{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:25:55Z","timestamp":1791206755068,"version":"4.1.0"},"reference-count":38,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,8,18]]},"abstract":"<jats:p>Estrogen deficiency causes bone loss, which can be prevented by estrogen replacement therapy. Using a recently developed technique for isolation of highly purified mammalian osteoclasts, we showed that 17 \u03b2-estradiol (E2) was able to directly inhibit osteoclastic bone resorption. At concentrations effective for inhibiting bone resorption, E2 also directly induced osteoclast apoptosis in a dose- and time-dependent manner. ICI164,384 and tamoxifen, as pure and partial antagonists, respectively, completely or partially blocked the effect of E2 on both inhibition of osteoclastic bone resorption and induction of osteoclast apoptosis. These data suggest that the protective effects of estrogen against postmenopausal osteoporosis are mediated in part by the direct induction of apoptosis of the bone-resorbing osteoclasts by an estrogen receptor\u2013 mediated mechanism.<\/jats:p>","DOI":"10.1084\/jem.186.4.489","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"489-495","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":414,"title":["Estrogen Inhibits Bone Resorption by Directly Inducing Apoptosis of the Bone-resorbing Osteoclasts"],"prefix":"10.1084","volume":"186","author":[{"given":"Takashi","family":"Kameda","sequence":"first","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Mano","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuhisa","family":"Yuasa","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Mori","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshi","family":"Miyazawa","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Shiokawa","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiya","family":"Nakamaru","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Hiroi","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Hiura","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Kameda","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na N.","family":"Yang","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Hakeda","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Kumegawa","sequence":"additional","affiliation":[{"name":"From the *Department of Orthodontics, Nippon Dental University School of Dentistry at Niigata, Niigata 951, Japan; \u2021Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-02, Japan; and \u00a7Endocrine Research, Eli Lilly & Co., Indianapolis, Indiana 46285"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1997,8,18]]},"reference":[{"key":"2023072507361337000_B1","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/S0140-6736(76)92217-0","article-title":"Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment","volume":"1","author":"Lindsay","year":"1976","journal-title":"Lancet"},{"key":"2023072507361337000_B2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.7326\/0003-4819-102-3-319","article-title":"Long-term estrogen replacement therapy prevents bone loss and fractures","volume":"102","author":"Ettinger","year":"1985","journal-title":"Ann Intern Med"},{"key":"2023072507361337000_B3","first-page":"964","article-title":"Menopausal changes in bone remodeling","volume":"92","author":"Heaney","year":"1978","journal-title":"J Lab Clin Med"},{"key":"2023072507361337000_B4","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1042\/cs0690265","article-title":"Early effects of ethinyloestradiol and norethisterone treatment in post-menopausal women on bone resorption and calcium regulating hormones","volume":"69","author":"Selby","year":"1985","journal-title":"Clin Sci (Lond)"},{"key":"2023072507361337000_B5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/00003086-198806000-00033","article-title":"Cellular biology and biochemical mechanism of bone resorption. A review of recent developments on the formation, activation, and mode of action of osteoclasts","volume":"231","author":"Vaes","year":"1988","journal-title":"Clin Orthop Relat Res"},{"key":"2023072507361337000_B6","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.4049\/jimmunol.135.4.2562","article-title":"Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 beta","volume":"135","author":"Dewhirst","year":"1985","journal-title":"J Immunol"},{"key":"2023072507361337000_B7","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 osteoclast-like cells in vitro","volume":"4","author":"Pfeilschifter","year":"1989","journal-title":"J Bone Miner Res"},{"key":"2023072507361337000_B8","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/319516a0","article-title":"Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors","volume":"319","author":"Bertolini","year":"1986","journal-title":"Nature (Lond)"},{"key":"2023072507361337000_B9","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/0006-291X(89)90851-6","article-title":"Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis","volume":"162","author":"Lowik","year":"1989","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1677\/joe.0.1020281","article-title":"Effect of parathyroid hormone and calcitonin on the cytoplasmic spreading of isolated osteoclasts","volume":"102","author":"Chambers","year":"1984","journal-title":"J Endocrinol"},{"key":"2023072507361337000_B11","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1677\/joe.0.1260473","article-title":"Evidence that the action of calcitonin on rat osteoclasts is mediated by two G proteins acting via separate post-receptor pathways","volume":"126","author":"Zaidi","year":"1990","journal-title":"J Endocrinol"},{"key":"2023072507361337000_B12","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1006\/bbrc.1996.0436","article-title":"Vitamin K2inhibits osteoclastic bone resorption by inducing osteoclast apoptosis","volume":"220","author":"Kameda","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B13","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/jbmr.5650101008","article-title":"Bisphosphonates promote apoptosis in murine osteoclasts in vivo and in vitro","volume":"10","author":"Hughes","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2023072507361337000_B14","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0074-7696(08)62312-8","article-title":"Cell death: the significance of apoptosis","volume":"6","author":"Wyllie","year":"1980","journal-title":"Int Rev Cytol"},{"key":"2023072507361337000_B15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/path.1711420112","article-title":"Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis","volume":"142","author":"Wyllie","year":"1984","journal-title":"J