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Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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-
B activation and up-regulated TNF-
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.
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