TNF-α通过影响circHmbox1/microRNA-1247-5p/mRNA调控轴参与绝经后骨质疏松发生的机制研究

TNF-α促进破骨细胞分化是绝经后骨质疏松（PMOP）骨丢失的重要原因。我们前期发现，TNF-α增加了破骨细胞中circHmbox1的表达并促使其分泌富含circHmbox1的外泌体；circHmbox1能够与miR-1247-5p结合参与TNF-α促进破骨细胞形成，而富含circHmbox1的外泌体抑制了成骨细胞分化。因此，推测TNF-α可能通过circHmbox1/miR-1247-5p/mRNA调控轴直接或间接调节破骨细胞及成骨细胞分化。本研究拟通过体内和体外实验，结合分子生物学及生物信息学技术，确定circHmbox1在TNF-α直接或间接调节破骨细胞及成骨细胞分化中的作用；明确TNF-α通过circHmbox1/miR-1247-5p/mRNA调控轴调节破骨细胞及成骨细胞分化的分子机制；验证circHmbox1作为PMOP功能性靶点潜在应用性。本研究有助于阐释PMOP的发病机制。

The increasing of TNF-αlevel is associated with PMOP in postmenopausal women. Studies showed that TNF-α-induced osteoclastogenesis is a leading cause of bone loss in PMOP, but which mechanisms are not fully elucidated. We previously studies showed that TNF-αcould increase the expression of circHmbox1 in the cytoplasm of osteoclast and promote the production of exosomes-contained circHmbox1 by osteoclasts .Silencing of circHmbox1 could obviously alleviate TNF-α-induced osteoclastogenesis. The exosomes-contained circHmbox1 could inhibited osteoblasts differentiation. Further studies showed that microRNA-1247-5p bonding to circHmbox1 was involved in TNF-α-induced osteoclastogenesis. Thus, we speculated that TNF-αmay increase osteoclastogenesis through circHmbox1/miR-1247-5p/ mRNA axis and indirectly decrease osteoblasts differentiation through affecting circHmbox1/miR-1247-5p/mRNA axis by osteoclasts-derived exosomes-contained circHmbox1.To test this hypothesis, the experiments will be designed in vivo and in vitro. SiRNA and overexpression will be applied to further confirm that circHmbox1 is critical in TNF-α-mediated osteoclastogenesis and osteoblasts differentiation. Furthermore, the exact mechanisms of circHmbox1/miR-1247-5p/mRNA axis involved in TNF-α-mediated osteoclastogenesis and osteoblasts differentiation will be elucidated in this project. Moreover, whether circHmbox1 is a treatment potential target for PMOP will be tested. This study provides an important theoretical basis for clarifying the etiology of PMOP.