Effect of Bifidobacterium on osteoclasts: TNF-α/NF-κB inflammatory signal pathway-mediated mechanism

Abstract

Osteoporosis is a systemic multifactorial bone disease characterized by low bone quality and density and bone microstructure damage, increasing bone fragility and fracture vulnerability. Increased osteoclast differentiation and activity are important factors contributing to bone loss, which is a common pathological manifestation of bone diseases such as osteoporosis. TNF-a/NF-κB is an inflammatory signaling pathway with a key regulatory role in regulating osteoclast formation, and the classical pathway RANKL/RANK/OPG assists osteoclast formation. Activation of this inflammatory pathway promotes the formation of osteoclasts and accelerates the process of osteoporosis. Recent studies and emerging evidence have consistently demonstrated the potential of probiotics to modulate bone health. Secretions of Bifidobacterium, a genus of probiotic bacteria in the phylum Actinobacteria, such as short-chain fatty acids, equol, and exopolysaccharides, have indicated beneficial effects on bone health. This review discusses the molecular mechanisms of the TNF-a/NF-κB inflammatory pathway in regulating osteoclast formation and describes the secretions produced by Bifidobacterium and their potential effects on bone health through this pathway, opening up new directions for future research.

Keywords: Bifidobacterium; NF-κB; TNF-α; inflammation; osteoclast.

Figure 1

TNF-α/NF-κB signaling pathway.

Figure 2

RANKL/RANK/OPG is the most important signaling pathway regulating osteoclasts formation. The interaction between RANK and RANKL (which can exacerbate this effect in the presence of M-CSF) promotes the recruitment of the TRAF family bridging proteins, one of which TRAF6 contributes to OC formation and activation of the NF-κB signaling pathway, leading to the transcription of genes involved in OC formation and OC production. OPG is a decoy receptor that binds RANKL and can block the binding and activation of RANK and RANKL, reducing OC production. TNF-α/NF-κB is an inflammatory signaling pathway. In the presence of TNF-α, NF-κB pathway is activated, OC production is increased, and the interaction between RANKL and RANK is enhanced, which results in activation of the downstream signaling pathways. In addition to the above-mentioned effects, TNF-α also synergizes with RANKL and directly promotes OC production. In the presence of RANKL and M-CSF, the expression of genes involved in OC formation leading to the development of mature OC.

Figure 3

Bifidobacterium mainly produces SCFA, Eq and EPS. These three substances inhibit the TNF-α/NF-κB signaling pathway, reduces the production of inflammatory mediators, and blocks the activation of inflammatory mediators, thereby preventing the formation of OC. SCFA can promote the production of Treg cells, indirectly inhibit the TNF-α/NF-κB signaling pathway, and also regulate OC formation through Treg cells. In addition, SCFA plays a role in the maintenance of the intestinal mucosal barrier, blocking the entry of inflammatory factors into the bloodstream, and reducing inflammation, leading to the inhibition of OC formation. More importantly, it has been shown that SCFA also increases the production of OPG. Eq also decreases the production of inflammatory factors, such as IL-6, inhibits RANK and RANKL, and can upregulate OPG expression. EPS mainly inhibits the production of inflammatory factors.