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The role of TGFβ Mediated Osteocytic Perilacunar/canalicular Remodeling in Age-related Bone Fragility


Age-related bone fragility results from the decline of both bone mass and quality over a lifetime. While therapies exist that focus on bolstering bone mass, little is known about the cellular and molecular mechanisms controlling bone quality (BQ). Osteocytes comprise 90-95% of all bone cells and regulate local quality through perilacunar/canalicular remodeling (PLR). However, little is known about their role in the age-related bone fragility. Aging in bone leads to several bone quality defects including uncoupling of bone deposition and resorption, alterations to bone material properties, and degeneration of the underlying osteocyte Lacuno/canalicular Network (LCN). While the coordinated decline of these behaviors remains unexplained the role of osteocytes in each of these processes implicate osteocytes in bone aging.Several hallmarks of aged bone also appear in bone from mice with limited transforming growth factor beta (TGF) signaling in osteocytes, including poor fracture resistance and degeneration of the osteocyte LCN. Loss of TGFβ signaling in osteocytes also results in decreased expression of PLR enzymes responsible for maintaining bone material properties. Thus, a similar phenotype arises with aging and with the losses to TGFβ signaling in osteocytes. However, the extent to which these similarities are mechanistically related remains unclear. This work outlines the study of PLR and tracks TGFβ signaling and PLR in osteocytes over a lifetime to uncover molecular and mechanical mechanisms partially responsible for age-related bone fragility. Identification of specific mechanical weaknesses, the molecular and chemical players behind them, and the cellular processes responsible for their emergence provide new therapeutic targets for improving bone quality and fracture resistance with age.

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