Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns

Abstract

Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization domains. Pathogenic bacteria such as Porphyromonas gingivalis and Staphylococcus aureus tend to induce bone destruction and cause various inflammatory bone diseases including periodontal diseases, osteomyelitis, and septic arthritis. On the other hand, probiotic bacteria such as Lactobacillus and Bifidobacterium species can prevent bone loss. In addition, bacterial metabolites and various secretory molecules such as short chain fatty acids and cyclic nucleotides can also affect bone homeostasis. This review focuses on the regulation of osteoclast and osteoblast by MAMPs including cell wall components and secretory microbial molecules under in vitro and in vivo conditions. MAMPs could be used as potential molecular targets for treating bone-related diseases such as osteoporosis and periodontal diseases.

Keywords: bacteria; bone diseases; bone homeostasis; microbe-associated molecular patterns; osteoblast; osteoclast; pattern-recognition receptors; secretory microbial molecules.

Figure 1

Illustration of lipopolysaccharide (LPS) structure. LPS is a potent immuno-stimulatory molecule of Gram-negative bacteria. It is composed of O antigen, outer or inner core polysaccharide, and lipid A. O antigen consists of repeating sugar molecules (n can be up to 40 repeats) and outer or inner core is a continuous polysaccharide chain. Composition and length of the O antigen and core polysaccharide are varied among bacterial strains. Lipid A consists of two phosphorylated glucosamines and acyl chains. The number of acyl chains and branched points in lipid A vary among bacterial species. Man, Mannose; Par, Paratose; Rha, Rhamnose; Abe, Abequose; Col, Colitose; Glc, Glucose; Gal, Galactose; Hep, Heptose; Kdo, 3-deoxy-d-manno-2-octulosonic acid; GlcN, Glucosamine; P, phosphate.

Figure 2

Illustration of lipoteichoic acid (LTA) structure. LTA is a Gram-positive bacterial cell wall component which is responsible for stimulating immune responses of hosts. There are five types of LTA which varies among bacterial species. Gro, Glycerol; Glc, Glucose; Gal, Galactose; β-Glu, β-Glucan; AAT-Gal, 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose; Gal-NAc, N-acetylgalactosamine; Rto, Ribitol; Glc-NAc, N-acetylglucosamine.

Figure 3

Structures of Toll-like receptor (TLR) 2 heterodimers and lipoproteins (LPPs). TLRs consist of extracellular leucine-rich repeat, transmembrane helix, and intracellular Toll/interleukin-1 receptor domain. Bacterial LPPs bind to the extracellular domains of TLR. Especially, TLR2/TLR6 heterodimers recognize diacylated LPPs and TLR1/TLR2 heterodimers sense triacylated LPPs.

Figure 4

Illustration of peptidoglycan (PGN) structure. PGN is composed of two amino sugars, N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG), and amino acids. NAM and NAG are connected by β-1,4-glycosidic linkage. The peptide chain of three to five amino acids attaches to NAM. Lysine-type PGN and diaminopimelic acid (DAP)-type PGN contain a lysine and a meso-DAP at the third position of the peptide stem and predominantly found in Gram-positive and Gram-negative bacteria, respectively.

Figure 5

Signaling pathway of nucleotide-binding oligomerization domain (NOD) 1 and NOD2. d-glutamyl-meso-diaminopimelic acid (iE-DAP) of Gram-negative bacteria and muramyl dipeptide (MDP) of both Gram-positive and Gram-negative bacteria are recognized by NOD1 and NOD2, respectively. After activation of NODs, RICK is recruited through CARD-CARD interactions, leading to the activation of NF-κB and MAPK pathways.

Figure 6

Signaling pathway of stimulator of interferon genes (STING). Bacterial cyclic dinucleotides (CDNs) are recognized by STING localized at endoplasmic reticulum. When STING is activated by CDNs, it is translocated from endoplasmic reticulum to the Golgi complex. This translocation triggers the STING-TBK1-IRF3 signaling cascade to increase expression of type I interferons.