{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T14:52:27Z","timestamp":1760885547005,"version":"3.40.3"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2012,2,1]],"date-time":"2012-02-01T00:00:00Z","timestamp":1328054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-\u03baB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti\u2013GM-CSF\u2013neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c+ cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast\u2013DC-like cell conversion.<\/jats:p>","DOI":"10.4049\/jimmunol.1101174","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T04:56:36Z","timestamp":1326776196000},"page":"1772-1781","source":"Crossref","is-referenced-by-count":32,"title":["Tetracyclines Convert the Osteoclastic-Differentiation Pathway of Progenitor Cells To Produce Dendritic Cell-like Cells"],"prefix":"10.1093","volume":"188","author":[{"given":"Saya","family":"Kinugawa","sequence":"first","affiliation":[{"name":"Graduate School of Oral Medicine, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Koide","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihide","family":"Mizoguchi","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadashi","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Muto","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Kawahara","sequence":"additional","affiliation":[{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midori","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisataka","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Planning and Development Group, Bioindustry Division, Oriental Yeast Co., Ltd , Tokyo 174-8505 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Graduate School of Oral Medicine, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]},{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuyuki","family":"Udagawa","sequence":"additional","affiliation":[{"name":"Graduate School of Oral Medicine, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]},{"name":"Institute for Oral Science, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]},{"name":"Department of Biochemistry, Matsumoto Dental University , Nagano 399-0781 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,2,15]]},"reference":[{"key":"2025032409510363400_r1","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nrg1122","article-title":"Genetic regulation of osteoclast development and function","volume":"4","author":"Teitelbaum","year":"2003","journal-title":"Nat. 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Metab."},{"key":"2025032409510363400_r31","first-page":"2088","article-title":"RelA\/p65 promotes osteoclast differentiation by blocking a RANKL-induced apoptotic JNK pathway in mice","volume":"118","author":"Vaira","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2025032409510363400_r32","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1359\/jbmr.091030","article-title":"The pivotal role of the alternative NF-kappaB pathway in maintenance of basal bone homeostasis and osteoclastogenesis","volume":"25","author":"Soysa","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"2025032409510363400_r33","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1359\/jbmr.090302","article-title":"Diphenylhydantoin inhibits osteoclast differentiation and function through suppression of NFATc1 signaling","volume":"24","author":"Koide","year":"2009","journal-title":"J. Bone Miner. 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Oral Biol."},{"key":"2025032409510363400_r43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/36593","article-title":"A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function","volume":"390","author":"Anderson","year":"1997","journal-title":"Nature"},{"key":"2025032409510363400_r44","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1084\/jem.186.12.2075","article-title":"TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor","volume":"186","author":"Wong","year":"1997","journal-title":"J. Exp. 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