title: Small Molecule Inhibition of Transforming Growth Factor Beta Signaling Enables the Endogenous Regenerative Potential of the Mammalian Calvarium.
abstract: Current approaches for the treatment of skeletal defects are suboptimal, principally because the ability of bone to repair and regenerate is poor. Although the promise of effective cellular therapies for skeletal repair is encouraging, these approaches are limited by the risks of infection, cellular contamination, and tumorigenicity. Development of a pharmacological approach would therefore help avoid some of these potential risks. This study identifies transforming growth factor beta (TGFβ) signaling as a potential pathway for pharmacological modulation in vivo. We demonstrate that inhibition of TGFβ signaling by the small molecule SB431542 potentiates calvarial skeletal repair through activation of bone morphogenetic protein (BMP) signaling on osteoblasts and dura mater cells participating in healing of calvarial defects. Cells respond to inhibition of TGFβ signaling by producing higher levels of BMP2 that upregulates inhibitory Smad6 expression, thus providing a negative feedback loop to contain excessive BMP signaling. Importantly, study on human osteoblasts indicates that molecular mechanism(s) triggered by SB431542 are conserved. Collectively, these data provide insights into the use of small molecules to modulate key signaling pathways for repairing skeletal defects.
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.|2 Department of Craniofacial Development and Stem Cell Biology, Dental Institute , King's College London, London, United Kingdom .|3 Department of Plastic and Reconstructive Surgery, North Western Deanery , Manchester, United Kingdom .
authors.forename: Kshemendra
authors.initials: K
authors.lastname: Senarath-Yapa
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Shuli
authors.initials: S
authors.lastname: Li
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.|4 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, California.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Walmsley
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zielins
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Kevin
authors.initials: K
authors.lastname: Paik
authors.affiliation: 5 Department of Craniofacial Surgery, Great Ormond Street Hospital , London, United Kingdom .
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Britto
authors.affiliation: 2 Department of Craniofacial Development and Stem Cell Biology, Dental Institute , King's College London, London, United Kingdom .
authors.forename: Agamemnon E
authors.initials: AE
authors.lastname: Grigoriadis
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Derrick C
authors.initials: DC
authors.lastname: Wan
authors.affiliation: 2 Department of Craniofacial Development and Stem Cell Biology, Dental Institute , King's College London, London, United Kingdom .
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.|4 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, California.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.affiliation: 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine , Stanford, California.|6 Dipartimento di Scienze Biomediche Avanzate, Universita' degli Studi di Napoli Federico II , Napoli, Italy .
authors.forename: Natalina
authors.initials: N
authors.lastname: Quarto
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D001861:Bone Regeneration / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D012886:Skull / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051905:Smad6 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D004149:Dioxoles; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D016212:Transforming Growth Factor beta