Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways
Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways
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DOI：
10.1016/j.bone.2006.09.011
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发表时间：
2007-02-01
期刊：
影响因子：
4.1
通讯作者：
Graves, Dana T.
中科院分区：
文献类型：
--
作者：
Alikhani, Mani;Alikhani, Zoubin;Graves, Dana T.
我们之前已经证明，糖尿病显著促进体内成骨细胞的凋亡，并且这种增强的凋亡有助于糖尿病损害新骨形成。一个潜在的机制是促进晚期糖基化终产物(AGEs)刺激的细胞凋亡。为了进一步研究这一点，体内注射了一种先进的糖基化产物-羧甲基赖氨酸修饰的胶原(CML-胶原)，并刺激了颅骨骨膜细胞的凋亡，比未修饰的胶原增加了5倍。还可诱导原代培养的人或新生大鼠成骨细胞或体外培养的MC3T3-E1细胞发生凋亡。此外，细胞凋亡作用主要是通过RAGE受体介导的。CML-胶原蛋白使p38和JNK活性分别增加3.2倍和4.4倍。抑制p38和JNK使CML-胶原刺激的细胞凋亡率分别减少45%和59%，联合应用时减少90%(P<；0.05)。CML-胶原诱导的细胞凋亡途径主要涉及caspase-8对caspase-3的激活，而不依赖于NF-kappaB的激活。当成骨细胞与CML-胶原长期低剂量孵育时，与短期孵育相比，有更高程度的凋亡。在分化程度较高的成骨细胞培养中，细胞凋亡进一步增强。这些结果表明，糖尿病和老年人体内积累的晚期糖基化终产物可能促进成骨细胞的凋亡，从而导致骨形成不足。(C)2006 Elsevier Inc.保留所有权利。
We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation end products (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen), was injected in vivo and stimulated a 5-fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2- and 4.4-fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P < 0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-kappa B activation. When osteoblastic cells were exposed to a long-term low dose incubation with CML-collagen, there was a higher degree of apoptosis compared to short-term incubation. In more differentiated osteoblastic cultures, apoptosis was enhanced even further. These results indicate that advanced glycation end products, which accumulate in diabetic and aged individuals, may promote apoptosis of osteoblastic cells and contribute to deficient bone formation. (c) 2006 Elsevier Inc. All rights reserved.