{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T09:15:39Z","timestamp":1759482939932},"reference-count":22,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Klotho gene mutant mice (klotho mice, also called kl\/kl) exhibit osteopetrosis in the metaphysis of femora and tibiae and die within 3 months. We previously showed by semiquantitative RT-PCR that osteoprotegerin (opg) expression levels in klotho mice were about 2-fold higher than those in wild-type mice in the bone marrow, spleen, and lung. To examine whether the high osteoprotegerin expression levels account for the osteopetrotic phenotype in the klotho homozygous mutant mice in vivo, we made double mutant mice by crossing klotho mutant and osteoprotegerin-deficient mice. Micro computed tomography analysis in the two-dimensional sagittal planes of the metaphyses and cross-sections of femoral midshaft revealed that the abnormally high fractional trabecular bone volume in klotho homozygous mice (kl\/kl; 29.71%), which was about 4-fold higher compared with that of wild-type [klotho (+\/+) opg (+\/+)] mice (7.81%), was rescued by the coexistence of heterozygous mutation in opg gene locus (+\/\u2212; 8.36%). Single heterozygous mutation in the opg gene locus alone (without klotho mutation) did not show phenotype (trabecular bone volume, 5.84%; not significantly different from wild type). High levels of osteoprotegerin mRNA expression in the bone marrow in klotho mutant mice were reduced by the heterozygous mutation in the opg gene locus. Furthermore, high osteoprotegerin protein levels in klotho mutant mice were also reduced by the heterozygous mutations in opg gene locus. Thus, elevated levels of osteoprotegerin in mutant mice contribute at least in part to reveal the osteopetrotic phenotype in klotho mice.<\/jats:p>","DOI":"10.1210\/en.2002-220602","type":"journal-article","created":{"date-parts":[[2002,11,23]],"date-time":"2002-11-23T05:26:31Z","timestamp":1038029191000},"page":"4711-4717","source":"Crossref","is-referenced-by-count":16,"title":["Double Mutations in Klotho and Osteoprotegerin Gene Loci Rescued Osteopetrotic Phenotype"],"prefix":"10.1210","volume":"143","author":[{"given":"Teruhito","family":"Yamashita","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology (T.Y., M.N.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Development Genetics (S.O.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanji","family":"Higashio","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science (K.H.), Snow Brand Milk Products Co., Ltd., Tochigi 329-0512, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yo-ichi","family":"Nabeshima","sequence":"additional","affiliation":[{"name":"Department of Pathology and Tumor Biology (Y.N.), Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"},{"name":"Core Research for Evolutional Science and Technology (Y.N.), Japan Science and Technology Corp., Tokyo, Japan 102-8666"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology (T.Y., M.N.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071619404689200_R1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse klotho gene leads to a syndrome resembling ageing","volume":"278","author":"Kuro-o","year":"1997","journal-title":"Nature"},{"key":"2020071619404689200_R2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/joe.0.1590001","article-title":"Elongation of the epiphyseal trabecular bone in transgenic mice carrying a klotho gene locus mutation that leads to a syndrome resembling aging","volume":"159","author":"Yamashita","year":"1998","journal-title":"J Endocrinol"},{"key":"2020071619404689200_R3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1172\/JCI5705","article-title":"Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia","volume":"104","author":"Kawaguchi","year":"1999","journal-title":"J Clin Invest"},{"key":"2020071619404689200_R4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S0014-5793(98)00127-6","article-title":"Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein","volume":"424","author":"Shiraki-Iida","year":"1998","journal-title":"FEBS Lett"},{"key":"2020071619404689200_R5","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1210\/endo.141.1.7252","article-title":"Retardation in bone resorption after bone marrow ablation in klotho mutant mice","volume":"141","author":"Yamashita","year":"2000","journal-title":"Endocrinology"},{"key":"2020071619404689200_R6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0092-8674(00)80209-3","article-title":"Osteoprotegerin: a novel secreted protein involved in the regulation of bone density","volume":"89","author":"Simonet","year":"1997","journal-title":"Cell"},{"key":"2020071619404689200_R7","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1073\/pnas.95.7.3597","article-title":"Osteoclast differentiation factor is a ligand for osteoprotegerin\/osteoclastogenesis-inhibitory factor and is identical to