<br>使用 P7C3 作为针对绝经后骨质疏松症去卵巢大鼠模型骨质流失和脆性的对策的多功能治疗策略,Advanced Science

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使用 P7C3 作为针对绝经后骨质疏松症去卵巢大鼠模型骨质流失和脆性的对策的多功能治疗策略
Advanced Science ( IF 14.3 ) Pub Date : 2024-03-13 , DOI: 10.1002/advs.202308698
Fei Wei ₁ , Megan Hughes ₂ , Mahmoud Omer ₁ , Christopher Ngo _{1,

3} , Abinaya Sindu Pugazhendhi ₁ , Elayaraja Kolanthai ₄ , Matthew Aceto ₃ , Yasmine Ghattas ₃ , Mehdi Razavi _{1,

3} , Thomas J Kean _{1,

3} , Sudipta Seal _{1,

3,

4} , Melanie Coathup _{1,

3}

Affiliation

到 2060 年，估计有四分之一的美国人将是老年人。因此，骨质疏松症和脆性骨折的患病率也会增加。目前，没有可用的干预措施可以明确预防或控制骨质疏松症。本研究探讨了 Pool 7 化合物 3 (P7C3) 是否可以减少卵巢切除 (OVX) 诱发的骨质疏松症发生后进行性骨质流失和脆性。结果证实了 OVX 引起的骨质疏松、骨质疏松以及脂肪生成体重的显着增加。 P7C3 治疗显着降低了破骨细胞活性、骨髓肥胖、全身体重增加，并保留了骨面积、结构和机械强度。分析显示血小板衍生生长因子-BB 和白血病抑制因子显着上调，而白细胞介素-1 R6 和核因子 kappa-B (RANK) 受体激活剂下调。总之，蛋白质组数据表明，通过转化生长因子-β/SMAD 和 Wingless 相关整合位点/be-catenin 信号通路，靶向炎症、骨骼和脂肪周转的几个关键调节因子。据了解，这是通过 RANK 预防骨质流失干预措施的第一个证据。肠道微生物群的宏转录组分析显示，P7C3 增加了卟啉单胞菌科细菌、Candidatus Melainabacteria 和Ruminococcaceae细菌的丰度，可能有助于观察到的有利炎症和脂肪成骨代谢调节。结果揭示了一种尚未发现的多功能治疗策略，可以预防 OVX 诱导的骨质流失的病理进展。

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

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.

更新日期：2024-03-13

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