{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T03:03:23Z","timestamp":1767927803092,"version":"3.49.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2004,2,1]],"date-time":"2004-02-01T00:00:00Z","timestamp":1075593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>op\/op mice have a severe deficiency of osteoclasts because of lacking functional M-CSF that is an essential factor of osteoclast differentiation and function. We now report that OVX induces osteoclast formation and cures osteopetrosis by increasing the VEGF that regulates osteoclast formation in these mice.<\/jats:p>\n               <jats:p>Introduction: We have found that estrogen deficiency induced by ovariectomy (OVX) upregulated osteoclast formation in op\/op mice. We have recently demonstrated that vascular endothelial growth factor (VEGF) could substitute for macrophage colony-stimulating factor (M-CSF) in the support of osteoclastic bone resorption in these mice. Therefore, in this study, we wished to assess the effects of VEGF on bone loss induced by OVX in these mice.<\/jats:p>\n               <jats:p>Materials and Methods: Eight-week-old op\/op mice were bilateral OVX or sham-operated. Mice were killed at 8, 10, and 12 weeks of age, and femurs were removed for preparations. Some OVX mice were treated with three consecutive injections of 120 \u03bcl\/body of VEGF-neutralizing antibody at 12-h intervals starting from 36 h before death at 4 weeks after OVX. VEGFR-1\/Fc chimeric protein (600 \u03bcg\/kg\/day) or 17\u03b2-estradiol (0.16 \u03bcg\/day) was administered in a dorsal subcutaneous pocket of the mice at the time of OVX. These mice were killed 2 weeks after surgery. Changes of serum levels of VEGF were measured by ELISA. Changes of mRNA levels of VEGF, Flt-1, interleukin-6, and osteoclast differentiation factor (ODF\/TRANCE\/RANKL) in bone tissue were measured by reverse transcriptase-polymerase chain reaction.<\/jats:p>\n               <jats:p>Results: In OVX op\/op mice, trabecular bone volume of the femur was decreased, and the number of osteoclasts was significantly increased. Serum levels of VEGF were demonstrated to be higher in OVX mice than in sham-operated mice. VEGF mRNA, Flt\u20131 mRNA, interleukin-6 mRNA, and RANKL mRNA levels in bone tissue were elevated in OVX mice over that in sham-operated mice. The increase in osteoclast number was inhibited by VEGF antagonist treatment in OVX mice.<\/jats:p>\n               <jats:p>Conclusions: In this study, we have demonstrated that the production of VEGF and RANKL stimulated by OVX results in increased osteoclast formation in op\/op mice.<\/jats:p>","DOI":"10.1359\/jbmr.0301229","type":"journal-article","created":{"date-parts":[[2006,4,27]],"date-time":"2006-04-27T06:49:17Z","timestamp":1146120557000},"page":"200-206","source":"Crossref","is-referenced-by-count":41,"title":["Estrogen Regulates the Production of VEGF for Osteoclast Formation and Activity in <i>op\/op<\/i> Mice"],"prefix":"10.1093","volume":"19","author":[{"given":"Ichiro","family":"Kodama","sequence":"first","affiliation":[{"name":"Department of Oral Growth and Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"},{"name":"Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shumpei","family":"Niida","sequence":"additional","affiliation":[{"name":"Department of Geriatric Research, National Institute for Longevity Sciences (NILS), Aichi, Japan"},{"name":"Department of Oral Growth and Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiro","family":"Sanada","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Yoshiko","sequence":"additional","affiliation":[{"name":"Department of Oral Growth and Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikio","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihiko","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Oral Growth and Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koso","family":"Ohama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,2]]},"reference":[{"key":"2024013019214981200_bib1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1056\/NEJM199502023320506","article-title":"Bone marrow, cytokines, and bone remodeling","volume":"332","author":"Manolagas","year":"1995","journal-title":"N Engl J Med"},{"key":"2024013019214981200_bib2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1172\/JCI116179","article-title":"Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors","volume":"91","author":"Tanaka","year":"1993","journal-title":"J Clin Invest"},{"key":"2024013019214981200_bib3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/jcp.1040910303","article-title":"Conditions controlling the proliferation of haemopoietic stem cells in vitro","volume":"91","author":"Dexter","year":"1977","journal-title":"J Cell Physiol"},{"key":"2024013019214981200_bib4","first-page":"197","volume-title":"The Molecules and Their Emerging Role in Medicine","author":"Chaplin","year":"1992"},{"key":"2024013019214981200_bib5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/jbmr.5650040116","article-title":"Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro","volume":"4","author":"Pfeilschifter","year":"1989","journal-title":"J Bone Miner Res"},{"key":"2024013019214981200_bib6","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1210\/endo-129-3-1596","article-title":"Two distinct effects of recombinant human tumor necrosis factor-alpha o n osteoclast development and subsequent resorption of mineralized matrix","volume":"129","author":"van der Pluijm","year":"1991","journal-title":"Endocrinology"},{"key":"2024013019214981200_bib7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1006\/bbrc.1998.8586","article-title":"Osteoclast differentiation factor (ODF) induces osteoclast-like formation in human peripheral blood mononuclear