title: Nck influences preosteoblastic/osteoblastic migration and bone mass.
abstract: Migration of the cells in osteoblastic lineage, including preosteoblasts and osteoblasts, has been postulated to influence bone formation. However, the molecular bases that link preosteoblastic/osteoblastic cell migration and bone formation are incompletely understood. Nck (noncatalytic region of tyrosine kinase; collectively referred to Nck1 and Nck2) is a member of the signaling adaptors that regulate cell migration and cytoskeletal structures, but its function in cells in the osteoblastic lineage is not known. Therefore, we examined the role of Nck in migration of these cells. Nck is expressed in preosteoblasts/osteoblasts, and its knockdown suppresses migration as well as cell spreading and attachment to substrates. In contrast, Nck1 overexpression enhances spreading and increases migration and attachment. As for signaling, Nck double knockdown suppresses migration toward IGF1 (insulin-like growth factor 1). In these cells, Nck1 binds to IRS-1 (insulin receptor substrate 1) based on immunoprecipitation experiments using anti-Nck and anti-IRS-1 antibodies. In vivo, Nck knockdown suppresses enlargement of the pellet of DiI-labeled preosteoblasts/osteoblasts placed in the calvarial defects. Genetic experiments indicate that conditional double deletion of both Nck1 and Nck2 specifically in osteoblasts causes osteopenia. In these mice, Nck double deficiency suppresses the levels of bone-formation parameters such as bone formation rate in vivo. Interestingly, bone-resorption parameters are not affected. Finally, Nck deficiency suppresses repair of bone injury after bone marrow ablation. These results reveal that Nck regulates preosteoblastic/osteoblastic migration and bone mass.
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Smriti
authors.initials: S
authors.lastname: Aryal A C
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Miyai
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Izu
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Hayata
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Notomi
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan noda.mph@mri.tmd.ac.jp ezura.mph@mri.tmd.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan noda.mph@mri.tmd.ac.jp ezura.mph@mri.tmd.ac.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology* / Q000000981:diagnostic imaging / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011859:Radiography; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C078332:Nck protein; C117758:Nck2 protein, mouse; D015513:Oncogene Proteins; D007334:Insulin-Like Growth Factor I
keywords: Nck; bone remodeling; bone repair; migration; osteoblast