# Osteocyte Control of Bone Remodeling

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $334,400

## Abstract

Abstract
Osteoclast formation depends on the cytokine receptor activator of NFB ligand (RANKL), whose actions are
inhibited by the decoy receptor osteoprotegerin (OPG). Osteocytes are an important source of RANKL and we
have recently shown that osteoblasts, but not osteocytes, are an essential source of the OPG that suppresses
resorption of cancellous bone. In contrast, osteoblasts and osteocytes provide only a portion of the OPG
protecting cortical bone. Thus, the identity of the cells providing the OPG that protects large regions of cortical
bone remains unclear, but may involve osteoblast progenitors and vascular endothelial cells, both of which
express OPG. Previous studies suggest that a major function of beta-catenin is to promote OPG expression in
osteocytes. Our finding that osteoblasts, but not osteocytes, are a major source of OPG necessitates a
reevaluation of the role of beta-catenin in osteocytes. Previous beta-catenin loss-of-function studies have been
hampered by the lack of Cre driver strains that can distinguish between osteoblasts and osteocytes and by the
dramatic bone loss caused by beta-catenin deletion in late-stage osteoblastic cells. That osteoblasts are an
important source of OPG also suggests that the rapid increase in resorption and rebound bone loss following
discontinuation of anti-RANKL (denosumab) therapy may be due, in part, to the absence of osteoblasts, and
thus OPG, during the period following discontinuation. Based on these findings, we propose the hypotheses
that osteoblast progenitors or vascular endothelial cells are important sources of the OPG protecting cortical
bone and that the beta-catenin pathway in osteocytes contributes to bone remodeling independent of its control
of OPG expression. We also propose that the lack of osteoblasts, and thus OPG, contributes to the rebound
resorption following discontinuation of denosumab. Aim 1 will identify cellular sources of OPG that control cortical
bone resorption by deleting a conditional OPG allele in mesenchymal progenitors using Prx1-Cre mice, and
vascular endothelial cells using Tek-Cre mice, and compare the effects on cortical bone to those seen in OPG-
null mice. Aim 2 will determine the role of beta-catenin in osteocytes by deletion of beta-catenin using Sost-Cre
mice, which delete target genes in osteocytes but not osteoblasts. Aim 3 will determine whether the rebound
resorption caused by discontinuation of denosumab results in part from the profound lack of osteoblasts
producing OPG using a novel humanized RANKL mouse line treated with denosumab. These mice will be used
to map the cellular and molecular conditions associated with discontinuation of denosumab and to determine
whether promotion of osteoblast formation via anti-sclerostin antibody administration can restore OPG levels
and ameliorate rebound resorption.

## Key facts

- **NIH application ID:** 10590622
- **Project number:** 5R01AR049794-17
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** CHARLES A O'BRIEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $334,400
- **Award type:** 5
- **Project period:** 2003-09-29 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590622

## Citation

> US National Institutes of Health, RePORTER application 10590622, Osteocyte Control of Bone Remodeling (5R01AR049794-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10590622. Licensed CC0.

---

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