cell cultures","volume":"246","author":"Matsuzaki","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"2024013019214981200_bib8","doi-asserted-by":"crossref","first-page":"25190","DOI":"10.1074\/jbc.272.40.25190","article-title":"TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells","volume":"272","author":"Wong","year":"1997","journal-title":"J Biol Chem"},{"key":"2024013019214981200_bib9","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/aja.1001630205","article-title":"Morphological evidence of reduced bone resorption in osteopetrotic (op) mice","volume":"163","author":"Marks","year":"1982","journal-title":"Am J Anat"},{"key":"2024013019214981200_bib10","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1084\/jem.156.5.1516","article-title":"Hematological characterization of congenital osteopetrosis in op\/op mouse","volume":"156","author":"Wiktor-Jedrzejczak","year":"1982","journal-title":"J Exp Med"},{"key":"2024013019214981200_bib11","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1084\/jem.177.1.237","article-title":"Delayed hematopoietic development in osteopetrotic (op\/op) mice","volume":"177","author":"Begg","year":"1993","journal-title":"J Exp Med"},{"key":"2024013019214981200_bib12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1084\/jem.190.2.293","article-title":"Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption","volume":"190","author":"Niida","year":"1999","journal-title":"J Exp Med"},{"key":"2024013019214981200_bib13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1084\/jem.173.1.269","article-title":"Congenital osteoclast deficiency in osteopetrotic (op\/op) mice is cured by injections of macrophage colony-stimulating factor","volume":"173","author":"Kodama","year":"1991","journal-title":"J Exp Med"},{"key":"2024013019214981200_bib14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/jbmr.5650080107","article-title":"Transient recruitment of osteoclasts and expression of their function in osteopetrotic (op\/op) mice by a single injection of macrophage colony-stimulating factor","volume":"8","author":"Kodama","year":"1993","journal-title":"J Bone Miner Res"},{"key":"2024013019214981200_bib15","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jbmr.5650090613","article-title":"Expression of Mac-2 antigen in the preosteoclast and osteoclast identified in the op\/op mouse injected with macrophage colony-stimulating factor","volume":"9","author":"Niida","year":"1994","journal-title":"J Bone Miner Res"},{"key":"2024013019214981200_bib16","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1006\/bbrc.1998.8787","article-title":"Comparative expression of novel vascular endothelial growth factor\/vascular permeability factor transcripts in skin, papillomas, and carcinomas of v-Ha-ras Tg. AC transgenic mice and FVB\/N mice","volume":"247","author":"Tober","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"2024013019214981200_bib17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1210\/mend.13.4.0265","article-title":"Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity","volume":"13","author":"He","year":"1999","journal-title":"Mol Endocrinol"},{"key":"2024013019214981200_bib18","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S8756-3282(99)00176-3","article-title":"Bidirectional signaling between stromal and haemopoietic cells regulates interleukin-1 expression during human osteoclast formation","volume":"25","author":"Haynes","year":"1999","journal-title":"Bone"},{"key":"2024013019214981200_bib19","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1128\/IAI.68.4.2034-2042.2000","article-title":"Cytokine gene expression in innately susceptible BALB\/c mice and relatively resistant C57BL\/6 mice during infection with virulent Burkholderia pseudomallei","volume":"68","author":"Ulett","year":"2000","journal-title":"Infect Immun"},{"key":"2024013019214981200_bib20","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S8756-3282(00)00280-5","article-title":"Coordinated cytokine expression by stromal and hematopoietic cells during human osteoclast formation","volume":"26","author":"Atkins","year":"2000","journal-title":"Bone"},{"key":"2024013019214981200_bib21","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1006\/bbrc.1993.2112","article-title":"Non-radioisotropic quantitative RT-PCR to detect changes in mRNA levels during early mouse embryo development","volume":"195","author":"Yokoi","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"2024013019214981200_bib22","doi-asserted-by":"crossref","first-page":"28890","DOI":"10.1074\/jbc.271.46.28890","article-title":"Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1 and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production","volume":"271","author":"Kimble","year":"1996","journal-title":"J Biol Chem"},{"key":"2024013019214981200_bib23","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1172\/JCI117606","article-title":"Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice","volume":"94","author":"Kitazawa","year":"1994","journal-title":"J Clin Invest"},{"key":"2024013019214981200_bib24","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1172\/JCI4561","article-title":"Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1","volume":"102","author":"Srivastava","year":"1998","journal-title":"J Clin Invest"},{"key":"2024013019214981200_bib25","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1538\/expanim.48.125","article-title":"Congenital osteoclast deficiency in osteopetrotic (op\/op) mice is improved by ovariectomy and orchiectomy","volume":"48","author":"Kawata","year":"1999","journal-title":"Exp Anim"},{"key":"2024013019214981200_bib26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0014-5793(00)01520-9","article-title":"Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts","volume":"473","author":"Nakagawa","year":"2000","journal-title":"FEBS