雌激素受体ERβ在青春期脊柱椎体线性生长中的作用及机制研究

Spinal deformity,with high morbidity and disability, is difficult to be treated clinically. Studies have shown that The development of spinal deformity was associated with vertebral linear growth. Data also demonstrated that vertebral body growth and development involved in estrogen was regulated by TGF-β and RANKL signaling pathways. But the mechanism is still unclear. Our previous studies have shown that ERβ can induce osteoblast proliferation and differentiation, affecting the linear growth of vertebral body; Accordingly, we hypothesize that ERβ-specific binding to estrogen can stimulate activation of ERK signaling, induce the transformation and proliferation of the vertebral epiphyseal plate chondrocytes into osteoblasts by Smads- mediated activation of the TGF-β/Smads/runt and RANKL/RANK/ OPG pathways, regulating the spinal vertebrae linear growth. Our approach is that ERβ-shRNA gene silencing retroviral vectors were built with the RNAi technology, and transfected into chondrocytes and osteoblasts of mice. ERβ-shRNA cell models or animal models are established to observe the distribution of the ERβ in cell substructure, to explore osteoblasts and osteoclasts proliferation and differentiation and to research the regulation of signaling pathways and related cytokines. Expected, experiments may reveal the function of ERβ in regulating the linear growth of the adolescent vertebral spine in vitro and in vivo. to lay the foundation for candidate therapeutic targets, clinical decision-making and therapeutic markers.

脊柱畸形发病率、致残率高，是临床治疗的难点。研究表明，脊柱畸形的发生发展与椎体线性生长异常有关，而新近研究发现：椎体线性生长与雌激素作用有密切联系，但其具体机制尚不清楚。我们前期的研究已证明：雌激素受体ERβ可诱导成骨细胞增殖和分化，影响椎体线性生长。据此我们推论：雌激素与ERβ结合，调控ERK信号传递，经Smads介导，调控TGF-β/Smads /runt信号通路和RANKL/RANK/ OPG信号通路的活性，影响椎体骺板软骨细胞向成骨细胞转化和增殖，进而调控脊柱椎体线性生长。为进一步探索其机制，我们拟采用RNAi技术，建立ERβ沉默细胞模型和动物模型，并用ERβ表达载体转染基因敲除小鼠，于体外和体内分别研究ERβ对关键信号因子的调控，观察椎体生长板软骨细胞转化情况，以期揭示ERβ在青春期椎体线性生长中的作用及机制，为脊柱畸形候选治疗靶点、诊疗标记物和临床决策的研究奠定基础。

脊柱畸形发病率、致残率高，是临床治疗的难点。研究表明，脊柱畸形的发生发展与椎体线性生长异常有关，而新近研究发现：椎体线性生长与雌激素作用有密切联系，但其具体机制尚不清楚。 我们前期的研究已证明： 雌激素受体ERβ可诱导成骨细胞增殖和分化，影响椎体线性生长。据此我们推论：雌激素与ERβ结合，调控ERK 信号传递，经Smads介导，调控TGF-β/Smads/runt 信号通路和RANKL/RANK/OPG信号通路的活性，影响椎体骺板软骨细胞向成骨细胞转化和增殖，进而调控脊柱椎体线性生长。为进一步探索其机制，我们拟采用 RNAi 技术，建立ERβ沉默细胞模型和动物模型，并用ERβ表达载体转染基因敲除小鼠，于体外和体内分别研究ERβ对关键信号因子的调控，观察椎体生长板软骨细胞转化情况，以期揭示ERβ在青春期椎体线性生长中的作用及机制，为脊柱畸形候选治疗靶点、诊疗标记物和临床决策的研究奠定基础。