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Considering estrogen is the main variable, we assumed that estrogen participated in this alteration. To determine whether and how estrogen contributes to the change of the M1\/M2 ratio, we first isolated bone marrow macrophages (BMMs) from mice femur and stimulated the cells with lipopolysaccharide (LPS)\/interferon \u03b3 (IFN-\u03b3) for M1 polarization and interleukin 4 (IL-4)\/IL-13 for M2 polarization. M1 and M2 macrophages were then exposed to RANKL stimulation, we found that M2 macrophage but not M1 macrophage differentiated into functional osteoclast leading to increased M1\/M2 ratio. Intriguingly, 17\u03b2-estradiol (E2) pretreatment prevented osteoclastogenesis from M2 macrophages. By constructing shRNA lentivirus interfering the expression of different estrogen receptors in M2 macrophages, we found that estrogen protects M2 macrophage from receptor activator of nuclear factor \u03baB ligand (RANKL) stimulation selectively through estrogen receptor \u03b1 (ER\u03b1) and the downstream blockage of NF-\u03baB p65 nuclear translocation. Animal studies showed that ER\u03b1 selective agonist 4,4\u2032,4\u2033-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) was able to replicate the therapeutic effects of E2 in treating osteoporotic OVX mice. Together, our findings reveal that estrogen deficiency\u2013mediated M2 macrophage osteoclastogenesis leads to increased M1\/M2 ratio in OVX mice. Reducing the M1\/M2 ratio is a potential therapeutic target in treating postmenopausal osteoporosis. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3364","type":"journal-article","created":{"date-parts":[[2017,12,27]],"date-time":"2017-12-27T14:58:49Z","timestamp":1514386729000},"page":"899-908","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":162,"title":["Estrogen Deficiency\u2013Mediated M2 Macrophage Osteoclastogenesis Contributes to M1\/M2 Ratio Alteration in Ovariectomized Osteoporotic Mice"],"prefix":"10.1093","volume":"33","author":[{"given":"Ce","family":"Dou","sequence":"first","affiliation":[{"name":"Department of OrthopedicsSouthwest HospitalThird Military Medical UniversityChongqingChina"},{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunrong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyong","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of OrthopedicsSouthwest HospitalThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijie","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of OrthopedicsSouthwest HospitalThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of OrthopedicsSouthwest HospitalThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of OrthopedicsSouthwest HospitalThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwu","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of TraumaBurns and Combined InjuryThird Military Medical UniversityChongqingChina"},{"name":"Department of Biomedical Materials ScienceSchool of Biomedical EngineeringThird Military Medical UniversityChongqingChina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,12,27]]},"reference":[{"issue":"9319","key":"2024021014350414500_jbmr3364-bib-0001","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1016\/S0140-6736(02)08657-9","article-title":"Epidemiology and outcomes of osteoporotic fractures","volume":"359","author":"Cummings","year":"2002","journal-title":"Lancet"},{"issue":"2 Suppl 1","key":"2024021014350414500_jbmr3364-bib-0002","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.bone.2005.11.024","article-title":"Osteoporosis: a still increasing prevalence","volume":"38","author":"Reginster","year":"2006","journal-title":"Bone"},{"issue":"9","key":"2024021014350414500_jbmr3364-bib-0003","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1002\/jbmr.5650070902","article-title":"Perspective. 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