Osteocytes play a critical role in bone homeostasis by regulating the production and activity of osteoblasts and osteoclasts; but less is known about osteocyte function in bone pathophysiology. Work by the PI during the previous funding period of this Merit award showed that activation of parathyroid hormone 1 receptor (PTH1R) signaling in osteocytes inhibits the expression of Sost/sclerostin, the osteocyte-derived inhibitor of bone formation, and increases in osteocytes the expression of RANKL, the master inducer of osteoclast differentiation. Moreover, deletion of PTH-regulated domains in the RANKL promoter abolished resorption driven by PTH1R activation in osteocytes. Further, mice with osteocytic deletion of PTH1R exhibit decreased resorption and defective anabolic response to PTH. Work leading to this application also established that mice with diabetes mellitus induced by streptozotocin (S-DM) exhibit low bone mass and inferior mechanical and material properties; increased resorption, decreased formation, and increased bone marrow adipocytes (BMAT); as well as increased osteocyte apoptosis and high expression of Sost/sclerostin. Further, treatment of S-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. We hypothesize that PTH1R signaling in osteocytes activated by 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 two murine models of established type 1 and type 2 DM, S-DM and high fat diet (HFD-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 S-DM or HFD-DM mice (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 in S-DM, HFD-DM 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 S-DM or HFD- 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 S-DM and HFD-DM induced effects on bone.
This proposal addresses a significant health problem in the general population and in particular in the US Veteran community and their families. Diabetes Mellitus is a highly prevalent disease that affects 200 million people worldwide and has a very negative impact on the skeleton, with significant increases in bone fracture risk. There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes and to develop therapeutic approaches to treat diabetic bone fragility. Successful completion of the proposed studies will advance our understanding of the mechanisms by which osteocytes orchestrate bone remodeling in disease states, will open new avenues for developing therapeutic strategies to manage the damaging skeletal effects of diabetes by targeting osteocytes and their derived factors, and will provide new opportunities to develop precision medicine approaches that design the right therapy for specific patient needs.
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