Transforming growth factor-β prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling
Transforming growth factor-β prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling
复制标题
DOI：
10.1152/ajpendo.00791.2007
复制
发表时间：
2008-04-01
影响因子：
5.1
通讯作者：
Marie, Pierre J.
中科院分区：
文献类型：
--
作者：
Dufour, Cecilie;Holy, Xavier;Marie, Pierre J.
机械负荷的丧失会导致成骨细胞生成减少和骨形成减少，从而导致快速的骨丢失。这种对骨骼代谢的有害影响所涉及的信号机制仍然知之甚少。我们先前已经证明，大鼠的后肢悬吊增加了成骨细胞的凋亡，并与磷脂酰肌醇3-激酶(PI3K)信号的减少有关。在这项研究中，我们研究了转化生长因子-β2是否可以阻止体内骨骼卸载引起的信号改变和成骨细胞的凋亡。后肢悬吊引起的骨体积减少与卸载骨中α(5)β(1)整合素蛋白水平和PI3K/Akt信号的降低有关。用渗透性微泵持续给予转化生长因子-β2，可阻止去负荷骨中α(5)-β(1)-整合素表达的降低和PI3K/Akt信号的降低，从而阻止成骨细胞的凋亡。我们还发现，转化生长因子-β2可阻止卸载引起的Bcl-2水平的降低，提示转化生长因子-β2通过PI3K/Akt靶向抑制去负荷骨中的成骨细胞的凋亡。此外，我们还发现，转化生长因子-β2阻止了由卸载引起的磷酸化Bad的减少，Bad是促凋亡蛋白Bad的非活性形式。这些结果表明，转化生长因子-β2可能通过α(5)-β(1)/PI3K/Akt信号通路及其下游的Bcl2和磷酸化Bad存活蛋白在机械负荷诱导的成骨细胞凋亡中发挥保护作用。因此，我们提出了一种新的作用，即转化生长因子-β2在体内保护卸载诱导的细胞凋亡。
Loss of mechanical loading induces rapid bone loss resulting from reduced osteoblastogenesis and decreased bone formation. The signaling mechanisms involved in this deleterious effect on skeletal metabolism remain poorly understood. We have previously shown that hindlimb suspension in rats increases osteoblast apoptosis associated with decreased phosphatidylinositol 3-kinase (PI3K) signaling. In this study, we investigated whether transforming growth factor (TGF)-beta 2 may prevent the altered signaling and osteoblast apoptosis induced by skeletal unloading in vivo. Hindlimb suspension-induced decreased bone volume was associated with reduced alpha(5)beta(1)-integrin protein levels and PI3K/Akt signaling in unloaded bone. Continuous administration of TGF-beta 2 using osmotic minipumps prevented the decreased alpha(5)beta(1)-integrin expression and the reduced PI3K/Akt signaling in unloaded bone, resulting in the prevention of osteoblast apoptosis. We also show that TGF-beta 2 prevented the decreased Bcl-2 levels induced by unloading, which suggests that TGF-beta 2 targets Bcl-2 via PI3K/Akt to prevent osteoblast apoptosis in unloaded bone. Furthermore, we show that TGF-beta 2 prevented the decrease in phosphorylated Bad, the inactive form of the proapoptotic protein Bad, induced by unloading. These results identify a protective role for TGF-beta 2 in osteoblast apoptosis induced by mechanical unloading via the alpha(5)beta(1)/PI3K/Akt signaling cascade and downstream Bcl-2 and phospho-Bad survival proteins. We thus propose a novel role for TGF-beta 2 in protection from unloading-induced apoptosis in vivo.