Lett"},{"key":"2024013019214981200_bib27","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0021-9150(99)00262-2","article-title":"Serum level of vascular endothelial growth factor is decreased by hormone replacement therapy in postmenopausal women without hypercholesterolemia","volume":"148","author":"Sumino","year":"2000","journal-title":"Atherosclerosis"},{"key":"2024013019214981200_bib28","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1002\/jbmr.5650100914","article-title":"Endogenous bone-resorbing factors in estrogen deficiency: Cooperative effects of IL-1 and IL-6","volume":"10","author":"Miyaura","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024013019214981200_bib29","first-page":"707","article-title":"Circulating cytokine levels in osteoporotic and normal women","volume":"79","author":"Khosla","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2024013019214981200_bib30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0378-5122(96)01080-8","article-title":"Increase in cytokine production (IL-1\u03b2, IL-6, TNF-\u03b1 but not IFN-\u03b3, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis","volume":"26","author":"Zheng","year":"1997","journal-title":"Maturitas"},{"key":"2024013019214981200_bib31","first-page":"3183","article-title":"Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor","volume":"60","author":"Hyder","year":"2000","journal-title":"Cancer Res"},{"key":"2024013019214981200_bib32","first-page":"2898","article-title":"Vascular endothelial growth factor (VEGF) in breast cancer: Comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen","volume":"60","author":"Adams","year":"2000","journal-title":"Cancer Res"},{"key":"2024013019214981200_bib33","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1210\/endo.137.6.8641174","article-title":"Enhanced expression of vascular endothelial growth factor in human SaOS-2 osteoblast-like cells and murine osteoblasts induced by insulin-like growth factor I","volume":"137","author":"Goad","year":"1996","journal-title":"Endocrinology"},{"key":"2024013019214981200_bib34","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/9467","article-title":"VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation","volume":"5","author":"Gerber","year":"1999","journal-title":"Nat Med"},{"key":"2024013019214981200_bib35","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s001099900019","article-title":"Molecular and biological properties of vascular endothelial growth factor","volume":"77","author":"Ferrara","year":"1999","journal-title":"J Mol Med"},{"key":"2024013019214981200_bib36","first-page":"325","article-title":"Regulation of VEGF in the reproductive tract by sex-steroid hormones","volume":"15","author":"Hyder","year":"2000","journal-title":"Histol Histopathol"},{"key":"2024013019214981200_bib37","first-page":"374","article-title":"Hypoxic stimulation of vascular endothelial growth factor expression in vivo and in vitro","volume":"71","author":"Minchenko","year":"1994","journal-title":"Lab Invest"},{"key":"2024013019214981200_bib38","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/BF03401566","article-title":"Hypoxic induction of endothelial cell growth factors in retinal cells: Identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen","volume":"1","author":"Shima","year":"1995","journal-title":"Mol Med"},{"key":"2024013019214981200_bib39","doi-asserted-by":"crossref","first-page":"C853","DOI":"10.1152\/ajpcell.2000.278.4.C853","article-title":"VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism","volume":"278","author":"Steinbrech","year":"2000","journal-title":"Am J Physiol Cell Physiol"},{"key":"2024013019214981200_bib40","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.1210\/jc.2001-011223","article-title":"Hormone replacement effects on endothelial function measured in the forearm resistance artery in normocholesterolemic and hypercholesterolemic postmenopausal women","volume":"87","author":"Sanada","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2024013019214981200_bib41","first-page":"93","article-title":"Endothelium-derived nitric oxide in the control of tissue perfusion and oxygen supply: Physiological and pathophysiological implications","volume":"14","author":"Pohl","year":"1993","journal-title":"Eur Heart J"},{"key":"2024013019214981200_bib42","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1359\/jbmr.2000.15.11.2240","article-title":"Nitroglycerin therapy is as efficacious as standard estrogen replacement therapy (Premarin) in prevention of oophorectomy-induced bone loss: A human pilot study","volume":"15","author":"Wimalawansa","year":"2000","journal-title":"J Bone Miner Res"},{"key":"2024013019214981200_bib43","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/8756-3282(96)00005-1","article-title":"Nitric oxide donor alleviates ovariectomy-induced bone loss","volume":"18","author":"Wimalawansa","year":"1996","journal-title":"Bone"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2FJBMR.0301229","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/19\/2\/200\/56473689\/5650190204.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/19\/2\/200\/56473689\/5650190204.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T15:06:06Z","timestamp":1710342366000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/19\/2\/200-206\/7592703"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,2,1]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2009,12,2]]},"published-print":{"date-parts":[[2004,2,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.0301229","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2004,2,1]]},"published":{"date-parts":[[2004,2,1]]}}}