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Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3\u00a0(P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)\u2010induced osteoporosis. Results confirm OVX\u2010induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole\u2010body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor\u2010BB and leukemia inhibitory factor, with downregulation of interleukin\u20101 R6, and receptor activator of nuclear factor kappa\u2010B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor\u2010beta\/SMAD, and Wingless\u2010related integration site\/be\u2010catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased <jats:italic>Porphyromonadaceae<\/jats:italic> bacterium, Candidatus Melainabacteria, and <jats:italic>Ruminococcaceae<\/jats:italic> bacterium abundance, potentially contributing to the favorable inflammatory, and adipo\u2010osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX\u2010induced bone loss.<\/jats:p>","DOI":"10.1002\/advs.202308698","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T08:40:18Z","timestamp":1710319218000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7577-6143","authenticated-orcid":false,"given":"Fei","family":"Wei","sequence":"first","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Hughes","sequence":"additional","affiliation":[{"name":"School of Biosciences Cardiff University  Wales CF10 3AT UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Omer","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Ngo","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"},{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abinaya Sindu","family":"Pugazhendhi","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elayaraja","family":"Kolanthai","sequence":"additional","affiliation":[{"name":"Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC) University of Central Florida  Orlando FL 32826 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Aceto","sequence":"additional","affiliation":[{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Ghattas","sequence":"additional","affiliation":[{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Razavi","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"},{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Kean","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"},{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipta","family":"Seal","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"},{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"},{"name":"Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC) University of Central Florida  Orlando FL 32826 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Coathup","sequence":"additional","affiliation":[{"name":"Biionix Cluster University of Central Florida  Orlando FL 82816 USA"},{"name":"College of Medicine University of Central Florida  Orlando FL 32827 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.5152\/eurjrheum.2016.048"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-021-05900-y"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.5312\/wjo.v7.i3.171"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85006"},{"key":"e_1_2_10_5_1","first-page":"1990","volume":"13","author":"Shen Y.","year":"2022","journal-title":"Front. 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