Although various anti-osteoporosis drugs are available, the limitations of these therapies, including drug resistance and collateral responses, require the development of novel anti-osteoporosis agents. Rhizoma Drynariae displays a promising anti-osteoporosis effect, while the effective component and mechanism remain unclear. Here, we revealed the therapeutic potential of Rhizoma Drynariae-derived nanovesicles (RDNVs) for postmenopausal osteoporosis and demonstrated that RDNVs potentiated osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) by targeting estrogen receptor-alpha (ER). RDNVs, a natural product isolated from fresh Rhizoma Drynariae root juice by differential ultracentrifugation, exhibited potent bone tissue-targeting activity and anti-osteoporosis efficacy in an ovariectomized mouse model. RDNVs, effectively internalized by hBMSCs, enhanced proliferation and ER expression levels of hBMSC, and promoted osteogenic differentiation and bone formation. Mechanistically, the ER signaling pathway, RDNVs facilitated mRNA and protein expression of bone morphogenetic protein 2 and runt-related transcription factor 2 in hBMSCs, which are involved in regulating osteogenic differentiation. Further analysis revealed that naringin, existing in RDNVs, was the active component targeting ER in the osteogenic effect. Taken together, our study identified that naringin in RDNVs displays exciting bone tissue-targeting activity to reverse osteoporosis by promoting hBMSCs proliferation and osteogenic differentiation through estrogen-like effects.

中文翻译：

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骨碎补衍生的纳米囊泡通过靶向 ERα 信号增强人骨髓间充质干细胞的成骨分化，从而逆转骨质疏松症

尽管有多种抗骨质疏松药物可用，但这些疗法的局限性，包括耐药性和附带反应，需要开发新型抗骨质疏松药物。骨碎补具有良好的抗骨质疏松作用，但其有效成分和机制尚不清楚。在这里，我们揭示了骨碎补衍生的纳米囊泡（RDNV）对绝经后骨质疏松症的治疗潜力，并证明RDNV通过靶向雌激素受体α（ER）增强人骨髓间充质干细胞（hBMSC）的成骨分化。RDNVs 是一种通过差速超速离心从新鲜骨碎补根汁中分离出来的天然产物，在卵巢切除小鼠模型中表现出有效的骨组织靶向活性和抗骨质疏松功效。RDNVs被hBMSCs有效内化，增强hBMSCs的增殖和ER表达水平，促进成骨分化和骨形成。从机制上讲，ER 信号通路、RDNV 促进 hBMSC 中骨形态发生蛋白 2 和 runt 相关转录因子 2 的 mRNA 和蛋白表达，参与调节成骨分化。进一步分析发现，RDNVs中存在的柚皮苷是成骨作用中靶向ER的活性成分。综上所述，我们的研究发现 RDNV 中的柚皮苷表现出令人兴奋的骨组织靶向活性，通过雌激素样作用促进 hBMSC 增殖和成骨分化，从而逆转骨质疏松症。