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BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD

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Recent advances in bone biology, to which research of my laboratory in part supported by the VA have significantly contributed, demonstrate that osteocytes (the most abundant bone cells) play a critical role in bone homeostasis by regulating the production and activity of osteoblasts and osteoclasts, the cells that form or dissolve bone, respectively. However, less is known about the function of osteocytes in bone pathophysiology. Our work showed that osteocytes are crucial target cells of parathyroid hormone (PTH) action and that activation of PTH 1 receptor (PTH1R) signaling in osteocytes increases bone formation and enhances bone remodeling, recognized features of PTH skeletal action. Osteocytic PTH1R signaling decreases the expression of Sost/sclerostin, an osteocyte-derived inhibitor of bone formation, and increases the expression of RANKL, the master inducer of osteoclast differentiation. We also showed that mice lacking the PTH1R in osteocytes exhibit decreased resorption and defective anabolic response to PTH. In more recent work, we established that the low bone mass and inferior mechanical and material properties exhibited by mice with diabetes mellitus (DM) is accompanied by decreased formation, increased resorption, and increased bone marrow adipocytes (BMAT), along with increased osteocyte apoptosis and high expression of Sost/sclerostin. Further, treatment of DM mice with a PTH related protein (PTHrP)-derived peptide (1-37), which acts through the PTH1R, corrected these changes, and activated survival signaling preventing osteocyte apoptosis. The long term goal of this research is to determine the potential of targeting osteocytes and their products for treating bone maladies. The specific goal of this proposal is to unveil the mechanisms underlying protection of skeletal deterioration by PTH1R signaling in DM. Our hypothesis is that activating PTH1R signaling in osteocytes PTH or abaloparatide (FDA-approved bone anabolic agents) counteracts the damaging actions of DM in bone by regulating osteocyte-derived factors, thus maintaining bone mass and strength, preserving osteocyte viability, and reducing BMAT. This hypothesis will be tested using murine models of established type 1 and type 2 DM, associated with low versus high insulinemia, respectively, and using pharmacologic and genetic tools to activate or inhibit PTH1R signaling, and to interfere with osteocytic gene products. We will pursue the following aims: Aim 1 will examine whether pharmacologic activation of PTH1R signaling with PTH or abaloparatide restores bone mass and strength in type 1 and type 2 DM mouse models (in inbred C57BL/6 and outbred Swiss Webster strains); and reveal underlying cellular and molecular mechanisms. Aim 2 will examine osteocyte contribution to PTH1R signaling protective action on DM bone disease, by investigating the effect of PTH or abaloparatide DM mice and control mice with deletion of the PTH1R in osteocytes (DMP1-8kb-Cre). And Aim 3 will examine the role of osteocyte-derived Wnt/?catenin antagonists on the skeletal deterioration induced by DM, by investigating whether mice lacking Sost, Dkk1, or both in osteocytes (Sostf/f; Dkk1f/f; DMP1-8kb-Cre) or mice expressing the LRP5 high bone mass mutation pG171V (resistant to Sost- and Dkk1-mediated inhibition of Wnt-?catenin signaling) are protected from the damaging effects of DM in bone.

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