: Ju-Yeon
authors: JY
authors: Lee
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.
authors: John
authors: J
authors: Nguyen
authors: 4 Department of Bioengineering, University of California , Los Angeles, California.
authors: Benjamin M
authors: BM
authors: Wu
authors: 3 Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry , Los Angeles, California.
authors: Tara
authors: T
authors: Aghaloo
authors: 1 Division of Advanced Prosthodontics, UCLA School of Dentistry , Los Angeles, California.|4 Department of Bioengineering, University of California , Los Angeles, California.
authors: Min
authors: M
authors: Lee
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019344:Lactic Acid / Q000737:chemistry; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D010012:Osteogenesis / Q000187:drug effects*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D055396:Bone Morphogenetic Protein 2; D018797:Cell Cycle Proteins; D051785:Smad Proteins; C474830:TRB3 protein, mouse; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; C047088:phenylamil; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000584:Amiloride; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases