MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway.
MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway.
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DOI：
10.1002/jbmr.2438
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Kobayashi T
中科院分区：
文献类型：
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作者：
Papaioannou G;Mirzamohammadi F;Lisse TS;Nishimori S;Wein MN;Kobayashi T
生长板软骨细胞经过多个分化步骤，最终成为肥大的软骨细胞。甲状旁腺激素(PTH)相关肽(PTHrP)信号通路在肥大分化的调控中起核心作用，至少部分是通过增强组蛋白脱乙酰基酶4(HDAC4)的活性，组蛋白脱乙酰基酶4是MEF2转录因子的负调控因子，推动肥厚分化。我们之前已经证明，软骨细胞特异性microRNA(MiRNA)miR-140的缺失会改变软骨细胞的分化，包括轻度加速肥大分化。在这里，我们提供了miR-140与PTHrP-HDAC4途径相互作用以控制软骨细胞分化的证据。在miR-140缺乏时，PTHrP或HDAC4的杂合性显著损害动物的生长，而这些突变在miR-140存在时没有影响。MIR-140缺失的软骨细胞表现出MEF2C的表达增加，而总的和磷酸化的HDAC4水平正常，这表明miR-140途径与PTHrP-HDAC4途径在MEF2C水平上合并。MIR-140负性调控p38丝裂原活化蛋白激酶(MAPK)信号转导，抑制P38 MAPK信号转导减少MEF2C的表达。这些结果表明，miR-140通过抑制MEF2C诱导的刺激来确保PTHrP/HDAC4调控系统的稳健性。
Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH)-related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte-specific microRNA (miRNA), miR-140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR-140 interacts with the PTHrP-HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR-140 deficiency, whereas these mutations had no effect in the presence of miR-140. miR-140–deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR-140 pathway merges with the PTHrP-HDAC4 pathway at the level of MEF2C. miR-140 negatively regulated p38 mitogen-activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR-140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C-inducing stimuli.