Stimulation by toll-like receptors inhibits osteoclast differentiation.
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.
Takami
Masamichi
M
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kim
Nacksung
N
Rho
Jaerang
J
Choi
Yongwon
Y
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation; D002470:Cell Survival; D029721:Drosophila Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D002352:Carrier Proteins; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D016173:Macrophage Colony-Stimulating Factor