{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:43:20Z","timestamp":1789127000016,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T00:00:00Z","timestamp":1646438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071165\uff1b31870895"],"award-info":[{"award-number":["32071165\uff1b31870895"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Wear particle-induced aseptic loosening is the most common complication of total joint arthroplasty (TJA). Excessive osteoclast formation and bone resorptive activation have been considered to be responsible for extensive bone destruction and prosthesis failure. Therefore, identification of anti-osteoclastogenesis agents is a potential therapy strategy for the treatment of aseptic loosening and other osteoclast-related osteolysis diseases. In the present study, we reported, for the first time, that piperlongumine (PL), a key alkaloid compound from Piper longum fruits, could significantly suppress the formation and activation of osteoclasts. Furthermore, PL effectively decreased the mRNA expressions of osteoclastic marker genes such as tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), and cathepsin K (CTSK). In addition, PL suppressed the receptor activator of nuclear factor-\u03baB ligand (RANKL)-induced activations of MAPKs (ERK, JNK and p38) and NF-\u03baB, which down-regulated the protein expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Using a titanium (Ti) particle-induced calvarial osteolysis model, we demonstrated that PL could ameliorate Ti particle-induced bone loss in vivo. These data provide strong evidence that PL has the potential to treat osteoclast-related diseases including periprosthetic osteolysis (PPO) and aseptic loosening.<\/jats:p>","DOI":"10.3390\/ijms23052868","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:38:16Z","timestamp":1646599096000},"page":"2868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Piperlongumine Inhibits Titanium Particles-Induced Osteolysis, Osteoclast Formation, and RANKL-Induced Signaling Pathways"],"prefix":"10.3390","volume":"23","author":[{"given":"Xuan","family":"Liu","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Diao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Mao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Shi","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.1039\/D0BM00718H","article-title":"Punicalagin ameliorates wear-particle-induced inflammatory bone destruction by bi-directional regulation of osteoblastic formation and osteoclastic resorption","volume":"8","author":"Wang","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.bbrc.2019.05.054","article-title":"Vx-11e protects against titanium-particle-induced osteolysis and osteoclastogenesis by supressing ERK activity","volume":"514","author":"Li","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1080\/03008207.2019.1593392","article-title":"Magnesium lithospermate B inhibits titanium particles-induced osteoclast formation by c-fos and inhibiting NFATc1 expression","volume":"60","author":"Miao","year":"2019","journal-title":"Connect. Tissue Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Li, H., Wang, J., Sun, Q., Chen, G., Sun, S., Ma, X., Qiu, H., Liu, X., Xu, L., and Liu, M. (2018). Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113698"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107459","DOI":"10.1016\/j.intimp.2021.107459","article-title":"Inhibitory effect of acetyl-11-keto-\u03b2-boswellic acid on titanium particle-induced bone loss by abrogating osteoclast formation and downregulating the ERK signaling pathway","volume":"94","author":"Shi","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1016\/j.bbadis.2015.07.007","article-title":"Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition","volume":"10","author":"Park","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11972","DOI":"10.1111\/jcmm.15821","article-title":"Puerarin inhibits titanium particle-induced osteolysis and RANKL-induced osteoclastogenesis via suppression of the NF-\u03baB signaling pathway","volume":"24","author":"Tang","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/j.biomaterials.2012.11.003","article-title":"The effects of a systemic single dose of zoledronic acid on post-implantation bone remodelling and inflammation in an ovariectomised rat model","volume":"34","author":"Cardemil","year":"2013","journal-title":"Biomaterials"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.amjmed.2012.06.023","article-title":"Bisphosphonate therapy for osteoporosis: Benefits, risks, and drug holiday","volume":"126","author":"McClung","year":"2013","journal-title":"Am. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.bone.2012.08.115","article-title":"Risk of osteomyelitis of the jaw induced by oral bisphosphonates in patients taking medications for osteoporosis: A hospital-based cohort study in Japan","volume":"51","author":"Yamazaki","year":"2012","journal-title":"Bone"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S210","DOI":"10.1080\/10408398.2019.1565489","article-title":"A systematic review on black pepper (Piper nigrum L.): From folk uses to pharmacological applications","volume":"59","author":"Takooree","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104772","DOI":"10.1016\/j.phrs.2020.104772","article-title":"Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent","volume":"156","author":"Tripathi","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41419-019-2212-y","article-title":"Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation","volume":"11","author":"Thatikonda","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"22283","DOI":"10.1038\/s41598-020-78220-6","article-title":"Biological and physical approaches on the role of piplartine (piperlongumine) in cancer","volume":"10","author":"Henrique","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1097\/FBP.0000000000000498","article-title":"Piperlongumine produces antidepressant-like effects in rats exposed to chronic unpredictable stress","volume":"30","author":"Zhang","year":"2019","journal-title":"Behav. Pharmacol."