HDAC4 is a class II histone deacetylation protein with a well-characterized role in chondrocyte differentiation and skeletal development, and dysregulated expression or haploinsufficiency of Hdac4 leads to skeletal formation and malformation disorders. The early lethality of hdac4 ablation mice hindered further investigation of its role in postnatal bone growth and development. Therefore, this study aims to investigate the significant role of Hdac4 in postnatal endochondral bone development using two mouse models with conditional deletion of Hdac4 in Sp7-expressing osteoprogenitors or chondrocytes and monitored postnatal bone development. The phenotype of Acan-CreERT2; Hdac4fl/fl mice largely resembled that of conventional Hdac4−/− mice. But phenotypic characterizations of mice with Hdac4 inactivation in Sp7-expressing osteoprogenitors (Sp7-Cre; Hdac4fl/fl) showed dwarfism with body and limb shortening and remarkable skeletal defects. Microcomputed tomography analysis of tibias further demonstrated that loss of Hdac4 expression impaired bone formation and microarchitecture, mainly characterized by dysplasia of trabecular and cortical bone in young mice. Our in vivo and in vitro data support a crucial role for Hdac4 in regulating osteoblast proliferation and differentiation, bone matrix protein production, angiogenesis, and ultimately trabecular and cortical bone formation. Moreover, RNA-seq analysis implicated Hdac4 in the regulation of key genes and pathways necessary to affect the accumulation of extracellular matrix, biological processes related to signal transduction, and skeletal growth. Collectively, our data show that postnatal expression of Hdac4 in Sp7-expressing osteoprogenitors provides essential regulatory oversight of endochondral bone formation, bone morphology, and homeostasis.

中文翻译：

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骨祖细胞中 Hdac4 的缺失会损害出生后小梁和皮质骨的形成，导致小鼠出现侏儒症和骨质减少表型


HDAC4 是一种 II 类组蛋白脱乙酰化蛋白，在软骨细胞分化和骨骼发育中具有明确的作用，Hdac4 的表达失调或单倍体不足会导致骨骼形成和畸形障碍。hdac4 消融小鼠的早期致死性阻碍了对其在出生后骨骼生长发育中的作用的进一步研究。因此，本研究旨在使用两种小鼠模型探讨 Hdac4 在出生后软骨内骨发育中的重要作用，这些小鼠模型在表达 Sp7 的骨祖细胞或软骨细胞中条件性缺失 Hdac4 并监测出生后骨骼发育。Acan-CreERT2 的表型;Hdac4fl/fl 小鼠在很大程度上类似于传统的 Hdac4 −/− 小鼠。但是在表达 Sp7 的骨祖细胞中具有 Hdac4 失活的小鼠的表型特征 （Sp7-Cre;Hdac4fl/fl）表现为侏儒症，体肢缩短，骨骼缺损明显。胫骨的显微计算机断层扫描分析进一步表明，Hdac4 表达的缺失损害了骨形成和微结构，主要以年轻小鼠小梁和皮质骨发育不良为特征。 我们的体内和 体外数据支持 Hdac4 在调节成骨细胞增殖和分化、骨基质蛋白产生、血管生成以及最终的小梁和皮质骨形成中起关键作用。此外，RNA-seq 分析表明 Hdac4 参与影响细胞外基质积累、与信号转导相关的生物过程和骨骼生长所必需的关键基因和通路的调节。 总的来说，我们的数据表明，Hdac4 在表达 Sp7 的骨祖细胞中的出生后表达为软骨内骨形成、骨形态和体内平衡提供了重要的调节监督。