WNT5A Regulates Chondrocyte Differentiation through Differential Use of the CaN/NFAT and IKK/NF-κB Pathways
WNT5A Regulates Chondrocyte Differentiation through Differential Use of the CaN/NFAT and IKK/NF-κB Pathways
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DOI：
10.1210/me.2010-0037
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发表时间：
2010-08-01
影响因子：
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通讯作者：
Drissi, M. Hicham
中科院分区：
文献类型：
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作者：
Bradley, Elizabeth W.;Drissi, M. Hicham
尽管遗传证据表明在软骨发育过程中对Wnt5a的要求很少，但对WNT5A调节的软骨细胞生长和分化的机制知之甚少。因此，我们研究了WNT5A影响软骨发生和分化与肥大的信号通路。 WNT5A治疗软骨元素细胞的处理增加了软骨细胞肥大，并且与活化T细胞的核因子（NFAT）的增加以及核因子-KAPPA B（NF-KAPPA B）激活有关。相反，WNT5A抑制软骨细胞肥大。肥大的抑制是随着相互信号的激活而发生的，因为观察到NFAT的降低和NF-kappa B激活的增加。此外，通过钙调蛋白激酶或NFAT的功能丧失阻止了软骨元基因细胞通过WNT5A处理的增加。此外，通过NF-kappa B的功能丧失，消除了观察到的软骨细胞肥大的抑制。 Wnt5a下游的NFAT途径的激活也对NF-KAPPA B活性负面调节，提供了这两种途径之间对抗的证据。从机械上讲，WNT5A通过钙调蛋白激酶 /NFAT依赖性SOX9的诱导来增加在早期的软骨细胞分化。相反，Wnt5a通过NF-kappa b依赖性runx2表达抑制软骨细胞肥大。这些数据表明，Wnt5a通过NFAT和NF-KAPPA B依赖性信号转导的差异利用，以阶段依赖性方式调节软骨生成和软骨细胞肥大。 （分子内分泌学24：1581-1593，2010）
Although genetic evidence demonstrated a requirement for Wnt5a during cartilage development, little is known about the mechanisms underlying Wnt5a-regulated chondrocyte growth and differentiation. We therefore investigated the signaling pathways by which Wnt5a influences chondrogenesis and differentiation to hypertrophy. Wnt5a treatment of chondroprogenitor cells increased chondrocyte hypertrophy and was associated with an increase in nuclear factor of activated T cells (NFAT) and a decrease in nuclear factor-kappa B (NF-kappa B) activation. In contrast, Wnt5a inhibited chondrocyte hypertrophy. This inhibition of hypertrophy occurred with the reciprocal signaling activation, in that a decrease in NFAT and an increase in NF-kappa B activation was observed. Furthermore, the increase in chondroprogenitor cell differentiation with Wnt5a treatment was blocked by calmodulin kinase or NFAT loss of function. In addition, the repression of chondrocyte hypertrophy observed was abrogated by NF-kappa B loss of function. Activation of the NFAT pathway downstream of Wnt5a also negatively regulated NF-kappa B activity, providing evidence of antagonism between these two pathways. Mechanistically, Wnt5a acts to increase chondrocyte differentiation at an early stage through calmodulin kinase /NFAT-dependent induction of Sox9. Conversely, Wnt5a represses chondrocyte hypertrophy via NF-kappa B-dependent inhibition of Runx2 expression. These data indicate that Wnt5a regulates chondrogenesis and chondrocyte hypertrophy in a stage-dependent manner through differential utilization of NFAT- and NF-kappa B-dependent signal transduction. (Molecular Endocrinology 24: 1581-1593, 2010)