Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
Theranostics. 2024 Jun 24;14(10):3945-3962. doi: 10.7150/thno.95423. eCollection 2024.
NLRP3 inflammasome is critical in the development and progression of many metabolic diseases driven by chronic inflammation, but its effect on the pathology of postmenopausal osteoporosis (PMOP) remains poorly understood. We here firstly examined the levels of NLRP3 inflammasome in PMOP patients by ELISA. Then we investigated the possible mechanisms underlying the effect of NLRP3 inflammasome on PMOP by RNA sequencing of osteoblasts treated with NLRP3 siRNA and qPCR. Lastly, we accessed the effect of decreased NLRP3 levels on ovariectomized (OVX) rats. To specifically deliver NLRP3 siRNA to osteoblasts, we constructed NLRP3 siRNA wrapping osteoblast-specific aptamer (CH6)-functionalized lipid nanoparticles (termed as CH6-LNPs-siNLRP3). We found that the levels of NLRP3 inflammasome were significantly increased in patients with PMOP, and were negatively correlated with estradiol levels. NLRP3 knock-down influenced signal pathways including immune system process, interferon signal pathway. Notably, of the top ten up-regulated genes in NLRP3-reduced osteoblasts, nine genes (except Mx2) were enriched in immune system process, and five genes were related to interferon signal pathway. The results showed that CH6-LNPs-siNLRP3 was relatively uniform with a dimeter of 96.64 ± 16.83 nm and zeta potential of 38.37 ± 1.86 mV. CH6-LNPs-siNLRP3 did not show obvious cytotoxicity and selectively delivered siRNA to bone tissue. Moreover, CH6-LNPs-siNLRP3 stimulated osteoblast differentiation by activating ALP and enhancing osteoblast matrix mineralization. When administrated to OVX rats, CH6-LNPs-siNLRP3 promoted bone formation and bone mass, improved bone microarchitecture and mechanical properties by decreasing the levels of NLRP3, IL-1β and IL-18 and increasing the levels of OCN and Runx2. NLRP3 inflammasome may be a new biomarker for PMOP diagnosis and plays a key role in the pathology of PMOP. CH6-LNPs-siNLRP3 has potential application for the treatment of PMOP.
NLRP3 炎性小体在许多由慢性炎症驱动的代谢疾病的发展和进展中起着关键作用，但它对绝经后骨质疏松症 (PMOP) 的病理学影响仍知之甚少。我们首先通过 ELISA 检查了 PMOP 患者 NLRP3 炎性小体的水平。然后，我们通过用 NLRP3 siRNA 处理成骨细胞的 RNA 测序和 qPCR 研究了 NLRP3 炎性小体对 PMOP 的可能作用机制。最后，我们评估了 NLRP3 水平降低对去卵巢 (OVX) 大鼠的影响。为了将 NLRP3 siRNA 特异性递送至成骨细胞，我们构建了 NLRP3 siRNA 包裹成骨细胞特异性适体 (CH6)-功能化脂质纳米颗粒（称为 CH6-LNPs-siNLRP3）。我们发现，PMOP 患者的 NLRP3 炎性小体水平显着升高，并且与雌二醇水平呈负相关。NLRP3 敲低会影响信号通路，包括免疫系统过程、干扰素信号通路。值得注意的是，在 NLRP3 减少的成骨细胞中上调的前 10 个基因中，除 Mx2 外，有 9 个基因（除 Mx2 外）富集在免疫系统过程中，有 5 个基因与干扰素信号通路有关。结果表明，CH6-LNPs-siNLRP3 相对均匀，直径为 96.64 ± 16.83nm，zeta 电位为 38.37 ± 1.86mV。CH6-LNPs-siNLRP3 没有显示出明显的细胞毒性，并且可以选择性地将 siRNA 递送到骨组织。此外，CH6-LNPs-siNLRP3 通过激活 ALP 和增强成骨细胞基质矿化来刺激成骨细胞分化。当给予 OVX 大鼠时，CH6-LNPs-siNLRP3 通过降低 NLRP3、IL-1β 和 IL-18 的水平和增加 OCN 和 Runx2 的水平来促进骨形成和骨量、改善骨微结构和机械性能。NLRP3 炎性小体可能是 PMOP 诊断的新生物标志物，在 PMOP 的病理学中起着关键作用。CH6-LNPs-siNLRP3 具有治疗 PMOP 的应用潜力。
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