ABSTRACTOsteocytes are bone matrix-entombed cells that form an interconnected network of processes called the lacunar/canalicular system, which enables osteocytes to coordinate bone formation and resorption. Osteocytes indirectly regulate osteoblast and osteoclast activity on bone surfaces but also directly resorb and deposit their surrounding bone matrix through perilacunar/canalicular remodeling. However, the molecular mechanisms by which osteocytes control bone remodeling remain unclear. We previously reported that the transcriptional regulators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) promote bone acquisition in osteoblast-lineage cells. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8kb-DMP1-Cre. Osteocyte conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together impaired bone mechanical properties. YAP/TAZ deletion reduced osteoblast number and activity and increased osteoclast activity. In addition, YAP/TAZ deletion directly impaired osteocyte lacunar/canalicular network remodeling, reducing canalicular density, length, and branching, but did not alter lacunar size or shape. Further, consistent with recent studies identifying TGF-β signaling as a key inducer of perilacunar/canalicular remodeling through expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases Mmp13, Mmp14, and Cathepsin K. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced protease gene expression. Together, these data show that YAP and TAZ act downstream of TGF-β in osteocytes to control bone matrix accrual, organization, and mechanical properties indirectly by coordinating osteoblast/osteoclast activity and directly by regulating perilacunar/canalicular remodeling.
