{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:00:46Z","timestamp":1790996446137,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2011,12,23]],"date-time":"2011-12-23T00:00:00Z","timestamp":1324598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:p>\n                    Bone diseases such as postmenopausal osteoporosis are primarily caused by excessive formation and activity of osteoclasts (OCLs). Receptor activator of nuclear factor\u2010\u03baB ligand (RANKL) is a key initiating cytokine for OCL differentiation and function. RANKL induces calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) oscillations, resulting in selective and robust induction of nuclear factor of activated T cells c1 (NFATc1), a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010responsive transcription factor that drives osteoclastogenesis. Store\u2010operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE) is a major Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx pathway in most nonexcitable cell types and is activated by any stimulus that depletes Ca\n                    <jats:sup>2+<\/jats:sup>\n                    stores in the endoplasmic reticulum. Although the role of Orai1, a SOCE channel in the plasma membrane, in maintaining Ca\n                    <jats:sup>2+<\/jats:sup>\n                    oscillations and transactivation of NFAT in other cell types is well known, its contribution to osteoclastogenesis remains unclear. We show here that silencing of the\n                    <jats:italic>Orai1<\/jats:italic>\n                    gene with viral delivery of shRNA reduces SOCE and inhibits RANKL\u2010induced osteoclastogenesis of RAW264.7 cells, a murine monocyte\/ macrophage cell line, by suppressing the induction of NFATc1. This was accompanied by defective induction of OCL\u2010specific genes, such as tartrate\u2010resistant acid phosphatase and immunoreceptor OCL\u2010associated receptor, which are known to be direct transcriptional targets of NFATc1 during osteoclastogenesis. In addition, maturation of OCLs was abrogated by defective cell fusion of pre\u2010OCLs depleted of Orai1, consistent with defective RANKL\u2010mediated induction of d2 isoform of vacuolar ATPase V\n                    <jats:sub>o<\/jats:sub>\n                    domain that is involved in cell fusion of pre\u2010OCLs. We found that the functional bone resorbing capacity was severely impaired in OCLs depleted of Orai1, potentially related to the observed decrease in the induction of cathepsin K, a major bone matrix degrading protease. Our results indicate that Orai1 plays a critical role in the differentiation and function of OCLs, suggesting that Orai1 might be a potential therapeutic target for the treatment or prevention of bone loss caused by OCLs.\u2014Hwang, S.\u2010Y., Putney, J. W. Orai1\u2010mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    26, 1484\u20101492 (2012).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.11-194399","type":"journal-article","created":{"date-parts":[[2011,12,23]],"date-time":"2011-12-23T23:45:13Z","timestamp":1324683913000},"page":"1484-1492","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Orai1\u2010mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1"],"prefix":"10.1096","volume":"26","author":[{"given":"Sung\u2010Yong","family":"Hwang","sequence":"first","affiliation":[{"name":"Laboratory of Signal Transduction National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Putney","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,12,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/01.blo.0000132404.30139.f2","article-title":"Osteoporosis: a review","author":"Lin J. 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