miR-103对成骨细胞成骨能力的调控及其在绝经后骨质疏松症中的病理作用

In the process of bone formation, osteoblasts undergo proliferation, differentiation and mineralization according to a certain law, and finally form the bone with special biological characteristics. A large number of literatures and our researches show that osteogenic potential of osteoblasts and bone formation are decreased after menopause, which lead to postmenopausal osteoporosis. However, the possible mechanisms underlying remain to be defined. Based on our previous study that miR-103 plays a negative role in the osteogenic potential of osteoblasts in the development of disuse osteoporosis, and a recent finding that miR-103 is up-regulated in femur and primary osteoblasts derived from osteoporotic postmenopausal mice and the expression of miR-103 is gradually down-regulated with the differentiation and maturation of osteoblasts, it is intriguing to hypothesize that miR-103 regulates osteogenic potential of osteoblasts in the development of postmenopausal osteoporosis. On this basis, the current study aims to investigate how miR-103 regulates osteogenic potential of osteoblasts in postmenopausal osteoporosis development; to unveil the possible mechanisms underlying; to reveal the role of miR-103 in the pathogenesis of postmenopausal osteoporosis; to explore the potential therapeutic strategies of miR-103 for postmenopausal osteoporosis. This findings would offer theoretical reflections on the molecular mechanism and pathogenesis of postmenopausal osteoporosis, as well as a deeper understanding on the development of therapeutic target to postmenopausal osteoporosis.

在骨形成过程中，成骨细胞按一定规律增殖和分化，并最终矿化形成具有特殊生物学特性的骨骼。大量文献和我们的研究证明，绝经后成骨细胞的成骨能力减弱，骨形成减少，引起绝经后骨质疏松症，但成骨细胞成骨能力减弱的机制尚未阐明。我们既往报道miR-103在废用性骨质疏松中对成骨细胞的功能具有负性调控作用，并在近期工作中发现miR-103在绝经后骨质疏松小鼠模型的股骨和成骨细胞中表达上调，且随着成骨细胞的分化成熟miR-103表达逐渐下降，提示miR-103可能通过调控成骨细胞的功能参与到绝经后骨质疏松症的病理过程。本课题拟在此基础上，深入研究miR-103对成骨细胞功能的调控规律及其分子机制，揭示miR-103在绝经后骨质疏松症中的病理作用，明确miR-103作为新靶点对绝经后骨质疏松症治疗的潜在价值。这些研究可拓展对绝经后骨质疏松症发病机制的认识，还可为其治疗提供新的思路，具有重要的理论和实际意义。

在骨形成过程中，成骨细胞按一定规律增殖和分化，并最终矿化形成具有特殊生物学特性的骨骼，在骨形成过程中发挥关键作用。而绝经后成骨细胞的成骨能力减弱，骨形成减少，但成骨细胞成骨能力减弱的机制尚未阐明。我们既往发现miR-103在废用性骨质疏松中对成骨细胞的功能具有负性调控作用，并在近期工作中发现miR-103在绝经后骨质疏松小鼠模型的股骨和成骨细胞中表达上调，且随着成骨细胞的分化成熟miR-103表达逐渐下降，提示miR-103可能通过调控成骨细胞的功能参与到绝经后骨质疏松症的病理过程。我们在此基础上，深入研究miR-103对成骨细胞功能的调控规律及其分子机制。结果发现：1、绝经后骨质疏松患者股骨样本、OVX小鼠股骨样本及原代成骨细胞分化过程中miR-103高表达，且与成骨指标呈负相关关系。2、miR-103能够在体和离体抑制成骨细胞功能并进一步抑制骨形成。3、miR-103通过功能性靶向m6A甲基化酶METTL14发挥对成骨细胞和骨形成的抑制作用。4、m6A甲基化酶METTL14能够正向调控成骨细胞的成骨功能，且能够反馈性抑制miR-103的生成。实验证实：在绝经后骨质疏松中miR-103/Mettl14/m6A轴通过负性调控成骨细胞成骨功能进而引起骨量减低。本研究初步揭示了miR-103在绝经后骨质疏松症中的病理作用，明确miR-103作为新靶点对绝经后骨质疏松症治疗的潜在价值，并且发现了绝经后骨质疏松症新的发病机制miR-103/Mettl14/m6A轴的负性调控作用，深化了对绝经后骨质疏松症发病机制的认识，丰富了相关的基础理论，为绝经后骨质疏松症的研究提供了有价值的参考和借鉴。