# Mechanisms of osteocyte induction and regulation of pathogen-induced osteolysis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $415,971

## Abstract

Recently, it has been discovered that osteocytes are multifunctional cells that can serve as targets to develop
new therapeutics. However, it is not known if osteocytes can be a therapeutic target for osteomyelitis and
periodontitis, and if so, which molecular mechanism can be targeted. To our surprise, the magnitude of
Pam3CSK4-induced calvarial osteolysis in “osteocyte MYD88-restoration mice” was similar to wild-type
animals even though MYD88 was globally deleted in all other cells including immune cells. Subcutaneous
inflammatory infiltrates expressed TNF-ɑ, IL-1β, and IL-6 and were rich in neutrophils and macrophages.
These findings suggest that osteocyte-derived inflammatory factors are inducing bone resorption and
inflammatory cell migration. In vitro, the multiplex analysis showed that Pam3CSK4 stimulates the secretion of
CCL2, CCL3, CXCL1, and IL-6 from primary osteocytes. In addition, “osteocyte MYD88-restoration mice”
exhibited bacterially-induced periodontitis with alveolar bone loss. Together, our data provide the novel
observation suggesting that MYD88 pathway activation of osteocytes alone is sufficient to trigger and develop
considerable inflammatory osteolysis. More importantly, these data offer the opportunity to target the
activation of immune cells and osteoclast progenitors on the bone surface through the osteocyte and its
molecular signaling mechanisms. However, it remains unknown how bacterially-induced osteolysis is
controlled by the osteocyte MYD88 pathway when normal (MYD88-sufficient) immune and osteoclast
progenitor cells are present. Furthermore, it remains untested if MYD88 is a convincing beneficial drug target
for osteolysis due to bone infections in vivo. We hypothesize that A) MYD88-mediated osteocyte inflammation
regulates osteolysis in cooperation with normal immune and osteoclast progenitor cells and B) blocking the
osteocyte MYD88 pathway by MYD88 inhibitors suppresses osteocyte-derived inflammatory mediators,
resulting in the protection against and treatment of osteolysis due to bone infections. To test the hypotheses,
the following specific aims are proposed: Aim 1) Determine the impact of the deletion of osteocyte MYD88
function on calvarial osteolysis. Aim 2) Determine the impact of the deletion of osteocyte MYD88 function on
P.gingivalis-induced periodontitis. Aim 3) Determine whether and how pharmacological inhibition of osteocyte
MYD88 can be effective for treating osteolysis due to bacterial inflammation. We propose that the osteocytes
play a role in bacterially-induced osteolysis conditions and understanding the important role could lead to new
therapeutics. We will uncover a novel and essential role of osteocytes as inflammatory cells that regulate
immune cell activation and osteoclast formation. The new aspect of osteocytes will provide new therapeutic
strategies for osteomyelitis and periodontitis.

## Key facts

- **NIH application ID:** 10890641
- **Project number:** 5R01DE032036-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Yasuyoshi Ueki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,971
- **Award type:** 5
- **Project period:** 2023-07-18 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890641

## Citation

> US National Institutes of Health, RePORTER application 10890641, Mechanisms of osteocyte induction and regulation of pathogen-induced osteolysis (5R01DE032036-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890641. Licensed CC0.

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