Blixt Nicholas C, Faulkner Bora K, Astleford Kristina, Lelich Rosemary, Schering Jacob, Spencer Ekaterina, Gopalakrishnan Rajaram, Jensen Eric D, Mansky Kim C
Departmment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, United States of America.
Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2017 Sep 27;12(9):e0185441. doi: 10.1371/journal.pone.0185441. eCollection 2017.
Histone deacetylases (HDACs) are negative regulators of transcription and have been shown to regulate specific changes in gene expression. In vertebrates, eighteen HDACs have thus far been identified and subdivided into four classes (I-IV). Key roles for several HDACs in bone development and biology have been elucidated through in vitro and in vivo models. By comparison, there is a paucity of data on the roles of individual HDACs in osteoclast formation and function. In this study, we investigated the gene expression patterns and the effects of suppressing individual class II (Hdac4, 5, 6, 9, and 10) and class IV (Hdac11) HDACs during osteoclast differentiation. We demonstrated that HDAC class II and IV members are differentially expressed during osteoclast differentiation. Additionally, individual shRNA-mediated suppression of Hdac4, 5, 9, 10 and 11 expression resulted in increased multinucleated osteoclast size and demineralization activity, with little to no change in the overall number of multinucleated osteoclasts formed compared with control shRNA-treated cells. We also detected increased expression of genes highly expressed in osteoclasts, including c-Fos, Nfatc1, Dc-stamp and Cathepsin K. These observations indicate that HDACs cooperatively regulate shared targets in a non-redundant manner.
组蛋白去乙酰化酶（HDACs）是转录的负调控因子，已被证明可调节基因表达的特定变化。在脊椎动物中，迄今为止已鉴定出18种HDACs，并将其分为四类（I-IV）。通过体外和体内模型已阐明了几种HDACs在骨骼发育和生物学中的关键作用。相比之下，关于单个HDACs在破骨细胞形成和功能中的作用的数据却很少。在本研究中，我们研究了破骨细胞分化过程中II类（Hdac4、5、6、9和10）和IV类（Hdac11）单个HDACs的基因表达模式及其抑制作用的影响。我们证明，HDAC II类和IV类成员在破骨细胞分化过程中差异表达。此外，单个shRNA介导的Hdac4、5、9、10和11表达抑制导致多核破骨细胞大小和脱矿活性增加，与对照shRNA处理的细胞相比，形成的多核破骨细胞总数几乎没有变化。我们还检测到破骨细胞中高表达的基因，包括c-Fos、Nfatc1、Dc-stamp和组织蛋白酶K的表达增加。这些观察结果表明，HDACs以非冗余方式协同调节共同的靶标。
