Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation.
Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation.
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相反的 TNF-α/IL-1β 和 BMP-2 激活的 MAPK 信号通路汇聚在 Runx2 上，调节 BMP-2 诱导的成骨细胞分化
DOI：
10.1038/cddis.2014.101
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发表时间：
2014-04-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
在使用外源性骨形态发生蛋白 - 2（BMP - 2）治疗骨折或骨缺损的患者中，血清中肿瘤坏死因子 - α（TNF - α）和白细胞介素 - 1β（IL - 1β）等炎性细胞因子水平显著升高，这可能影响骨再生的结果。丝裂原活化蛋白激酶（MAPK）级联，如细胞外信号调节激酶1/2（ERK1/2）、p38和c - Jun氨基末端激酶1/2（JNK1/2）在成骨分化中起关键作用，并且可被BMP - 2以及TNF - α/IL - 1β激活。然而，先前的研究表明，BMP - 2和TNF - α/IL - 1β在成骨细胞分化中的作用是相反的。在此，我们研究了在BMP - 2和TNF - α/IL - 1β共存的条件下MAPK的确切作用。TNF - α/IL - 1β处理抑制了BMP - 2诱导的碱性磷酸酶活性、钙沉积、成骨转录因子Runx2以及C2C12和MC3T3 - E1细胞中成骨标志物的表达。这种抑制作用不依赖于经典的BMP/Smad通路，提示存在一种调节BMP - 2诱导的Runx2活性及后续成骨细胞分化的替代调控通路。然后我们证实，BMP - 2、TNF - α和IL - 1β分别可单独激活p38、ERK1/2和JNK1/2。然而，仅需抑制p38和ERK1/2信号通路即可调节BMP - 2诱导的Runx2表达。最后，我们确定TNF - α/IL - 1β通过激活p38和ERK1/2信号通路降低BMP - 2诱导的Runx2表达。此外，通过转染CA - MKK3或CA - MEK1强烈激活p38和ERK1/2信号通路，可抑制BMP - 2诱导的C2C12和MC3T3 - E1细胞中Runx2表达和成骨细胞分化。基于这些结果，我们得出结论：TNF - α/IL - 1β和BMP - 2激活的p38和ERK1/2信号通路具有相反的作用，它们汇聚于Runx2以调节成骨细胞分化。对这些机制的阐明可能会加速新策略的开发，并提高BMP - 2在临床上的骨诱导功效，以增强成骨细胞分化和骨形成。
In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.
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