title: NEL-Like Molecule-1 (Nell1) Is Regulated by Bone Morphogenetic Protein 9 (BMP9) and Potentiates BMP9-Induced Osteogenic Differentiation at the Expense of Adipogenesis in Mesenchymal Stem Cells.
abstract: BACKGROUND
  BMP9 induces both osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs). Nell1 is a secretory glycoprotein with osteoinductive and anti-adipogenic activities. We investigated the role of Nell1 in BMP9-induced osteogenesis and adipogenesis in MSCs.
  
  
  METHODS
  Previously characterized MSCs iMEFs were used. Overexpression of BMP9 and NELL1 or silencing of mouse Nell1 was mediated by adenoviral vectors. Early and late osteogenic and adipogenic markers were assessed by staining techniques and qPCR analysis. In vivo activity was assessed in an ectopic bone formation model of athymic mice.
  
  
  RESULTS
  We demonstrate that Nell1 expression was up-regulated by BMP9. Exogenous Nell1 potentiated BMP9-induced late stage osteogenic differentiation while inhibiting the early osteogenic marker. Forced Nell1 expression enhanced BMP9-induced osteogenic regulators/markers and inhibited BMP9-upregulated expression of adipogenic regulators/markers in MSCs. In vivo ectopic bone formation assay showed that exogenous Nell1 expression enhanced mineralization and maturity of BMP9-induced bone formation, while inhibiting BMP9-induced adipogenesis. Conversely, silencing Nell1 expression in BMP9-stimulated MSCs led to forming immature chondroid-like matrix.
  
  
  CONCLUSIONS
  Our findings indicate that Nell1 can be up-regulated by BMP9, which in turn accelerates and augments BMP9-induced osteogenesis. Exogenous Nell1 may be exploited to enhance BMP9-induced bone formation while overcoming BMP9-induced adipogenesis in regenerative medicine.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Junyi
authors.initials: J
authors.lastname: Liao
authors.forename: Fugui
authors.initials: F
authors.lastname: Zhang
authors.forename: Dongzhe
authors.initials: D
authors.lastname: Song
authors.forename: Minpeng
authors.initials: M
authors.lastname: Lu
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.forename: Shengli
authors.initials: S
authors.lastname: Tang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Jiaming
authors.initials: J
authors.lastname: Fan
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zou
authors.forename: Dan
authors.initials: D
authors.lastname: Guo
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.forename: Xue
authors.initials: X
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Qu
authors.forename: Liqun
authors.initials: L
authors.lastname: Chen
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Weng
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lee
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Russell R
authors.initials: RR
authors.lastname: Reid
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010012:Osteogenesis / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D055427:Growth Differentiation Factor 2; C513122:Nell1 protein, mouse; D034741:RNA, Small Interfering
keywords: Adipogenesis; BMP-9; Mesenchymal stem cells; NEL-Like Molecule; Nell1; Osteogenic differentiation