# Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

> **NIH NIH R01** · NOVA SOUTHEASTERN UNIVERSITY · 2021 · $335,228

## Abstract

ABSTRACT
There is a critical need for new strategies to prevent and/or treat periodontal bone loss in the aging society of
the U.S. However, the underlying mechanisms for age-dependently elevated incidence and pathogenic
manifestations of periodontitis, especially bone resorption, remain elusive. This study will investigate the
novel host-bacterial interaction of which pathogenesis only emerges with aging in periodontitis. Our
earlier studies demonstrated that that a novel virulent lipid, phosphoglycerol dihydroceramide (PGDHC),
produced by the keystone pathogen Porphyromonas gingivalis upregulates RANKL-induced osteoclastogenesis
in vitro and in vivo, and that locally produced macrophage migration inhibitory factor (MIF) in inflammatory bone
resorption lesion induces chemotaxis of blood circulating osteoclast precursors to bone resorption site via binding
to its cognate receptor CXCR4. Our preliminary in vitro results showed that, PGDHC-induced MIF-production
from fibroblasts, a primary cellular source of MIF in periodontal lesions, is significantly upregulated by those
isolated from old mice, compared to young mice, while bacterial LPS did not show any age-dependent change
in production of MIF from fibroblasts. Other preliminary results demonstrated that host acid ceramidase (aCDase)
downregulates PGDHC-elicited osteoclastogenesis and that aCDase expression is significantly diminished
in healthy gingival tissue of aged mice compared to young mice. In relation to those results, our recent
publication reported that P. gingivalis downregulates expression of aCDase expression from host epithelial cells
in vitro. Collectively, it is highly plausible that host derived aCDase has a protective role against the virulent lipid
PGDHC, and age-dependently diminished aCDase activity may leads to breach of active PGDHC to periodontal
tissue. Thus, we hypothesized that age-dependently altered aCDase activity in periodontal lesions may be
responsible for protecting host from PGDHC lipid produced by P. gingivalis. The Aim 1 is designed to test
protective the role of age-dependently altered aCDase activity against PGDHC-mediated pathogenesis,
especially the local production of MIF. In Aim 2, effects of age-dependently increased tissue penetration of active
PGDHC on chemotaxis of blood circulating osteoclast precursors to bone resorption site will be examined in
vitro as well as in periodontatis induced in young and aged mice. Completion of these studies is anticipated to
cause the paradigm-shit in the study of host-oral bacterial interaction in age-associated periodontitis and help
development of novel diagnostic tools and therapeutic regimes for age-associated periodontitis.

## Key facts

- **NIH application ID:** 10168429
- **Project number:** 5R01AG064003-03
- **Recipient organization:** NOVA SOUTHEASTERN UNIVERSITY
- **Principal Investigator:** Alexandru Movila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,228
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-01-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168429

## Citation

> US National Institutes of Health, RePORTER application 10168429, Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging (5R01AG064003-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168429. Licensed CC0.

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