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

> **NIH VA IK6** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2020 · —

## Abstract

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 exam...

## Key facts

- **NIH application ID:** 10328422
- **Project number:** 7IK6BX004596-03
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** Teresita M. Bellido
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328422

## Citation

> US National Institutes of Health, RePORTER application 10328422, BLR&D Research Career Scientist Award Application for Teresita Bellido, PhD (7IK6BX004596-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328422. Licensed CC0.

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