Osteoporosis (OP) is a metabolic bone disease characterized by decreased bone mass and increased bone fragility. The imbalance of bone homeostasis modulated by osteoclasts and osteoblasts is the most crucial pathological change in osteoporosis. As a novel treatment strategy, nanomedicine has been applied in drug delivery and targeted therapy due to its high efficiency, precision, and fewer side effects. Gold nanospheres (GNS), as a common kind of gold nanoparticles (GNPs), possess significant antimicrobial and anti-inflammatory activity, which have been applied for the treatment of eye diseases and rheumatoid arthritis. However, the effect of GNS on osteoporosis remains elusive. In this study, we found that GNS significantly prevented ovariectomy (OVX)-induced osteoporosis in a gut microbiota-dependent manner. 16S rDNA gene sequencing demonstrated GNS markedly altered the gut microbial diversity and flora composition. In addition, GNS reduced the abundance of TMAO-related metabolites in OVX mice. Low TMAO levels might alleviate the bone loss phenomenon by reducing the inflammation response. Therefore, we investigated the alteration of cytokine profiles in OVX mice. GNS inhibited the release of pro-osteoclastogenic or proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL)-6, and granulocyte colony-stimulating factor (G-CSF) in the serum. In conclusion, GNS suppressed estrogen deficiency-induced bone loss by regulating the destroyed homeostasis of gut microbiota so as to reduce its relevant TMAO metabolism and restrain the release of proinflammatory cytokines. These results demonstrated the protective effects of GNS on osteoporosis as a gut microbiota modulator and offered novel insights into the regulation of the “gut–bone” axis.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of “microbiota-gut-joint” axis, which might provide promising therapeutic strategies for OA.

Bile acids (BAs), synthesized in the liver and modified by the gut microbiota, have been widely appreciated not only as simple lipid emulsifiers, but also as complex metabolic regulators and momentous signaling molecules, which play prominent roles in the complex interaction among several metabolic systems. Recent studies have drawn us eyes on the diverse physiological functions of BAs, to enlarge the knowledge about the "gut-bone" axis due to the participation about the gut microbiota-derived BAs to modulate bone homeostasis at physiological and pathological stations. In this review, we have summarized the metabolic processes of BAs and highlighted the crucial roles of BAs targeting bile acid-activated receptors, promoting the proliferation and differentiation of osteoblasts (OBs), inhibiting the activity of osteoclasts (OCs), as well as reducing articular cartilage degradation, thus facilitating bone repair. In addition, we have also focused on the bidirectional effects of BA signaling networks in coordinating the dynamic balance of bone matrix and demonstrated the promising effects of BAs on the development or treatment for pathological bone diseases. In a word, further clinical applications targeting BA metabolism or modulating gut metabolome and related derivatives may be developed as effective therapeutic strategies for bone destruction diseases.

Over the past few decades, accumulating evidence has demonstrated that gut microbiota engages in a sustained dialog with the immune system, leading to microbiota-driven immune responses that mediate the regulation of bone-related diseases. Despite the complexity of the dynamic interactions within the gut-immune-bone axis, advancements in high-throughput multi-omics sequencing have significantly facilitated the detailed exploration of this intricate network, thereby providing the potential to develop novel therapeutic strategies for bone-related diseases. In this review, we first summarize the variations in gut microbiota composition observed in patients with bone-related diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and osteoporosis (OP), in comparison to healthy controls, along with the factors influencing these changes. The review that follows synthesize evidences highlighting the profound effects of gut microbial dysbiosis on immune homeostasis and bone microenvironment, respectively. We further elaborate that the gut-immune axis and gut-bone axis are not independent but three-dimensional networks, emphasizing gut microbial dysbiosis as a pivotal driver of immune dysregulation and subsequent bone homeostasis imbalance. Therapeutic strategies to manipulate the gut-immune-bone axis based on the use of probiotics as well as prebiotics, fecal microbiota transplantation, dietary modifications, and pharmacological interventions are also discussed. Finally, we discuss the challenges of current research on the gut-immune-bone axis and propose future directions for identifying novel therapeutic targets based on this axis to treat these diseases.

Extracellular vesicles (EVs) play critical roles in regulating bone metastatic microenvironment through mediating intercellular crosstalks. However, little is known about the contribution of EVs derived from cancer cells to the vicious cycle of bone metastasis. Here, we report a direct regulatory mode between tumour cells and osteoclasts in metastatic niche of prostate cancer via vesicular miRNAs transfer. Combined analysis of miRNAs profiles both in tumour‐derived small EVs (sEVs) and osteoclasts identified miR‐152‐3p as a potential osteolytic molecule. sEVs were enriched in miR‐152‐3p, which targets osteoclastogenic regulator MAFB. Blocking miR‐152‐3p in sEVs upregulated the expression of MAFB and impaired osteoclastogenesis in vitro. In vivo experiments of xenograft mouse model found that blocking of miR‐152‐3p in sEVs significantly slowed down the loss of trabecular architecture, while systemic inhibition of miR‐152‐3p using antagomir‐152‐3p reduced the osteolytic lesions of cortical bone while preserving basic trabecular architecture. Our findings suggest that miR‐152‐3p carried by prostate cancer‐derived sEVs deliver osteolytic signals from tumour cells to osteoclasts, facilitating osteolytic progression in bone metastasis.