铁蓄积影响骨细胞凋亡及Sclerostin、RANKL分泌在绝经后骨质疏松发病中的作用及机制研究

Iron accumulation is a risk factor for postmenopausal osteoporosis, however the pathogenesis mechanism is still elusive. Recent studies showed that osteocytes played a critically important role in bone metabolism. Bone remodeling started from apoptosis of osteocytes. The apoptosis osteocytes affect the differentiation of osteclast via secretion of RANKL, which further initiate the bone resorption; on the other hand, the apoptosis osteocytes have an influence in osteoblasts by secretion of sclerostin. However, until now, there was no study about the apoptosis of osteocytes and the bone remodeling mediated by osteocytes in iron accumulation environment. Our preliminary expriment indicated that ferric ion could regulate expression of sclerostin and RANKL in osteocytes, and the level of sclerostin and RANKL were significantly increased in iron accumulative bone/serum specimen. Therefore, this study tries to disclose the influence of iron accumulation on apoptosis of osteocytes and resultant bone remodeling alteration brought about by osteocytes from cells and mice model levels. Meanwhile, the protective effect of "bone seeking" iron chelator synthesised by our research team on osteocytes and bone tissue will be evaluated. This project might be favorable to further elucidate the pathogenesis mechanism of iron accumulation induced osteoporosis in postmenopausal women and provide new target for the prevention and treatment of such osteoporosis.

“铁蓄积”是女性绝经后骨质疏松发病的危险因素之一，但其致病机制仍然不清。近些年的研究认为骨细胞在骨代谢中承担了极其重要的作用。骨改建始于骨细胞凋亡，骨细胞凋亡后通过分泌核因子κB受体活化因子配体(RANKL)影响破骨细胞；另一方面，通过分泌骨硬化蛋白（Sclerostin）影响成骨细胞。然而，目前还没有铁蓄积环境下骨细胞凋亡及其介导的骨改建变化情况的相关报道。我们的预实验发现铁离子能够调控骨细胞Sclerostin和RANKL的表达，铁蓄积骨骼/血清标本中Sclerostin和RANKL含量明显增高。因此，本研究尝试在细胞和动物模型层面揭示“铁蓄积”对骨细胞的凋亡以及骨细胞介导的骨改建的影响，同时评价我们团队合成的“趋骨性”铁螯合剂对铁蓄积环境下骨细胞及骨组织的保护作用。本项目有利于揭示绝经后铁蓄积骨质疏松新的发病机制，以及为铁蓄积骨质疏松的防治提供新的靶点。

“铁蓄积”是女性绝经后骨质疏松发病的独立危险因素之一，但其致病机制仍然不清。近些年的研究认为骨细胞在骨代谢中承担了极其重要的作用。骨改建始于骨细胞凋亡，骨细胞凋亡后通过分泌核因子κB受体活化因子配体(RANKL)影响破骨细胞；另一方面，通过分泌骨硬化蛋白（Sclerostin）影响成骨细胞。本项目研究发现：(1)铁离子干预骨细胞后可提高骨细胞内活性氧，使骨细胞凋亡增加，通过JNK和ERK1/2信号通路上调骨细胞Sclerostin和RANKL/OPG表达;(2)铁蓄积环境下骨细胞作为骨代谢调控的中心环节，可抑制成骨细胞分化，同时促进破骨细胞分化；(3)通过繁殖Hepcidin敲除小鼠（Hep-/-）建立铁蓄积小鼠模型，利用趋骨性铁螯合剂SF-去铁胺（DFO）和抗氧化剂（NAC）干预铁蓄积小鼠，结果提示DFO和NAC可减少骨细胞凋亡，增加骨细胞数量，恢复骨细胞形态，从而促进铁蓄积环境下骨形成和抑制骨吸收，最终在一定程度上提高铁蓄积小鼠模型的骨密度、骨量、骨强度，部分恢复小鼠的骨结构。该研究揭示了骨细胞在铁蓄积骨质疏松发病过程中的中心环节作用，表明Sclerostin和RANKL/OPG改变是引起铁蓄积骨质疏松的主要分子机制，为研发铁蓄积骨质疏松新的防治方法提供了一定实验基础。