Bone has self-healing and regenerative abilities and contains three types of cells in adults, including osteoblasts and osteocytes from mesenchymal stem cells and osteoclasts from haematopoietic cells in bone marrow. There are two key cell types that play an important role in bone homeostasis: osteoclasts that absorb bone matrix and osteoblasts that synthesise bone matrix. Osteocytes promote the balance of osteoblasts and osteoclasts in bone construction and bone remodeling, and maintain bone homeostasis by ensuring the balance of calcium and phosphorus metabolism [10]. Bone homeostasis is related to cell development and activation as well as mediation of metabolic and immune activities via signaling pathways. Recent research has shown that the BMP/SMADs, Wnt/β-catenin and OPG/RANKL/RANK signaling pathways play primary roles in bone homeostasis [11,12].Although research on the osteal signaling pathway has progressed, understanding of gut microbialdependent signaling pathways for metabolic and immune bone homeostasis remains elusive. In recent years, the study of gut microbiota has shed light on our understanding of bone homeostasis. Here, we review microbiota-mediated gut-bone crosstalk via bone morphogenetic protein/SMADs, Wnt and OPG/receptor activator of nuclear factor-kappa B ligand signaling pathways in direct (translocation) and indirect (metabolite) manners. The mechanisms underlying gut microbiota involvement in these signaling pathways are relevant in immune responses, secretion of hormones, fate of osteoblasts and osteoclasts and absorption of calcium. Collectively, we propose a signaling network for maintaining a dynamic homeostasis between the skeletal system and the gut ecosystem. Additionally, the role of gut microbial improvement by dietary intervention in osteal signaling pathways has also been elucidated. This review provides unique resources from the gut microbial perspective for the discovery of new strategies for further improving treatment of bone diseases by increasing the abundance of targeted gut microbiota.

Background To investigate the ameliorative effects of glucosamine (GS), chondroitin sulphate (CS) and glucosamine plus chondroitin sulphate (GC) on rheumatoid arthritis (RA) in rats, and to explore the mechanism of GS, CS and GC in improving RA based on the gut microbiota. Methods RA rat models were effectively developed 14 days after CFA injection, and then garaged with GS, CS and GC. Body weight and paw volume of rats were monitored at multiple time points at the beginning of CFA injection. Until D36, serum and ankle tissue specimens were used to measure levels of circulating inflammatory factors (TNF-α, IL-1β, MMP-3, NO and PGE2) and local inflammatory indicators (TLR-4 and NF-κB). On D18, D25, and D36, intergroup gut microbiota was compared using 16S rRNA gene sequencing and bioinformatics analysis. We also performed the correlation analysis of gut bacteria, joint swelling and inflammatory indicators. Results GC, rather than GS and CS, could reduce right paw volumes, levels of TLR-4 and NF-κB in synovial tissues. In addition, enriched genera in RA model rats screened out by LEfSe analysis could be inhibited by GC intervention, including potential LPS-producing bacteria (Enterobacter, Bacteroides, Erysipelotrichaceae_unclassified and Erysipelotrichaceae_uncultured) and some other opportunistic pathogens (Esherichia_Shigella, Nosocomiicoccus, NK4A214_group, Odoribacter, Corynebacterium and Candidatus_Saccharimonas.etc.) that positively correlated with pro-inflammatory cytokines, right paw volume, and pathology scores. Furthermore, the gut microbiota dysbiosis was observed to recover before alleviating joint swelling after interventions. Conclusions GC could inhibit potential LPS-producing bacteria and the activation of TLR-4/NF-κB pathway in RA rats, thus alleviating RA-induced joint injury.

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