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We report here that<jats:italic>S. pyogenes<\/jats:italic>strain JRS4 (M6) attached to and invaded mouse primary osteoblasts. Reverse transcription-PCR demonstrated that<jats:italic>S. pyogenes<\/jats:italic>infection of osteoblasts stimulated expression of mRNA for the receptor activator of NF-\u03baB ligand (RANKL). Western blot analysis followed by ligand precipitation with the receptor activator of NF-\u03baB receptor showed that there was an increase in RANKL protein in infected osteoblasts. Production of interleukin-6 was also stimulated, but no production of interleukin-1\u03b2 or tumor necrosis factor alpha was observed. Stimulation of RANKL production was not observed in osteoblasts stimulated with heat-inactivated<jats:italic>S. pyogenes<\/jats:italic>, suggesting that an active interaction of<jats:italic>S. pyogenes<\/jats:italic>with osteoblasts is essential for this phenomenon. A Western blot analysis performed with antibodies specific for phosphorylated signal transduction proteins demonstrated that<jats:italic>S. pyogenes<\/jats:italic>infection induces phosphorylation of p38 mitogen-activated protein kinase. A specific inhibitor of this kinase, SB203580, inhibited RANKL production by infected osteoblasts. These results suggest that infection of osteoblasts by<jats:italic>S. pyogenes<\/jats:italic>stimulates RANKL production and may trigger bone destruction in infected bone tissue.<\/jats:p>","DOI":"10.1128\/iai.71.2.948-955.2003","type":"journal-article","created":{"date-parts":[[2003,1,22]],"date-time":"2003-01-22T23:03:20Z","timestamp":1043276600000},"page":"948-955","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Infection by<i>Streptococcus pyogenes<\/i>Induces the Receptor Activator of NF-\u03baB Ligand Expression in Mouse Osteoblastic Cells"],"prefix":"10.1128","volume":"71","author":[{"given":"Nobuo","family":"Okahashi","sequence":"first","affiliation":[{"name":"Departments of Oral and Molecular Microbiology"},{"name":"Oral Frontier Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuo","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Departments of Oral and Molecular Microbiology"},{"name":"Pediatric Dentistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita-Osaka 565-0871"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Departments of Oral and Molecular Microbiology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taku","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Pediatric Dentistry, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita-Osaka 565-0871"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigetada","family":"Kawabata","sequence":"additional","affiliation":[{"name":"Departments of Oral and Molecular Microbiology"},{"name":"PRESTO, Japan Science and Technology Corporation, Kawaguchi-Saitama 332-0012, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuo","family":"Amano","sequence":"additional","affiliation":[{"name":"Oral Frontier Biology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeyuki","family":"Hamada","sequence":"additional","affiliation":[{"name":"Departments of Oral and Molecular Microbiology"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/90609"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/36593"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002281-200007000-00013"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/315138"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.9.5075-5083.2000"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-1825-3_136"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(00)00413-0"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/35065000"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.13.3.470"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.11.5871"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.9.5235-5242.2001"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198503213121206"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.13.6172"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.8.4254"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1999.0283"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.5.3574"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/46303"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/16852"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200105)44:5<1003::AID-ANR179>3.0.CO;2-#"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.25.12115"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1462-5822.2001.00122.x"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3379"},{"key":"e_1_3_2_24_2","doi-asserted-by":"crossref","first-page":"758","DOI":"10.4049\/jimmunol.156.2.758","volume":"156","year":"1996","unstructured":"Onoe, Y., C. 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