WNT4 acts downstream of BMP2 to mediate the regulation of ATRA signaling on RUNX1 expression: Implications for terminal differentiation of antler chondrocytes
WNT4 acts downstream of BMP2 to mediate the regulation of ATRA signaling on RUNX1 expression: Implications for terminal differentiation of antler chondrocytes
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WNT4 作用于 BMP2 下游，介导 ATRA 信号对 RUNX1 表达的调节：对鹿角软骨细胞终末分化的影响
DOI：
10.1002/jcp.25972
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发表时间：
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通讯作者：
Guo B
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作者：
Zhang HL;Yang ZQ;Duan CC;Geng S;Wang K;Yu HF;Yue ZP;Guo B
虽然全反式维甲酸参与调节软骨细胞的增殖和分化，但其潜在的机制尚不清楚。在这里，我们发现ATRA可以刺激鹿茸软骨细胞的增殖和COL X和MMP 13的表达，这是肥大软骨细胞的两个众所周知的标志物。CRABP 2的沉默阻止了ATRA对软骨细胞终末分化的诱导，而CRABP 2的过表达则表现出相反的效果。CYP 26 A1和CYP 26 B1降低了鹿茸软骨细胞对ATRA的敏感性。进一步分析表明，ATRA可能通过RARα/RXRα诱导软骨细胞终末分化并调节BMP 2、WNT 4和RUNX 1的表达。BMP 2的敲低增强了ATRA对COL X和MMP 13表达的诱导作用，而BMP 2的过表达废除了这种有效性。WNT 4可能介导ATRA和BMP 2对软骨细胞终末分化的影响。BMP-2表达异常可影响ATRA对WNT-4表达的调控。ATRA对转染RUNX 1 siRNA的鹿茸软骨细胞诱导分化失败。相反，rRUNX 1增强ATRA对COL X和MMP 13表达的刺激。同时，RUNX 1在软骨细胞终末分化中是BMP 2和WNT 4的下游效应子。此外，WNT 4可能在BMP 2和RUNX 1之间的串扰中起重要作用。BMP 2或WNT 4的减弱增强了ATRA与RUNX 1之间的相互作用，而BMP 2或WNT 4的组成性表达逆转了ATRA对RUNX 1的调节。总体而言，WNT 4可能作用于BMP 2的下游，通过靶向RUNX 1介导ATRA对鹿茸软骨细胞终末分化的影响。
Although ATRA is involved in regulating the proliferation and differentiation of chondrocytes, its underlying mechanism remains unknown. Here we showed that ATRA could stimulate the proliferation of antler chondrocytes and expression of COL X and MMP13 which were two well‐known markers for hypertrophic chondrocytes. Silencing of CRABP2 prevented the induction of ATRA on chondrocyte terminal differentiation, while overexpression of CRABP2 exhibited the opposite effects. CYP26A1 and CYP26B1 weakened the sensitivity of antler chondrocytes to ATRA. Further analysis evidenced that ATRA might induce chondrocyte terminal differentiation and modulate the expression of BMP2, WNT4, and RUNX1 through RARα/RXRα. Knockdown of BMP2 enhanced the induction of ATRA on the expression of COL X and MMP13, whereas overexpression of BMP2 abrogated this effectiveness. WNT4 might mediate the effects of ATRA and BMP2 on chondrocyte terminal differentiation. Dysregulation of BMP2 impaired the regulation of ATRA on WNT4 expression. Administration of ATRA to antler chondrocytes transfected with RUNX1 siRNA failed to induce the differentiation. Conversely, rRUNX1 strengthened the stimulation of ATRA on the expression of COL X and MMP13. Simultaneously, RUNX1 was a downstream effector of BMP2 and WNT4 in chondrocyte terminal differentiation. Moreover, WNT4 might play an important role in the crosstalk between BMP2 and RUNX1. Attenuation of BMP2 or WNT4 enhanced the interaction between ATRA and RUNX1, while constitutive expression of BMP2 or WNT4 reversed the regulation of ATRA on RUNX1. Collectively, WNT4 may act downstream of BMP2 to mediate the effects of ATRA on the terminal differentiation of antler chondrocytes through targeting RUNX1.