Roles of Toll-like Receptor Signaling in Inflammatory Bone Resorption

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors expressed in immune cells, including neutrophils, macrophages, and dendritic cells. Microbe-associated molecular patterns, including bacterial components, membranes, nucleic acids, and flagella are recognized by TLRs in inflammatory immune responses. Periodontal disease is an inflammatory disease known to cause local infections associated with gingival inflammation, subsequently leading to alveolar bone resorption. Prostaglandin E2 (PGE2) is a key mediator of TLR-induced inflammatory bone resorption. We previously reported that membrane-bound PGE synthase (mPGES-1)-deficient mice failed to induce bone resorption by lipopolysaccharide (LPS), a major pathogenic factor involved in periodontal bone resorption. Further experiments exploring specific pathogen-promoting osteoclast differentiation revealed that various TLR ligands induced osteoclast differentiation in a co-culture model. The ligands for TLR2/1, TLR2/6, TLR3, and TLR5, as well as TLR4, induce osteoclast differentiation associated with the production of PGE2 and the receptor activator of nuclear factor-kappa B ligand (RANKL), an inevitable inducer of osteoclast differentiation in osteoblasts. In vivo, local injection of TLR ligands, including TLR2/1, TLR2/6, and TLR3, resulted in severe alveolar bone resorption. This review summarizes the latest findings on TLR-mediated osteoclast differentiation and bone resorption in inflammatory diseases, such as periodontal diseases.

Keywords: Toll-like receptors; bone resorption; innate immunity; osteoblasts; osteoclasts; periodontal disease; prostaglandin E2.

Figure 1

TLR signaling pathways. TLR2/1, TLR2/6, and TLR4 transduce the TIRAP/MyD88-dependent pathway to activate NF-κB and AP-1 transcription, which induces the production of pro-inflammatory cytokines. TLR5, TLR7/8, and TLR9 activate the MyD88-dependent pathway without the TIRAP adaptor protein. In contrast, TLR3 and endocytosed TLR4 activate a TRIF-dependent pathway to activate both NF-κB and IRFs. Endocytosed TLR4 requires a TRAM adaptor protein. TLR7/8 and TLR9 also transduce the IRF7 and NF-κB pathways.

Figure 2

Roles of TLR signaling in osteoclast differentiation. In osteoblasts, TLR2/1, TLR2/6, TLR3, and TLR4 signaling activates the NF-κB pathway, leading to PGE2 production mediated by COX2 and mPGES-1. PGE2 activates EP4 signaling in an autocrine/paracrine manner, followed by RANKL expression. In addition, these signaling pathways directly activate the osteoclast function and survival via the NF-κB pathway. Both indirect and direct effects of TLR signaling induce osteoclastic bone resorption.

Figure 3

Schematic illustration of inflammatory bone resorption induced by TLR ligands. In inflammatory tissues, such as periodontal tissues infected with bacteria and arthritic joints, bacterial ligands derived from infected bacteria and endogenous ligands derived from host cells, such as immune cells and stromal cells, are recognized by the cell surface and endosomal/lysosomal TLRs and cytosolic sensors (RIG-I/MDA5, cGAS-STING, and inflammasomes), stimulating the production of inflammatory cytokines and PGE2. These factors induce osteoclast differentiation and bone resorption, which are associated with inflammation.