A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis

Abstract

By 2060, an estimated one in four Americans will be elderly. 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 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)‐induced osteoporosis. Results confirm OVX‐induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole‐body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor‐BB and leukemia inhibitory factor, with downregulation of interleukin‐1 R6, and receptor activator of nuclear factor kappa‐B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor‐beta/SMAD, and Wingless‐related integration site/be‐catenin 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 Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo‐osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX‐induced bone loss.

Gut microbiota, plasma metabolites, and osteoporosis: unraveling links via Mendelian randomization

“…Yadav et al found that reducing 5-HT levels with synthetic molecular inhibitors could effectively prevent bone loss typically induced by ovariectomy (OVX) ( Yadav et al, 2010 ). Several studies, reinforcing our findings, indicate that the genus Ruminococcaceae UCG014 plays a beneficial role in the management and improvement of OP ( Liu et al, 2020 ; Ling et al, 2021 ; Wei et al, 2024 ). This beneficial effect aligns with recent research on strontium (Sr), a bioactive element recognized for its potential to enhance bone quality ( Schrooten et al, 2003 ; Wornham et al, 2014 ).…”