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.