title: Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover.
abstract: Reconstruction of craniofacial defects presents a substantial biomedical burden, and requires complex surgery. Interestingly, children after age 2 years and adults are unable to heal large skull defects. This nonhealing paradigm provides an excellent model system for craniofacial skeletal tissueengineering strategies. Previous studies have documented the in vivo osteogenic potential of adipose-derived stromal (ADS) cells and bone marrow-derived stromal (BMS) cells. This study investigates the ability to accelerate in vivo osteogenesis on ex vivo recombinant human bone morphogenetic protein 2 (BMP-2) and retinoic acid stimulation. Mouse osteoblasts, ADS cells, and BMS cells were seeded onto apatite-coated PLGA scaffolds, stimulated with rhBMP-2 and retinoic acid ex vivo for 4 weeks, and subsequently implanted into critically sized (4 mm) calvarial defects. Samples were harvested after 2, 4, 8, and 12 weeks. Areas of complete bony bridging were noted as early as 2 weeks in vivo; however, osteoclasts were attracted to the scaffold as identified by calcitonin receptor staining and tartrate-resistant acid phosphatase activity staining. Although the optimal method of in vitro osteogenic priming for mesenchymal cells remains unknown, these results provide evidence that BMP-2 and retinoic acid stimulation of multipotent cells ex vivo can subsequently induce significant quantities of bone formation within a short time period in vivo.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cowan
authors.forename: Oliver O
authors.initials: OO
authors.lastname: Aalami
authors.forename: Yun-Ying
authors.initials: YY
authors.lastname: Shi
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Chou
authors.forename: Carina
authors.initials: C
authors.lastname: Mari
authors.forename: Romy
authors.initials: R
authors.lastname: Thomas
authors.forename: Natalin
authors.initials: N
authors.lastname: Quarto
authors.forename: Randall P
authors.initials: RP
authors.lastname: Nacamuli
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage*; D016723:Bone Remodeling / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019465:Craniofacial Abnormalities / Q000473:pathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D039902:Multipotent Stem Cells / Q000473:pathology / Q000637:transplantation*; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D014212:Tretinoin