# PTH receptor Signaling and Diabetes-induced Bone Disease

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2023 · —

## Abstract

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/βcatenin antagonists on the skeletal deterioration induced by S-DM or HFD-
DM, by investigating whether mice lacking Sost, Dkk1, or both in osteocytes ...

## Key facts

- **NIH application ID:** 10695925
- **Project number:** 5I01BX002104-11
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** Teresita M. Bellido
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695925

## Citation

> US National Institutes of Health, RePORTER application 10695925, PTH receptor Signaling and Diabetes-induced Bone Disease (5I01BX002104-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695925. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*