锂盐对Wnt通路的调控及掺锂盐多孔n-HA/胶原复合BMSCs治疗股骨头坏死研究

Osteonecrosis of the femoral head (ONFH) is a disease in which necrotic bone lesions usually progresses to femoral head collapse and sympatomatic hip arthritis; the disease mainly affects individuals in their thirty to sixty years of age. Theorectically, the necrotic bone can be repaired by the bone progenitor cells in the femoral head. However, it has been shown to be decreased in number and activity of bone marrow stromal cells (BMSCs) and osteoblasts(OBs) , and osteocytes and bone lining cells undego apoptosis. This altered bone remodeling can be responsible for the pathogenesis of osteonecrosis(ON): the apperance of ON itself, the insufficient bone repair, and its evolution to the subchondral fracture. This findings raised interest for pathophysiological appraoch of ON treatment by implantion of BMSCs in the necrotic lesion..Wnt signaling plays a vital role in the regulation proliferation and differentiation, and activites osteogenesis in BMSCs under certain cellular contexts. Canconial Wnt signaling promotes the osteoblastogenesis of puripotent mesenchymal and osteoprogenitor. Wnt signaling has been shown to reponse bone remodeling, a dynamic process that involves the resorption of the mineralized bone matrix by osteoclasts and sunsequently new bone foramtion by OBs. .Lithium is a mood stabilizing drug that affects embryonic development by altering cell fate and determination and pattern foramtion. Lithium inhibition of glycogen synthease kinase 3(GSK3) mimics the effects of canconical Wnt signaling. Activation of Wnt signaling leads to inhibition of GSK3 mediated phosphoxylation of a downstream transcription factor ?-catenin and prevents its sunsequent degradation by the preoteasome complex. Accumulation cytosolic ?-catenin then localizes to the nucleus and promotes the expression of genes regulated by Lef-Tcf transcription factor. .The synergism of stem cell biologiy and biomaterial technology promises to have a profound impact on stem cell-base clinical application for tissue regeneration. Biomaterials development is rapidly advancing display properties that, in a precise and physiological fashion, could drive stem cell fate both in vivo and in vitro. Thus, design a novel material is trying to recapitulate the molecular events involoved in the production, clearance and interaction of molecules within tissue in pathologic conditions and regeneration of tissue/organs..To improve the osteoblastic differentiation of BMSCs for the treatment of early stage ONFH, we planing to design a new biomaterial which is composed of the nano-hydroxyapatite(n-HA) and collagen fibers, and doped the lithium. The lithium-doped n-HA/collagen combined with BMSCs to treat the procollapsed ONFH. Lithium activites the Wnt signaling by inhibiting GSK3，and the Wnt signaling regulating BMSCs differentiation and now bone formtion to repair the osteonecrotic bone and provide the biomechanical support to prevent the femoral head collapse.

股骨头坏死（ONFH）发生、进展与局部骨髓基质细胞(BMSCs)和成骨细胞（OBs）数量、功能及活性下降密切相关。Wnt信号通路是调控BMSCs向OBs增殖、分化、成骨并抑制成脂及OBs、骨细胞凋亡及破骨细胞活性的关键通路。锂盐可促进成骨，抑制糖原合成激酶3β（GSK-3β）阻断其对Wnt通路关键因子β-catenin磷酸化被认为是锂盐激活Wnt信号通路、促进成骨的基础。基于干细胞生物特性和新型生物材料技术协同的组织工程，新型生物材料激活相关信号通路，调控BMSCs定向分化、增殖及活性表达，促进组织、器官的再生。本研究将多孔掺锂盐n-HA/胶原支架复合BMSC，研究锂盐对Wnt通路的激活及BMSCs成骨分化的调控；并植入股骨头,锂盐通过激活Wnt通路促进BMSCs向成骨细胞分化、成骨，修复ONFH死骨清除后的骨缺损、重建力学性能,获得良好的生物学和生物力学效果，避免股骨头塌陷、保留股骨头

股骨头坏死（ONFH）发生、进展与局部骨髓基质细胞(BMSCs)和成骨细胞（OBs） 数量、功能及活性下降密切相关。Wnt 信号通路是调控BMSCs 向OBs 增殖、分化、成骨并抑制成脂及OBs、骨细胞凋亡及破骨细胞活性的关键通路。锂盐可促进成骨，抑制糖原合成激酶3β （GSK-3β ）阻断其对Wnt 通路关键因子β -catenin 磷酸化被认为是锂盐激活Wnt 信号通路、促进成骨的基础。基于干细胞生物特性和新型生物材料技术协同的组织工程，新型生物材料激活相关信号通路，调控BMSCs 定向分化、增殖及活性表达，促进组织、器官的再生。本研究将多孔掺锂盐n-HA/胶原支架复合BMSC，研究锂盐对Wnt 通路的激活及BMSCs 成骨分化的调控；并植入股骨头,锂盐通过激活Wnt 通路促进BMSCs 向成骨细胞分化、成骨， 修复ONFH 死骨清除后的骨缺损、重建力学性能,获得良好的生物学和生物力学效果，避免股骨头塌陷、保留股骨头。