title: Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2.
abstract: The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poor-quality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis.
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California.
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California.
authors.forename: Shen
authors.initials: S
authors.lastname: Pang
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California; UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California.
authors.forename: Janette N
authors.initials: JN
authors.lastname: Zara
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Greg
authors.initials: G
authors.lastname: Asatrian
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Chiang
authors.affiliation: Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Min
authors.initials: M
authors.lastname: Lee
authors.affiliation: UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California.
authors.forename: Kevork
authors.initials: K
authors.lastname: Khadarian
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Alan
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Siu
authors.affiliation: Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, California.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tetradis
authors.affiliation: Division of Growth and Development and Section of Orthodontics, UCLA School of Dentistry, Los Angeles, California. Electronic address: kting@dentistry.ucla.edu.
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.affiliation: UCLA Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center at UCLA, Los Angeles, California. Electronic address: bsoo@ucla.edu.
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D050156:Adipogenesis; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D001861:Bone Regeneration / Q000502:physiology*; D002135:Calcium-Binding Proteins; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000502:physiology
chemical_list: C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins