{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:06:00Z","timestamp":1792796760283,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Lianyungang City maternal and child health research project","award":["F202319"],"award-info":[{"award-number":["F202319"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1\u03b1 expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1\u03b1 gene, which, in turn, regulated HIF-1\u03b1 expression. Furthermore, the suppression of HIF-1\u03b1 abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4\u2019s inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.<\/jats:p>","DOI":"10.1038\/s41598-024-63219-0","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T18:03:11Z","timestamp":1717437791000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SPA inhibits hBMSC osteogenic differentiation and M1 macrophage polarization by suppressing SETD2 in acute suppurative osteomyelitis"],"prefix":"10.1038","volume":"14","author":[{"given":"Dongsheng","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjia","family":"Qiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"63219_CR1","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.2147\/JIR.S410339","volume":"16","author":"D Zhu","year":"2023","unstructured":"Zhu, D., Zhu, Z. & Qi, H. NEAT1\/microRNA 339\u20135p\/SPI1 axis feedback loop contributes to osteogenic differentiation in acute suppurative osteomyelitis in children. J. Inflamm. Res. 16, 2675\u20132687 (2023).","journal-title":"J. Inflamm. Res."},{"issue":"9","key":"63219_CR2","first-page":"1027","volume":"84","author":"J Hatzenbuehler","year":"2011","unstructured":"Hatzenbuehler, J. & Pulling, T. J. Diagnosis and management of osteomyelitis. Am. Fam. Phys. 84(9), 1027\u20131033 (2011).","journal-title":"Am. Fam. Phys."},{"key":"63219_CR3","doi-asserted-by":"publisher","DOI":"10.1136\/bcr.08.2008.0651","author":"RA Dunsmuir","year":"2009","unstructured":"Dunsmuir, R. A., McGarrity, G. & Barnes, S. \u201cGoalkeeper\u2019s hip\u201d: Acute haematogenous osteomyelitis secondary to apophyseal fractures. Case Rep. https:\/\/doi.org\/10.1136\/bcr.08.2008.0651 (2009).","journal-title":"Case Rep."},{"issue":"8","key":"63219_CR4","doi-asserted-by":"publisher","first-page":"e2885","DOI":"10.1097\/MD.0000000000002885","volume":"95","author":"A Brischetto","year":"2016","unstructured":"Brischetto, A., Leung, G., Marshall, C. S. & Bowen, A. C. A retrospective case-series of children with bone and joint infection from Northern Australia. Medicine 95(8), e2885 (2016).","journal-title":"Medicine"},{"key":"63219_CR5","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00932-19","author":"KL Urish","year":"2020","unstructured":"Urish, K. L. & Cassat, J. E. Staphylococcus aureus osteomyelitis: Bone, bugs, and surgery. Infect. Immun. https:\/\/doi.org\/10.1128\/IAI.00932-19 (2020).","journal-title":"Infect. Immun."},{"issue":"3","key":"63219_CR6","doi-asserted-by":"publisher","first-page":"276","DOI":"10.31486\/toj.18.0165","volume":"19","author":"S Solooki","year":"2019","unstructured":"Solooki, S., Hoveidaei, A. H., Kardeh, B., Azarpira, N. & Salehi, E. Xanthogranulomatous osteomyelitis of the Tibia. Ochsner J. 19(3), 276\u2013281 (2019).","journal-title":"Ochsner J."},{"key":"63219_CR7","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-023-04809-w","author":"Y Lin","year":"2023","unstructured":"Lin, Y. et al. Roles of extracellular vesicles on macrophages in inflammatory bone diseases. Mol. Cell. Biochem. https:\/\/doi.org\/10.1007\/s11010-023-04809-w (2023).","journal-title":"Mol. Cell. Biochem."},{"issue":"6","key":"63219_CR8","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1097\/SHK.0000000000001549","volume":"54","author":"H Deng","year":"2020","unstructured":"Deng, H. et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate LPS-induced ARDS by modulating macrophage polarization through inhibiting glycolysis in macrophages. Shock 54(6), 828\u2013843 (2020).","journal-title":"Shock"},{"issue":"7","key":"63219_CR9","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/cr.2015.68","volume":"25","author":"B Kelly","year":"2015","unstructured":"Kelly, B. & O\u2019Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25(7), 771\u2013784 (2015).","journal-title":"Cell Res."},{"issue":"8","key":"63219_CR10","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.4049\/jimmunol.1901246","volume":"204","author":"Z Wang","year":"2020","unstructured":"Wang, Z. et al. Zhx2 accelerates sepsis by promoting macrophage glycolysis via Pfkfb3. J. Immunol. 204(8), 2232\u20132241 (2020).","journal-title":"J. Immunol."},{"issue":"1","key":"63219_CR11","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/leu.2017.183","volume":"32","author":"G Martinelli","year":"2018","unstructured":"Martinelli, G. et al. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis. Leukemia 32(1), 139\u2013148 (2018).","journal-title":"Leukemia"},{"key":"63219_CR12","doi-asserted-by":"publisher","first-page":"10347","DOI":"10.1038\/ncomms10347","volume":"7","author":"Y Kim","year":"2016","unstructured":"Kim, Y. et al. Methylation-dependent regulation of HIF-1\u03b1 stability restricts retinal and tumour angiogenesis. Nat. Commun. 7, 10347 (2016).","journal-title":"Nat. Commun."},{"issue":"1","key":"63219_CR13","first-page":"331","volume":"18","author":"J Liu","year":"2019","unstructured":"Liu, J. et al. Loss of SETD2 induces a metabolic switch in renal cell carcinoma cell lines toward enhanced oxidative phosphorylation. J. Proteome Res. 18(1), 331\u2013340 (2019).","journal-title":"J. Proteome Res."},{"key":"63219_CR14","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.2147\/OTT.S191157","volume":"12","author":"J Mu","year":"2019","unstructured":"Mu, J., Fan, L., Liu, D. & Zhu, D. Overexpression of shugoshin1 predicts a poor prognosis for prostate cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Onco Targets Ther. 12, 1111\u20131118 (2019).","journal-title":"Onco Targets Ther."},{"issue":"7","key":"63219_CR15","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1021\/acsmedchemlett.2c00167","volume":"13","author":"JS Alford","year":"2022","unstructured":"Alford, J. S. et al. Conformational-design-driven discovery of EZM0414: A selective, potent SETD2 inhibitor for clinical studies. ACS Med. Chem. Lett. 13(7), 1137\u20131143 (2022).","journal-title":"ACS Med. Chem. Lett."},{"issue":"4","key":"63219_CR16","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1016\/j.ajpath.2012.07.005","volume":"181","author":"SA Horst","year":"2012","unstructured":"Horst, S. A. et al. A novel mouse model of Staphylococcus aureus chronic osteomyelitis that closely mimics the human infection: An integrated view of disease pathogenesis. Am. J. Pathol. 181(4), 1206\u20131214 (2012).","journal-title":"Am. J. Pathol."},{"key":"63219_CR17","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.bbrc.2021.08.086","volume":"577","author":"H Wen","year":"2021","unstructured":"Wen, H., Chen, Z., Cui, Y. & Xu, Y. LncRNA NONHSAT009968 inhibits the osteogenic differentiation of hBMMSCs in SA-induced inflammation via Wnt3a. Biochem. Biophys. Res. Commun. 577, 24\u201331 (2021).","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"1","key":"63219_CR18","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.jss.2013.06.063","volume":"185","author":"S Deshpande","year":"2013","unstructured":"Deshpande, S. et al. Reconciling the effects of inflammatory cytokines on mesenchymal cell osteogenic differentiation. J. Surg. Res. 185(1), 278\u2013285 (2013).","journal-title":"J. Surg. Res."},{"key":"63219_CR19","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.2147\/TCRM.S440996","volume":"19","author":"H Qi","year":"2023","unstructured":"Qi, H., Zhu, Z. & Zhu, D. Erythrocyte sedimentation rate for assisted diagnosis of pediatric osteomyelitis: A meta-analysis. Ther. Clin. Risk Manag. 19, 1039\u20131049 (2023).","journal-title":"Ther. Clin. Risk Manag."},{"issue":"2","key":"63219_CR20","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/s41564-019-0627-y","volume":"5","author":"SE Rowe","year":"2020","unstructured":"Rowe, S. E. et al. Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat. Microbiol. 5(2), 282\u2013290 (2020).","journal-title":"Nat. Microbiol."},{"key":"63219_CR21","doi-asserted-by":"publisher","first-page":"102004","DOI":"10.1016\/j.redox.2021.102004","volume":"43","author":"M Liu","year":"2021","unstructured":"Liu, M. et al. The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis. Redox Biol. 43, 102004 (2021).","journal-title":"Redox Biol."},{"issue":"9","key":"63219_CR22","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1002\/jcp.26429","volume":"233","author":"A Shapouri-Moghaddam","year":"2018","unstructured":"Shapouri-Moghaddam, A. et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 233(9), 6425\u20136440 (2018).","journal-title":"J. Cell. Physiol."},{"issue":"22","key":"63219_CR23","doi-asserted-by":"publisher","first-page":"12394","DOI":"10.1073\/pnas.1922211117","volume":"117","author":"AD Potter","year":"2020","unstructured":"Potter, A. D. et al. Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection. Proc. Natl. Acad. Sci. U. S. A. 117(22), 12394\u201312401 (2020).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"10","key":"63219_CR24","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1248\/bpb.b21-00457","volume":"44","author":"Q Chen","year":"2021","unstructured":"Chen, Q. et al. Norisoboldine attenuates sepsis-induced acute lung injury by modulating macrophage polarization via PKM2\/HIF-1\u03b1\/PGC-1\u03b1 pathway. Biol. Pharm. Bull. 44(10), 1536\u20131547 (2021).","journal-title":"Biol. Pharm. Bull."},{"key":"63219_CR25","doi-asserted-by":"publisher","first-page":"985467","DOI":"10.3389\/fcimb.2022.985467","volume":"12","author":"CA Ford","year":"2022","unstructured":"Ford, C. A. et al. Loss of Vhl alters trabecular bone loss during S. aureus osteomyelitis in a cell-specific manner. Front. Cell. Infect. Microbiol. 12, 985467 (2022).","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"2","key":"63219_CR26","doi-asserted-by":"publisher","first-page":"e2202937","DOI":"10.1002\/advs.202202937","volume":"10","author":"N Niu","year":"2023","unstructured":"Niu, N. et al. Tumor cell-intrinsic SETD2 deficiency reprograms neutrophils to foster immune escape in pancreatic tumorigenesis. Adv. Sci. 10(2), e2202937 (2023).","journal-title":"Adv. Sci."},{"key":"63219_CR27","doi-asserted-by":"publisher","first-page":"5281795","DOI":"10.1155\/2020\/5281795","volume":"2020","author":"Y Lu","year":"2020","unstructured":"Lu, Y. et al. The degree of Helicobacter pylori Infection affects the state of macrophage polarization through crosstalk between ROS and HIF-1\u03b1. Oxid. Med. Cell. Longev. 2020, 5281795 (2020).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"63219_CR28","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.bone.2017.04.004","volume":"101","author":"OH Sandberg","year":"2017","unstructured":"Sandberg, O. H., T\u00e4tting, L., Bernhardsson, M. E. & Aspenberg, P. Temporal role of macrophages in cancellous bone healing. Bone 101, 129\u2013133 (2017).","journal-title":"Bone"},{"key":"63219_CR29","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.biomaterials.2017.12.025","volume":"196","author":"J Pajarinen","year":"2019","unstructured":"Pajarinen, J. et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 196, 80\u201389 (2019).","journal-title":"Biomaterials"},{"issue":"12","key":"63219_CR30","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1016\/j.exphem.2009.09.004","volume":"37","author":"J Kim","year":"2009","unstructured":"Kim, J. & Hematti, P. Mesenchymal stem cell-educated macrophages: A novel type of alternatively activated macrophages. Exp. Hematol. 37(12), 1445\u20131453 (2009).","journal-title":"Exp. Hematol."},{"issue":"1","key":"63219_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2013.135","volume":"46","author":"DI Cho","year":"2014","unstructured":"Cho, D. I. et al. Mesenchymal stem cells reciprocally regulate the M1\/M2 balance in mouse bone marrow-derived macrophages. Exp. Mol. Med 46(1), e70 (2014).","journal-title":"Exp. Mol. Med"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63219-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63219-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63219-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T18:06:34Z","timestamp":1717437994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63219-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,3]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["63219"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-63219-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,3]]},"assertion":[{"value":"7 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12728"}}