title: Role of inducible nitric oxide synthase in skeletal adaptation to acute increases in mechanical loading.
abstract: To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/- mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS-/- mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS-/- mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS-/- mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.
authors.affiliation: Department of Orthopedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Watanuki
authors.forename: Akinori
authors.initials: A
authors.lastname: Sakai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsurukami
authors.forename: Masao
authors.initials: M
authors.lastname: Miwa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D001842:Bone and Bones / Q000201:enzymology / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005269:Femur; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D005996:Nitroglycerin / Q000494:pharmacology; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics; D013314:Stress, Mechanical
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D006146:Guanidines; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000469:Alkaline Phosphatase; D005996:Nitroglycerin; C004479:pimagedine