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Stimulation by toll-like receptors inhibits osteoclast differentiation
Masamichi Takami1, Nacksung Kim, Jaerang Rho
1Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Abstract:
Osteoclasts, the cells capable of resorbing bone, are derived from hemopoietic precursor cells of monocyte-macrophage lineage. The same precursor cells can also give rise to macrophages and dendritic cells, which are essential for proper immune responses to various pathogens. Immune responses to microbial pathogens are often triggered because various microbial components induce the maturation and activation of immunoregulatory cells such as macrophages or dendritic cells by stimulating Toll-like receptors (TLRs). Since osteoclasts arise from the same precursors as macrophages, we tested whether TLRs play any role during osteoclast differentiation. We showed here that osteoclast precursors prepared from mouse bone marrow cells expressed all known murine TLRs (TLR1-TLR9). Moreover, various TLR ligands (e.g., peptidoglycan, poly(I:C) dsRNA, LPS, and CpG motif of unmethylated DNA, which act as ligands for TLR2, 3, 4, and 9, respectively) induced NF-kappa B activation and up-regulated TNF-alpha production in osteoclast precursor cells. Unexpectedly, however, TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts induced by TNF-related activation-induced cytokine. Rather, TLR stimulation maintained the phagocytic activity of osteoclast precursors in the presence of osteoclastogenic stimuli M-CSF and TNF-related activation-induced cytokine. Taken together, these results suggest that TLR stimulation of osteoclast precursors inhibits their differentiation into noninflammatory mature osteoclasts during microbial infection. This process favors immune responses and may be critical to prevent pathogenic effects of microbial invasion on bone.
Insights
Toll-like receptor (TLR) stimulation of osteoclast precursors inhibits their differentiation into bone-resorbing cells. This immune response favors pathogen defense and prevents bone damage during microbial infections.
Area of Science:
- Immunology
- Cell Biology
- Bone Biology
Background:
- Osteoclasts, responsible for bone resorption, originate from monocyte-macrophage lineage precursors.
- These same precursors also differentiate into macrophages and dendritic cells crucial for immune responses.
- Microbial components activate immune cells via Toll-like receptors (TLRs), initiating immune responses.
Purpose of the Study:
- To investigate the role of Toll-like receptors (TLRs) in osteoclast differentiation.
- To determine if microbial products stimulating TLRs affect osteoclast precursor development.
Main Methods:
- Osteoclast precursors were isolated from mouse bone marrow.
- Cells were stimulated with various Toll-like receptor (TLR) ligands (e.g., LPS, CpG DNA).
- Osteoclast differentiation was assessed by multinucleation and expression of osteoclast markers in the presence of M-CSF and TNF-related activation-induced cytokine.
Main Results:
- Osteoclast precursors expressed all known murine TLRs (TLR1-TLR9).
- TLR stimulation activated NF-kappa B and increased TNF-alpha production.
- Unexpectedly, TLR stimulation inhibited osteoclast differentiation while maintaining precursor phagocytic activity.
Conclusions:
- TLR stimulation of osteoclast precursors inhibits their differentiation into mature osteoclasts.
- This mechanism favors immune responses during microbial infection.
- Inhibition of osteoclastogenesis prevents potential bone damage from microbial invasion.