TRANCE\/RANKL","volume":"95","author":"Yasuda","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071619404689200_R8","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/16852","article-title":"OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis","volume":"397","author":"Kong","year":"1999","journal-title":"Nature"},{"key":"2020071619404689200_R9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0092-8674(00)81569-X","article-title":"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation","volume":"93","author":"Lacey","year":"1998","journal-title":"Cell"},{"key":"2020071619404689200_R10","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1073\/pnas.97.4.1566","article-title":"RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism","volume":"97","author":"Li","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071619404689200_R11","doi-asserted-by":"crossref","first-page":"4743","DOI":"10.1210\/endo.139.11.6433","article-title":"Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells","volume":"139","author":"Horwood","year":"1998","journal-title":"Endocrinology"},{"key":"2020071619404689200_R12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S8756-3282(99)00162-3","article-title":"Interleukin-1\u03b2 and tumor necrosis factor-\u03b1, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells","volume":"25","author":"Hofbauer","year":"1999","journal-title":"Bone"},{"key":"2020071619404689200_R13","doi-asserted-by":"crossref","first-page":"4367","DOI":"10.1210\/endo.140.9.7131","article-title":"Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells","volume":"140","author":"Hofbauer","year":"1999","journal-title":"Endocrinology"},{"key":"2020071619404689200_R14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1006\/bbrc.1999.1621","article-title":"Basic fibroblast growth factor inhibits osteoclast formation induced by 1\u03b1, 25-dihydroxyvitamin D(3) through suppressing the production of osteoclast differentiation factor","volume":"265","author":"Nakagawa","year":"1999","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071619404689200_R15","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1359\/jbmr.1999.14.9.1486","article-title":"Expression of osteoprotegerin (osteoclastogenesis inhibitory factor) in cultures of human dental mesenchymal cells and epithelial cells","volume":"14","author":"Sakata","year":"1999","journal-title":"J Bone Miner Res"},{"key":"2020071619404689200_R16","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1359\/jbmr.1999.14.4.518","article-title":"Immunological characterization of circulating osteoprotegerin\/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis","volume":"14","author":"Yano","year":"1999","journal-title":"J Bone Miner Res"},{"key":"2020071619404689200_R17","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1006\/bbrc.2000.2182","article-title":"Age-related decline in osteoprotegerin expression by human bone marrow cells cultured in three-dimensional collagen sponges","volume":"268","author":"Makhluf","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071619404689200_R18","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1101\/gad.12.9.1260","article-title":"osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification","volume":"12","author":"Bucay","year":"1998","journal-title":"Genes Dev"},{"key":"2020071619404689200_R19","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1006\/bbrc.1998.8697","article-title":"Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor\/osteoprotegerin","volume":"247","author":"Mizuno","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071619404689200_R20","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.4049\/jimmunol.167.5.2625","article-title":"Connection between B lymphocyte and osteoclast differentiation pathways","volume":"167","author":"Manabe","year":"2001","journal-title":"J Immunol"},{"key":"2020071619404689200_R21","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1093\/intimm\/12.6.861","article-title":"Impairment of B lymphopoiesis in precocious aging (klotho) mice","volume":"12","author":"Okada","year":"2000","journal-title":"Int Immunol"},{"key":"2020071619404689200_R22","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1210\/endo.143.2.8657","article-title":"Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1\u03b1-hydroxylase gene","volume":"143","author":"Yoshida","year":"2002","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/143\/12\/4711\/11128340\/endo4711.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/143\/12\/4711\/11128340\/endo4711.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T04:43:20Z","timestamp":1594961000000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/143\/12\/4711\/2880382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,12,1]]},"references-count":22,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2002,12,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2002-220602","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,12,1]]}}}