Nmp4/CIZ对成骨细胞功能的调节作用

Regulatory Role of Nmp4/CIZ in Osteoblasts

核基质蛋白4(nuclear matrix protein,Nmp4),亦称p130cas结合锌指蛋白(cas-interacting zinc finger protein,CIZ),是一种位于细胞核及粘附斑且具有核质穿梭功能的转录调控因子.体内实验证明,Nmp4/CIZ抑制骨形成活性进而抑制骨密度和骨量增加,而对骨吸收参数无显著影响.Nmp4/CIZ通过特异性结合成骨细胞Ⅰ型胶原α1链和基质金属蛋白酶启动子上游调控序列,调节其转录表达,促进骨转换.此外,Nmp4/CIZ抑制骨形态蛋白和甲状旁腺激素诱导的成骨细胞分化,抑制成骨细胞增殖并促进凋亡发生.Nmp4/CIZ参与调节成骨细胞力学-化学信号转导,其表达沉默可抑制尾悬吊诱导的小鼠骨量减少,并促进流体剪切力诱导的成骨细胞β-catenin信号途径.这些体内外实验证据表明,Nmp4/CIZ主要通过负调控机制发挥作用,提示这是一个潜在的骨丢失治疗药物靶点.

Nuclear matrix protein 4 （Nmp4）,also identified as cas-interacting zinc finger protein （CIZ）,is a transcription factor localized at the focal adhension sites and also in the nucleus.Nmp4 /CIZ reduces bone mineral density （BMD） and bone mass by inhibiting bone formation in vivo,but not affecting bone resorption parameters.Through binding to the upstream regulatory regions of type I collagen and matrix metalloproteinase promoters,Nmp4 /CIZ inhibits synthesis of type I collagen and upregulates expression of matrix metalloproteinases,thereby accelerates the bone turnover.Nmp4 /CIZ suppresses proliferation and promotes apoptosis of osteoblasts,also downregulates the differentiation of osteoblasts induced by bone morphogenic protein and parathyroid hormone.The bone mass loss induced by tail suspension was significantly attenuated in Nmp4 knockout （Nmp4-KO） mice compared to those of the widetype （WT） controls.In addition,the Nmp4-deficiency promoted the flow shear stress-induced βcatenin signaling pathway in osteoblasts.These suggested that Nmp4 /CIZ was an important molecule to regulate the mechanotransduction in bone cells and susceptible to the changes in the mechanical environment.Both in vivo and in vitro experimental results demonstrated that Nmp4 /CIZ acted as a negative regulator and could be a potential novel drug target to resist osteoporosis or bone loss.