Blocking of the Ubiquitin-Proteasome System Prevents Inflammation-Induced Bone Loss by Accelerating M-CSF Receptor c-Fms Degradation in Osteoclast Differentiation.
Blocking of the Ubiquitin-Proteasome System Prevents Inflammation-Induced Bone Loss by Accelerating M-CSF Receptor c-Fms Degradation in Osteoclast Differentiation.
复制标题
DOI：
10.3390/ijms18102054
复制
发表时间：
2017-09-25
影响因子：
5.6
通讯作者：
Jeong D
中科院分区：
文献类型：
--
作者：
Lee K;Kim MY;Ahn H;Kim HS;Shin HI;Jeong D
已知遍在蛋白-蛋白酶体系统的阻断剂硼替佐米的抗骨质疏松活性通过成骨细胞增加骨形成和破骨细胞减少骨破坏的直接相反作用来实现。然而，蛋白酶体阻滞剂抑制破骨细胞分化和功能的机制尚未完全清楚。在这里，我们观察到破骨细胞中的蛋白酶体抑制剂，如MG 132和硼替佐米，加速了c-Fms（巨噬细胞集落刺激因子（M-CSF）的同源受体）的降解，并且不影响核因子κ-B受体激活剂（RANK）（核因子κ-B受体激活剂配体（RANKL）的受体）的量。蛋白酶体抑制剂诱导的c-Fms降解受p38/肿瘤坏死因子-α转化酶（TACE）介导的调节性膜内蛋白水解（RIPping）的激活控制。这通过使用p38和TACE的特异性抑制剂恢复c-Fms以及刺激p38依赖性TACE得到了验证。此外，通过蛋白酶体抑制的c-Fms降解完全阻断了M-CSF介导的内在信号传导，并导致破骨细胞分化和骨吸收的抑制。在腹腔内给予脂多糖（LPS）刺激破骨细胞形成并导致骨丢失的小鼠模型中，蛋白酶体阻断剂由于c-Fms阳性破骨细胞数量减少而阻止了LPS诱导的炎性骨吸收。我们的研究表明，通过蛋白酶体抑制剂加速c-Fms蛋白水解可能是炎症诱导的骨丢失的治疗选择。
Anti-osteoporotic activity of a blocker of the ubiquitin-proteasome system, bortezomib, has known to be achieved by directly opposed action in increased bone formation by osteoblasts and in decreased bone destruction by osteoclasts. However, the mechanisms underlying the proteasome blocker inhibition of osteoclast differentiation and function are not fully understood. Here, we observed that proteasome inhibitors, such as MG132 and bortezomib, in osteoclasts accelerated the degradation of c-Fms, a cognate receptor of macrophage colony-stimulating factor (M-CSF), and did not affect the amount of receptor activator of nuclear factor kappa-B (RANK), a receptor of receptor activator of nuclear factor kappa-B ligand (RANKL). c-Fms degradation induced by proteasome inhibitors was controlled by the activation of p38/tumor necrosis factor-alpha converting enzyme (TACE)-mediated regulated intramembrane proteolysis (RIPping). This was validated through the restoration of c-Fms using specific inhibitors of p38 and TACE, and a stimulation of p38-dependent TACE. In addition, c-Fms degradation by proteasome inhibition completely blocked M-CSF-mediated intrinsic signalling and led to the suppression of osteoclast differentiation and bone resorption. In a mouse model with intraperitoneal administration of lipopolysaccharide (LPS) that stimulates osteoclast formation and leads to bone loss, proteasome blockers prevented LPS-induced inflammatory bone resorption due to a decrease in the number of c-Fms-positive osteoclasts. Our study showed that accelerating c-Fms proteolysis by proteasome inhibitors may be a therapeutic option for inflammation-induced bone loss.
登录
查看更多内容
影响因子：
11.4
作者：
CARLBERG, K;TAPLEY, P;ROHRSCHNEIDER, L
通讯作者：
ROHRSCHNEIDER, L
影响因子：
4.1
作者：
Killock, David J.;Ivetic, Aleksandar
通讯作者：
Ivetic, Aleksandar
影响因子：
2.7
作者：
Huang Hongming;Hou Han
通讯作者：
Hou Han
影响因子：
20.3
作者：
Giuliani, Nicola;Morandi, Francesca;Rizzoli, Vittorio
通讯作者：
Rizzoli, Vittorio
DOI：
10.1186/ar86
发表时间：
2000
期刊：
Arthritis research
影响因子：
--
作者：
Kinne RW;Bräuer R;Stuhlmüller B;Palombo-Kinne E;Burmester GR
通讯作者：
Burmester GR