title: Nell-1-induced bone regeneration in calvarial defects.
abstract: Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-beta1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration.
authors.affiliation: Dental and Craniofacial Research Institute, Department of Bioengineering, School of Dentistry, University of California, Los Angeles, 10833 Le Conte Ave., CHS 30-117, Los Angeles, CA 90095, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Aghaloo
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cowan
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Chou
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Haofu
authors.initials: H
authors.lastname: Lee
authors.forename: Steve
authors.initials: S
authors.lastname: Miao
authors.forename: Nichole
authors.initials: N
authors.lastname: Hong
authors.forename: Shun'ichi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis; D001861:Bone Regeneration / Q000235:genetics; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D003398:Craniosynostoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015675:Osteocalcin / Q000096:biosynthesis; D010012:Osteogenesis / Q000235:genetics; D051381:Rats; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis; D012886:Skull / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics
chemical_list: C525718:BMP2 protein, human; C525819:BMP7 protein, human; D015415:Biomarkers; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C525821:Bmp7 protein, rat; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D006023:Glycoproteins; C513122:Nell1 protein, mouse; D009419:Nerve Tissue Proteins; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2