},{"key":"ref_16","first-page":"884","article-title":"Increased Expression of FosB through Reactive Oxygen Species Accumulation Functions as Pro-Apoptotic Protein in Piperlongumine Treated MCF7 Breast Cancer Cells","volume":"42","author":"Park","year":"2019","journal-title":"Mol. Cells"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73497","DOI":"10.18632\/oncotarget.11988","article-title":"Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells","volume":"7","author":"Yao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.imlet.2014.05.001","article-title":"Piperlongumine alleviates lupus nephritis in MRL-Fas(lpr) mice by regulating the frequency of Th17 and regulatory T cells","volume":"161","author":"Yao","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/ptr.2630","article-title":"Antihyperlipidemic compounds from the fruit of Piper longum L.","volume":"23","author":"Jin","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ejphar.2007.05.073","article-title":"Piperlongumine, a constituent of Piper longum L., inhibits rabbit platelet aggregation as a thromboxane A(2) receptor antagonist","volume":"570","author":"Iwashita","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1600-0749.2005.00281.x","article-title":"Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression","volume":"19","author":"Kim","year":"2006","journal-title":"Pigment. Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1021\/acscentsci.1c00070","article-title":"Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression","volume":"7","author":"Conde","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_23","first-page":"233","article-title":"Piperlongumine inhibits the proliferation, migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis","volume":"67","author":"Xu","year":"2018","journal-title":"Inflamm. Res. Off. J. Eur. Histamine Res. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.3892\/mmr.2014.3001","article-title":"Piperlongumine attenuates collagen-induced arthritis via expansion of myeloid-derived suppressor cells and inhibition of the activation of fibroblast-like synoviocytes","volume":"11","author":"Sun","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.3389\/fphar.2019.01188","article-title":"Phillyrin Attenuates Osteoclast Formation and Function and Prevents LPS-Induced Osteolysis in Mice","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1749-6632.2011.06283.x","article-title":"The osteoclast and its unique cytoskeleton","volume":"1240","author":"Teitelbaum","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, P., Shang, G.Q., Xiang, S., Zhang, H.N., Wang, Y.Z., and Xu, H. (2021). Zoledronic acid and teriparatide have a complementary therapeutic effect on aseptic loosening in a rabbit model. BMC Musculoskelet. Disord., 22.","DOI":"10.1186\/s12891-021-04458-4"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115471","DOI":"10.1016\/j.bone.2020.115471","article-title":"Epigenetic and transcriptional regulation of osteoclast differentiation","volume":"138","author":"Kurotaki","year":"2020","journal-title":"Bone"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"706","DOI":"10.14348\/molcells.2017.0225","article-title":"Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation","volume":"40","author":"Park","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_30","first-page":"204","article-title":"Osteoclastogenesis\u2014Current knowledge and future perspectives","volume":"8","author":"Yavropoulou","year":"2008","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5762","DOI":"10.1111\/jcmm.14492","article-title":"Dehydrocostus lactone attenuates osteoclastogenesis and osteoclast-induced bone loss by modulating NF-\u03baB signalling pathway","volume":"23","author":"Hu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kwak, S.C., Cheon, Y.H., Lee, C.H., Jun, H.Y., Yoon, K.H., Lee, M.S., and Kim, J.Y. (2020). Grape Seed Proanthocyanidin Extract Prevents Bone Loss via Regulation of Osteoclast Differentiation, Apoptosis, and Proliferation. Nutrients, 12.","DOI":"10.3390\/nu12103164"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/jcp.29978","article-title":"Carnosol suppresses RANKL-induced osteoclastogenesis and attenuates titanium particles-induced osteolysis","volume":"236","author":"Li","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4741","DOI":"10.2147\/DDDT.S334421","article-title":"Inhibition of Lipopolysaccharide-Induced Inflammatory Bone Loss by Saikosaponin D is Associated with Regulation of the RANKL\/RANK Pathway","volume":"15","author":"Wu","year":"2021","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1159\/000371845","article-title":"The RANKL-RANK Story","volume":"61","author":"Nagy","year":"2015","journal-title":"Gerontology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4317","DOI":"10.1242\/jcs.00082","article-title":"JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms","volume":"115","author":"David","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jcb.10503","article-title":"Phosphatidylinositol 3-kinase coordinately activates the MEK\/ERK and AKT\/NFkappaB pathways to maintain osteoclast survival","volume":"89","author":"Gingery","year":"2003","journal-title":"J. Cell. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1210\/endo.143.8.8954","article-title":"p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function","volume":"143","author":"Li","year":"2002","journal-title":"Endocrinology"},{"key":"ref_39","first-page":"371","article-title":"TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB","volume":"35","author":"Lee","year":"2002","journal-title":"J. Biochem. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00774-008-0026-6","article-title":"Inhibition of the classical NF-kappaB pathway prevents osteoclast bone-resorbing activity","volume":"27","author":"Soysa","year":"2009","journal-title":"J. Bone Miner. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00418-018-1636-2","article-title":"Recent advances in osteoclast biology","volume":"149","author":"Ono","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1016\/j.ajpath.2015.06.017","article-title":"MAGED1 is a negative regulator of bone remodeling in mice","volume":"185","author":"Liu","year":"2015","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2868\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:32:48Z","timestamp":1760135568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2868"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,5]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052868"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052868","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,5]]}}}