Shen Jiawen, Chen Yuzhen, Pan Mingyue, Zhou Sirui, Xu Yukun, Liu Fubin, Qiu Tianxin, Li Dongxiao, Zhao Qing, Zhao Kewei
The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510378, China.
Department of Laboratory Medicine, Sichuan Provincial Women's and Children's Hospital, Chengdu, Sichuan 610045, China; Department of Laboratory Medicine, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan 610045, China.
Bone. 2025 Jul;196:117489. doi: 10.1016/j.bone.2025.117489. Epub 2025 Apr 14.
Osteoporosis (OP) is the most prevailing primary bone disease caused by the imbalance between bone resorption and formation. Rhizoma Drynariae-derived EV-like particles (RD-EVLP) perform the anti-osteoporosis effect by promoting the osteogenic differentiation of human bone marrow mesenchymal stem cells (h-BMSCs) which may be regulated by circular RNAs (circRNAs) and microRNAs (miRNAs). This study aimed to reveal the functional roles and mechanisms of the RD-EVLP regulating osteogenic differentiation of osteoporosis through the activation of hsa_circ_0001275 sponging miR-422a.
Notably, RD-EVLP isolated from fresh Rhizoma Drynariae via differential ultracentrifugation demonstrated three critical pharmacological attributes: (1) excellent biosafety profile with non-toxic and gastrointestinal stability, (2) bone-targeting specificity evidenced by femoral accumulation, and (3) potent anti-osteoporotic effects through promoting osteogenic differentiation in vivo. Meanwhile, RD-EVLP effectively internalized by h-BMSCs, enhanced proliferation of h-BMSCs, and promoted osteogenic differentiation and bone formation in vitro. For another, hsa_circ_0001275 and insulin like growth factor 1 receptor (IGF1R) expressions were upregulated while miR-422a expression was downregulated during osteogenic differentiation. Knockdown of hsa_circ_0001275 inhibited mineralized nodule formation. Moreover, miR-422a was a target of hsa_circ_0001275 and knockdown of miR-422a promoted mineralized nodule formation and greatly reinforced the expression of runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), osteocalcin (OCN). What's more, miR-422a suppressed h-BMSCs osteogenic differentiation by downregulating IGF1R. Finally, RD-EVLP promoted osteogenic differentiation by enhancing hsa_circ_0001275 and IGF1R while reducing miR-422a expression levels of h-BMSCs during osteogenic induction.
hsa_circ_0001275 could promote osteogenic differentiation by sponging miR-422a to upregulate IGF1R expression and RD-EVLP performed anti-OP activity through hsa_circ_0001275/miR-422a pathway.
骨质疏松症（OP）是由骨吸收与骨形成失衡导致的最常见的原发性骨病。骨碎补来源的细胞外囊泡样颗粒（RD-EVLP）通过促进人骨髓间充质干细胞（h-BMSCs）的成骨分化发挥抗骨质疏松作用，这一过程可能受环状RNA（circRNAs）和微小RNA（miRNAs）调控。本研究旨在揭示RD-EVLP通过激活hsa_circ_0001275海绵化miR-422a来调节骨质疏松症成骨分化的功能作用及机制。
值得注意的是，通过差速超速离心从新鲜骨碎补中分离得到的RD-EVLP具有三个关键药理学特性：（1）具有良好的生物安全性，无毒且在胃肠道稳定；（2）通过股骨蓄积证明具有骨靶向特异性；（3）在体内通过促进成骨分化具有强大的抗骨质疏松作用。同时，RD-EVLP能被h-BMSCs有效内化，增强h-BMSCs的增殖，并在体外促进成骨分化和骨形成。另一方面，在成骨分化过程中，hsa_circ_0001275和胰岛素样生长因子1受体（IGF1R）表达上调，而miR-422a表达下调。敲低hsa_circ_0001275可抑制矿化结节形成。此外，miR-422a是hsa_circ_0001275的靶标，敲低miR-422a可促进矿化结节形成，并显著增强 runt相关转录因子2（RUNX2）、骨形态发生蛋白2（BMP2）、骨钙素（OCN）的表达。而且，miR-422a通过下调IGF1R抑制h-BMSCs的成骨分化。最后，在成骨诱导过程中，RD-EVLP通过增强hsa_circ_0001275和IGF1R的表达，同时降低h-BMSCs的miR-422a表达水平来促进成骨分化。
hsa_circ_0001275可通过海绵化miR-422a上调IGF1R表达来促进成骨分化，且RD-EVLP通过hsa_circ_0001275/miR-422a途径发挥抗骨质疏松活性。
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