Finding a Toll on the Route: The Fate of Osteoclast Progenitors After Toll-Like Receptor Activation.

Pedro P C Souza,Ulf H Lerner

doi:10.3389/fimmu.2019.01663

Pedro P C Souza, Ulf H Lerner

Open Access

https://doi.org/10.3389/fimmu.2019.01663

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Abstract

M-CSF and RANKL are two crucial cytokines stimulating differentiation of mature, bone resorbing, multinucleated osteoclasts from mononucleated progenitor cells in the monocyte/macrophage lineage. In addition to the receptors for M-CSF and RANKL, osteoclast progenitor cells express receptors for several other pro- and anti-osteoclastogenic cytokines, which also regulate osteoclast formation by affecting signaling downstream M-CSF and RANKL receptors. Similar to many other cells originating from myeloid hematopoetic stem cells, also osteoclast progenitors express toll-like receptors (TLRs). Nine murine TLRs are expressed in the progenitors and all, with the exception of TLR2 and TLR4, are downregulated during osteoclastogenesis. Activation of TLR2, TLR4, and TLR9, but not TLR5, in osteoclast progenitors stimulated with M-CSF and RANKL arrests differentiation along the osteoclastic lineage and keeps the cells at a macrophage stage. When the progenitors are primed with M-CSF/RANKL and then stimulated with agonists for TLR2, TLR4, or TLR9 in the presence of M-CSF, but in the absence of RANKL, the cells differentiate to mature, bone resorbing osteoclasts. TLR 2, 4, 5, and 9 are also expressed on osteoblasts and their activation increases osteoclast differentiation by an indirect mechanism through stimulation of RANKL. In mice, treatment with agonists for TLR2, 4, and 5 results in osteoclast formation and extensive bone loss. It remains to be shown the relative importance of inhibitory and stimulatory effects by TLRs on osteoclast progenitors and the role of RANKL produced by TLR stimulated osteoblasts, for the bone resorbing effects in vivo.

Highlights

Human body is constantly exposed to microorganisms
It has been demonstrated that disturbances in normal microbial population are associated with effects on bone, due to impaired uptake of nutrients, and due to the activation of pattern-recognition receptors (PRRs) expressed in immune cells by microbe-associated molecular patterns
Microbial recolonization restores the capacity of sex steroid depletion to induce trabecular bone loss

Summary

Introduction

In addition to our own cells, humans host a vast community of microbes, with an estimation of the number of bacteria exceeding the number of host cells by a factor of 1.3 [1, 2] The majority of these microorganisms populate the gastrointestinal tract and regulate processing and absorption of nutrients and vitamin biosynthesis, which impacts the development and remodeling of multiple organs, including bone [3]. A shift in the normal microbial population by supplementation with probiotics protects mice from sex steroid depletion-induced bone loss Corroborating these observations in mice, a double blind, placebo-controlled clinical trial demonstrated that daily intake of Lactobacillus reuteri for 12 months reduces the loss of volumetric bone mineral density (BMD) in 75–80 year old women who had low BMD [8]

Objectives

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