Pathol"},{"key":"2023072507361337000_B16","doi-asserted-by":"crossref","first-page":"4616","DOI":"10.1073\/pnas.84.13.4616","article-title":"Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis","volume":"84","author":"Pacifici","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507361337000_B17","first-page":"1648","article-title":"Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines","volume":"77","author":"Cohen-Solal","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"2023072507361337000_B18","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1126\/science.1621100","article-title":"Increased osteoclast development after estrogen loss: mediation by interleukin-6","volume":"257","author":"Jilka","year":"1992","journal-title":"Science (Wash DC)"},{"key":"2023072507361337000_B19","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1006\/bbrc.1993.1954","article-title":"Ovariectomy decreases the mRNA levels of transforming growth factor-beta 1 and increases the mRNA levels of osteocalcin in rat bone in vivo","volume":"194","author":"Ikeda","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B20","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1126\/science.8480174","article-title":"Cytokines and estrogen in bone: anti-osteoporotic effects","volume":"260","author":"Horowitz","year":"1993","journal-title":"Science (Wash DC)"},{"key":"2023072507361337000_B21","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/nm1096-1132","article-title":"Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-\u03b2","volume":"2","author":"Hughes","year":"1996","journal-title":"Nat Med"},{"key":"2023072507361337000_B22","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1006\/bbrc.1996.0947","article-title":"Mammalian mature osteoclasts as estrogen target cells","volume":"223","author":"Mano","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B23","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1073\/pnas.91.12.5227","article-title":"Human giant cell tumors of the bone (osteoclastomas) are estrogen target cells","volume":"91","author":"Oursler","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507361337000_B24","doi-asserted-by":"crossref","first-page":"6613","DOI":"10.1073\/pnas.88.15.6613","article-title":"Avian osteoclasts as estrogen target cells","volume":"88","author":"Oursler","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507361337000_B25","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/BF02239480","article-title":"Isolation of highly enriched rabbit osteoclasts from collagen gels: a new assay system for bone-resorbing activity of mature osteoclasts","volume":"14","author":"Kakudo","year":"1996","journal-title":"J Bone Miner Metab"},{"key":"2023072507361337000_B26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0169-6009(92)90785-C","article-title":"A simple method to assess osteoclast-mediated bone resorption using unfractionated bone cells","volume":"17","author":"Takada","year":"1992","journal-title":"Bone Miner"},{"key":"2023072507361337000_B27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1006\/bbrc.1995.1251","article-title":"Detection and characterization of apoptosis in osteoclasts in vitro","volume":"207","author":"Kameda","year":"1995","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B28","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s002239900094","article-title":"Human calcitonin has the same inhibitory effect on osteoclastic bone resorption by human giant cell tumor cells as salmon calcitonin","volume":"59","author":"Iida","year":"1996","journal-title":"Calcif Tissue Int"},{"key":"2023072507361337000_B29","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1177\/15.9.542","article-title":"A technique for the fixation and decalcification of rat incisors for electron microscopy","volume":"15","author":"Warshawsky","year":"1967","journal-title":"J Histochem Cytochem"},{"key":"2023072507361337000_B30","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0021-9258(17)42227-7","article-title":"Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts","volume":"269","author":"Tezuka","year":"1994","journal-title":"J Biol Chem"},{"key":"2023072507361337000_B31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/0006-291X(92)90832-6","article-title":"Identification of osteopontin in isolated rabbit osteoclasts","volume":"186","author":"Tezuka","year":"1992","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B32","first-page":"18","article-title":"Patterns of cell death","volume":"13","author":"Walker","year":"1988","journal-title":"Methods Achiev Exp Pathol"},{"key":"2023072507361337000_B33","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1126\/science.8197458","article-title":"Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription","volume":"264","author":"Halachmi","year":"1994","journal-title":"Science (Wash DC)"},{"key":"2023072507361337000_B34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0092-8674(00)81118-6","article-title":"A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors","volume":"85","author":"Kamei","year":"1996","journal-title":"Cell"},{"key":"2023072507361337000_B35","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1677\/joe.0.1490503","article-title":"Selective toxic effects of tamoxifen on osteoclasts: comparison with the effects of oestrogen","volume":"149","author":"Arnett","year":"1996","journal-title":"J Endocrinol"},{"key":"2023072507361337000_B36","doi-asserted-by":"crossref","first-page":"4367","DOI":"10.1073\/pnas.92.10.4367","article-title":"Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary","volume":"92","author":"Friend","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507361337000_B37","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1006\/bbrc.1996.0308","article-title":"Identification of a novel isoform of estrogen receptor, a potential inhibitor of estrogen action, in vascular smooth muscle cells","volume":"219","author":"Inoue","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"2023072507361337000_B38","doi-asserted-by":"crossref","first-page":"5925","DOI":"10.1073\/pnas.93.12.5925","article-title":"Cloning of a novel estrogen receptor expressed in rat prostate and ovary","volume":"93","author":"Kuiper","year":"1996","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/4\/489\/1685578\/96-1573.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/186\/4\/489\/1685578\/96-1573.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:19:28Z","timestamp":1690273168000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/186\/4\/489\/7263\/Estrogen-Inhibits-Bone-Resorption-by-Directly"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,8,18]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1997,8,18]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.186.4.489","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,8,18]]}}}