PDF(Pubmed)
Abstract：
Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.
摘要：
破骨细胞过度激活,这取决于肌动蛋白动力学的戏剧性变化，骨质疏松症（OP）。破骨细胞激活与1型糖尿病（T1D）相关的OP的分子机制尚不清楚。胶质细胞成熟因子β(GMFB)被认为是神经胶质和神经元的生长和分化因子。这里,我们证明Gmfb缺乏通过抑制破骨细胞过度活动而有效改善大鼠T1D-OP表型。体外实验表明，GMFB参与了破骨细胞的活化而不是增殖。Gmfb缺乏不影响破骨细胞封闭区（SZ）的形成，但通过减少肌动蛋白解聚有效地减少了SZ面积。当GMFB在Gmfb缺陷型破骨细胞中过表达时，SZ区的大小以剂量依赖性方式增大.此外，肌动蛋白解聚减少导致核G-肌动蛋白减少，激活MKL1/SRF依赖性基因转录。我们发现，前破骨细胞因子（Mmp9和Mmp14）下调，而抗破骨细胞因子(Cftr和Fhl2)在GmfbKO破骨细胞中上调。一种GMFB抑制剂，获得靶向GMFB和Arp2/3的结合位点的DS-30。Biocore分析显示DS-30和GMFB之间的高亲和力呈剂量依赖性。不出所料,DS-30在体内和体外强烈抑制破骨细胞过度活跃。总之,我们的工作确定了T1D-OP治疗的新治疗策略.GMFB抑制剂的发现将有助于T1D-OP的转化研究。
