title: Nck1 deficiency accelerates unloading-induced bone loss.
abstract: Mechanical stress is an important signal to determine the levels of bone mass. Unloading-induced osteoporosis is a critical issue in bed-ridden patients and astronauts. Many molecules have been suggested to be involved in sensing mechanical stress in bone, though the mechanisms involved in this phenomenon are not fully understood. Nck1 is an adaptor protein known to mediate signaling from plasma membrane-activated receptors to cytosolic effectors regulating actin cytoskeleton remodeling. Nck1 has also been implicated in cellular responses to endoplasmic reticulum stress. In vitro, in case of cell stress the actin cytoskeleton is disrupted and in such cases Nck1 has been reported to enter the nucleus of the cells to mediate the nuclear actin polymerization. However, the role of Nck1 in vivo during the bone response to mechanical stimuli is unknown. The purpose of this study is to examine the role of Nck1 in unloading-induced bone loss in vivo. Sciatic and femoral nerve resection was conducted. Neurectomy-based unloading enhanced Nck1 gene expression in bone about twofold. Using the Nck1 deficient mice and control Nck1+/+, effects of neurectomy-based unloading on bone structure were examined. Unloading reduced bone volume in wild type mice by 30% whereas the levels in bone loss were exacerbated to 50% in Nck1 deficient mice due to neurectomy after 4 weeks. These data demonstrate that Nck1 gene deficiency accelerates the mechanical unloading-induced bone loss suggesting Nck1 to be a crucial molecule in mechanical stress mediated regulation in bone metabolism.
authors.affiliation: Department of Molecular Pharmacology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: A C Smriti
authors.initials: AC
authors.lastname: Aryal
authors.forename: Kentaro
authors.initials: K
authors.lastname: Miyai
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Hayata
authors.forename: Takuya
authors.initials: T
authors.lastname: Notomi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamoto
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001696:Biomechanical Phenomena; D001862:Bone Resorption / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D003714:Denervation; D005267:Femoral Nerve / Q000601:surgery; D015870:Gene Expression; D019417:Hindlimb Suspension / Q000009:adverse effects / Q000502:physiology; D006801:Humans; D008124:Locomotion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000503:physiopathology; D015513:Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D012584:Sciatic Nerve / Q000601:surgery
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins