Histone Deacetylase 7 (Hdac7) Suppresses Chondrocyte Proliferation and β-Catenin Activity during Endochondral Ossification
Histone Deacetylase 7 (Hdac7) Suppresses Chondrocyte Proliferation and β-Catenin Activity during Endochondral Ossification
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DOI：
10.1074/jbc.m114.596247
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发表时间：
2015-01-02
影响因子：
4.8
通讯作者：
Westendorf, Jennifer J.
中科院分区：
文献类型：
--
作者：
Bradley, Elizabeth W.;Carpio, Lomeli R.;Westendorf, Jennifer J.
背景：Hdac 7是骨骼组织中的转录辅阻遏物，但其在软骨细胞中的作用尚不清楚。结果如下：蛋白酶体降解降低了软骨形成成熟过程中的Hdac 7水平，软骨细胞中Hdac 7的条件性缺失增加了增殖和β-连环蛋白水平。结论：Hdac 7降解增强生长板软骨细胞β-catenin的转录活性。重要性：抑制Hdac 7水平增加软骨细胞增殖并促进软骨形成和再生。组蛋白去乙酰化酶（Hdacs）通过抑制基因转录和调节细胞对生长因子和细胞因子的反应来调节软骨内骨化。我们以前发现Hdac 7抑制Runx 2活性和成骨细胞分化。在这项研究中，我们研究了Hdac 7在出生后软骨细胞中的作用。hdac 7在生长板内的增殖细胞中高度表达。出生后的组织特异性消融Hdac 7与他莫昔芬诱导型胶原2a 1驱动的Cre重组酶增加增殖和-连环蛋白水平在生长板软骨细胞和扩大增殖区。在用腺病毒-Cre删除Hdac 7的原代软骨细胞培养物中获得了类似的结果。Hdac 7结合-连环蛋白在增殖的软骨细胞，但刺激软骨细胞成熟促进Hdac 7易位到细胞质中，它被降解的蛋白酶体。结果，β-连环蛋白水平和转录活性在细胞核中增加。这些数据表明Hdac 7抑制软骨细胞中的增殖和β-连环蛋白活性。降低早期软骨细胞中的Hdac 7水平可以促进软骨组织的扩张和再生。
Background: Hdac7 is a transcriptional co-repressor in skeletal tissues, but its role in chondrocytes is undefined. Results: Proteasomal degradation reduced Hdac7 levels during chondrogenic maturation and conditional deletion of Hdac7 in chondrocytes increased proliferation and -catenin levels. Conclusion: Hdac7 degradation enhances -catenin transcriptional activity in growth plate chondrocytes. Significance: Suppressing Hdac7 levels increases chondrocyte proliferation and promotes cartilage formation and regeneration.Histone deacetylases (Hdacs) regulate endochondral ossification by suppressing gene transcription and modulating cellular responses to growth factors and cytokines. We previously showed that Hdac7 suppresses Runx2 activity and osteoblast differentiation. In this study, we examined the role of Hdac7 in postnatal chondrocytes. Hdac7 was highly expressed in proliferating cells within the growth plate. Postnatal tissue-specific ablation of Hdac7 with a tamoxifen-inducible collagen type 2a1-driven Cre recombinase increased proliferation and -catenin levels in growth plate chondrocytes and expanded the proliferative zone. Similar results were obtained in primary chondrocyte cultures where Hdac7 was deleted with adenoviral-Cre. Hdac7 bound -catenin in proliferating chondrocytes, but stimulation of chondrocyte maturation promoted the translocation of Hdac7 to the cytoplasm where it was degraded by the proteasome. As a result, -catenin levels and transcription activity increased in the nucleus. These data demonstrate that Hdac7 suppresses proliferation and -catenin activity in chondrocytes. Reducing Hdac7 levels in early chondrocytes may promote the expansion and regeneration of cartilage tissues.