{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:14:13Z","timestamp":1790990053808,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2004,11,1]],"date-time":"2004-11-01T00:00:00Z","timestamp":1099267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Effective treatment for bacteria-induced bone lytic diseases is not yet available. In this study, we showed that PAR, an NF-\u03baB inhibitor found in medicinal herbs, can block LPS-induced osteolysis. PAR does this by inhibiting osteoclastogenesis and bone resorption and promoting apoptosis of osteoclasts through the suppression of NF-\u03baB activity.<\/jats:p>\n               <jats:p>Introduction: Osteolysis induced by chronic gram-negative bacterial infection underlies many bone diseases such as osteomyelitis, septic arthritis, and periodontitis. Drugs that inhibit lipopolysaccharide (LPS)-induced osteolysis are critically needed for the prevention of bone destruction in infective bone diseases. In this study, we investigated the effect of parthenolide (PAR) on LPS-induced osteolysis in vivo and studied its role in osteoclastogenesis, bone resorption, apoptosis, and NF-\u03baB activity.<\/jats:p>\n               <jats:p>Materials and Methods: The LPS-induced osteolysis in the mouse calvarium model was used to examine the effect of PAR in vivo. RANKL-induced osteoclast differentiation from RAW264.7 cells and bone resorption assays were used to assess the effect of PAR in vitro. Assays for NF-\u03baB activation, p65 translocation, and I\u03baB-\u03b1 degradation were used to determine the mechanism of action of PAR in osteoclasts and their precursors. Flow cytometry and confocal microscopic analysis were used to examine cell apoptosis. Semiquantitative RT-PCR was performed to examine the effect of PAR on gene expression of RANK and TRAF6.<\/jats:p>\n               <jats:p>Results: We found that PAR (0.5 and 1 mg\/kg), injected simultaneously with LPS (25 mg\/kg) or 3 days later, blocked the LPS-induced osteolysis in the mouse calvarium model. In vitro studies showed that low concentrations of PAR (&amp;lt;1 \u03bcM) inhibited in vitro osteoclastogenesis and osteoclastic bone resorption, whereas higher concentrations (&amp;gt;5 \u03bcM) triggered apoptotic cell death of osteoclasts and their precursor cells in a dose-dependent manner. Furthermore, PAR inhibited LPS-induced NF-\u03baB activation, p65 translocation, and I\u03baB-\u03b1 degradation both in mature osteoclasts and their precursors in a time- and dose-dependent manner. In addition, PAR inhibited NF-\u03baB activation induced by osteoclastogenic factors RANKL, interleukin (IL)-1\u03b2, or TNF-\u03b1 to varying degrees and reduced the gene expression of RANK and TRAF6.<\/jats:p>\n               <jats:p>Conclusion: The NF-\u03baB pathway is known to mediate both osteoclast differentiation and survival. These findings indicate that PAR blocks LPS-induced osteolysis through the suppression of NF-\u03baB activity and suggest that it might have therapeutic value in bacteria-induced bone destruction.<\/jats:p>","DOI":"10.1359\/jbmr.040919","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T23:27:15Z","timestamp":1146094035000},"page":"1905-1916","source":"Crossref","is-referenced-by-count":80,"title":["Sesquiterpene Lactone Parthenolide Blocks Lipopolysaccharide-Induced Osteolysis Through the Suppression of NF-\u03baB Activity"],"prefix":"10.1093","volume":"19","author":[{"given":"Kirk Ho Man","family":"Yip","sequence":"first","affiliation":[{"name":"Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming H","family":"Zheng","sequence":"additional","affiliation":[{"name":"Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao Tian","family":"Feng","sequence":"additional","affiliation":[{"name":"Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H","family":"Steer","sequence":"additional","affiliation":[{"name":"Western Australia Medical Research Institute Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Joyce","sequence":"additional","affiliation":[{"name":"Western Australia Medical Research Institute Pharmacology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western 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