Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss.

Authors

Elizabeth Staab, University of Nebraska Medical CenterFollow
Geoffrey M. Thiele, University of Nebraska Medical CenterFollow
Dillon Clarey, University of Nebraska Medical Center
Todd A. Wyatt, twyatt@unmc.eduFollow
Debra J. Romberger, University of Nebraska Medical CenterFollow
Adam D. Wells, University of Nebraska Medical CenterFollow
Anand Dusad, University of Nebraska Medical Center
Dong Wang, University of Nebraska Medical CenterFollow
Lynell W. Klassen, University of Nebraska Medical CenterFollow
Ted R. Mikuls, University of Nebraska Medical CenterFollow
Michael J. Duryee, University of Nebraska Medical CenterFollow
Jill A. Poole, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

PLoS One

Publication Date

Summer 8-1-2016

Volume

11

Abstract

Agriculture workers have increased rates of airway and skeletal disease. Inhalant exposure to agricultural organic dust extract (ODE) induces bone deterioration in mice; yet, mechanisms underlying lung-bone crosstalk remain unclear. Because Toll-like receptor 2 (TLR2) and TLR4 are important in mediating the airway consequences of ODE, this study investigated their role in regulating bone responses. First, swine facility ODE stimulated wild-type (WT) bone marrow macrophages to form osteoclasts, and this finding was inhibited in TLR4 knock-out (KO), but not TLR2 KO cells. Next, using an established intranasal inhalation exposure model, WT, TLR2 KO and TLR4 KO mice were treated daily with ODE or saline for 3 weeks. ODE-induced airway neutrophil influx and cytokine/chemokine release were similarly reduced in TLR2 and TLR4 KO animals as compared to WT mice. Utilizing micro-computed tomography (CT), analysis of tibia showed loss of bone mineral density, volume and deterioration of bone micro-architecture and mechanical strength induced by ODE in WT mice were significantly reduced in TLR4 but not TLR2 KO animals. Bone marrow osteoclast precursor cell populations were analyzed by flow cytometry from exposed animals. In WT animals, exposure to inhalant ODE increased osteoclast precursor cell populations as compared to saline, an effect that was reduced in TLR4 but not TLR2 KO mice. These results show that TLR2 and TLR4 pathways mediate ODE-induced airway inflammation, but bone deterioration consequences following inhalant ODE treatment is strongly dependent upon TLR4. Thus, the TLR4 signaling pathway appears critical in regulating the lung-bone inflammatory axis to microbial component-enriched organic dust exposures.

DOI Link

10.1371/journal.pone.0158735

ISSN

1932-6203

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Staab, Elizabeth; Thiele, Geoffrey M.; Clarey, Dillon; Wyatt, Todd A.; Romberger, Debra J.; Wells, Adam D.; Dusad, Anand; Wang, Dong; Klassen, Lynell W.; Mikuls, Ted R.; Duryee, Michael J.; and Poole, Jill A., "Toll-Like Receptor 4 Signaling Pathway Mediates Inhalant Organic Dust-Induced Bone Loss." (2016). Journal Articles: Internal Medicine. 3.
https://digitalcommons.unmc.edu/com_internal_articles/3