microRNA regulation of osteocyte metabolism in bone remodeling

骨骼中的基质转换是通过骨骼重塑发生的，对于维持骨骼的动态平衡和 健康。骨细胞是嵌入在骨基质中的细胞，它通过以下两种方式直接调节骨重建 控制成骨细胞和破骨细胞的活性，并间接通过钩骨周围/小管重塑 (PLR)。骨重建中骨细胞调节成骨细胞和破骨细胞活性的能力 动态平衡是众所周知的，但许多问题仍然是关于骨细胞通过 PLR处于骨骼动态平衡或疾病状态。在PLR中，骨细胞直接吸收和沉积骨基质 围绕着它们的腔隙-小管网络(LCN)。事实上，转化生长因子β信号在骨细胞中的内在缺失 TβRIIOCY−/−小鼠导致PLR和骨骼质量缺陷。此外，来自RNASEQ的初步数据 TβRIIocy−/−骨表现出明显的线粒体功能障碍。然而，其潜在的分子机制 转化生长因子β是如何调控骨细胞线粒体功能和PLR的，目前还知之甚少。 其他细胞/组织中线粒体功能和新陈代谢的最知名的分子调节器之一 类型为microRNAs(MiRs)。MIR是内源性的非编码小RNA，有助于序列依赖 转录后基因调控和复杂生物过程的协同靶基因网络， 比如细胞新陈代谢。然而，miRs在介导骨细胞线粒体功能中的作用尚未见报道。 已经被探索过了。 该项目将检验成骨细胞转化生长因子β信号调节线粒体功能的假设。 一种依赖miRNA的机制，通过集中在一个microRNA簇miR-181a/b来控制骨细胞功能。Aim 1将决定miR-181a/b对骨细胞功能的需求。目标2将决定 MiR-181a/b调控骨细胞线粒体功能的程度。目标3将决定是否 转化生长因子β对线粒体功能的调节依赖于miR-181a/b。这项研究将有助于我们对 负责维持体内平衡PLR的机制，并可能帮助开发新的、 治疗或预防骨骼疾病的创新方法，包括由于骨骼引起的头面部骨骼疾病 重塑缺陷。

Matrix turnover in bone occurs through bone remodeling and is essential to maintaining bone homeostasis and health. Osteocytes, which are cells embedded in the bone matrix, regulate bone remodeling both directly by controlling the activity of osteoblasts and osteoclasts and indirectly through perilacunar/canalicular remodeling (PLR). The ability of osteocytes to regulate osteoblast and osteoclast activity in bone remodeling and homeostasis is well known, but many questions remain about the direct role of osteocyte in remodeling via PLR in bone homeostasis or disease states. In PLR, osteocytes directly resorb and deposit bone matrix surrounding their lacuno-canalicular network (LCN). Indeed, osteocyte-intrinsic deletion of TGFβ signaling in TβRIIocy−/− mice causes defective PLR and bone quality. Furthermore, preliminary data from RNAseq of TβRIIocy−/− bone shows significant mitochondrial dysfunction. However, the underlying molecular mechanism of how TGFβ regulates mitochondrial function and PLR in osteocytes is currently poorly understood. One of the most well-known molecular regulators of mitochondrial function and metabolism in other cell/tissue types is microRNAs (miRs). miRs are endogenous, small non-coding RNAs that facilitate sequence-dependent post-transcriptional gene regulation and coordinately target gene networks of complex biological processes, such as cellular metabolism. However, the role of miRs in mediating osteocyte mitochondrial function has not been explored. This project will test the hypothesis that osteocytic TGFβ signaling regulates mitochondrial function via a miRNA-dependent mechanism to control osteocyte function by focusing on a microRNA cluster, miR-181a/b. Aim 1 will determine the requirement of miR-181a/b for osteocyte function. Aim 2 will determine the extent to which miR-181a/b regulate mitochondrial function in osteocytes. Aim 3 will determine whether the regulation of mitochondrial function by TGFβ is miR-181a/b-dependent. This study will aid our understanding of mechanisms responsible for maintaining homeostatic PLR and potentially aid in the development of new, innovative approaches to treat or prevent bone diseases, including in the craniofacial skeleton, due to bone remodeling defects.