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Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers to the bidirectional information network between the gut microbiota and OA, which may provide a new way to protect the OA. However, the role of gut microbiota‐derived metabolites in ferroptosis‐relative osteoarthritis remains unclear. The objective of this study was to analyze the protective effect of gut microbiota and its metabolite capsiate (CAT) on ferroptosis‐relative osteoarthritis in vivo and in vitro experiments. From June 2021 to February 2022, 78 patients were evaluated retrospectively and divided into two groups: The health group (n = 39) and the OA group (n = 40). Iron and oxidative stress indicators were determined in peripheral blood samples. And then in vivo and in vitro experiments, a surgically destabilized medial meniscus (DMM) mice model was established and treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) was utilized to inhibit SLC2A1 expression. Serum iron was increased significantly but total iron binding capacity was decreased significantly in OA patients than healthy people (p < 0.0001). The least absolute shrinkage and selection operator clinical prediction model suggested that serum iron, total iron binding capacity, transferrin, and superoxide dismutase were all independent predictors of OA (p < 0.001). Bioinformatics results suggested that SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript 1 (MALAT1), and HIF‐1α (Hypoxia Inducible Factor 1 Alpha)‐related oxidative stress signaling pathways play an important role in iron homeostasis and OA. In addition, gut microbiota 16s RNA sequencing and untargeted metabolomics were used to find that gut microbiota metabolites CAT in mice with osteoarthritis were negatively correlated with Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration (p = 0.0017). Moreover, CAT reduced ferroptosis‐dependent osteoarthritis in vivo and in vitro. However, the protective effect of CAT against ferroptosis‐dependent osteoarthritis could be eliminated by silencing SLC2A1. SLC2A1 was upregulated but reduced the SLC2A1 and HIF‐1α levels in the DMM group. HIF‐1α, MALAT1, and apoptosis levels were increased after SLC2A1 knockout in chondrocyte cells (p = 0.0017). Finally, downregulation of SLC2A1 expression by Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves osteoarthritis in vivo. Our findings indicated that CAT inhibited HIF‐1a expression and reduced ferroptosis‐relative osteoarthritis progression by activating SLC2A1. [ABSTRACT FROM AUTHOR]

Osteoporosis and osteoarthritis are common diseases in an aging society, are considered metabolic diseases, and affect the quality of life of older adults. In addition, the gut microbiome is considered an additional organ to regulate bone metabolism. In the past decade, people have been studying the relationship between gut microbiota and bone metabolism. The role and mechanism of the gut microbiota in regulating bone metabolism is very important to improve the development of osteoporosis and osteoarthritis. Depletion of the gut microbiota as a method of studying the role of the gut microbiota was provided strategies to enhance the role of the gut microbiota in regulating osteoporosis and osteoarthritis. In this review, we discuss how depletion of the gut microbiota affects osteoporosis and osteoarthritis. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis is a common bone metabolic disease, and gut microbiota (GM) imbalance plays an important role in the development of metabolic bone disease. Here, we show that ovariectomized mice had high levels of lipopolysaccharide in serum and gut microbiota dysbiosis through increases in luminal Firmicutes:Bacteroidetes ratio. We depleted the GM through antibiotic treatment and observed improvements in bone mass, bone microstructure, and bone strength in ovariectomized mice. Conversely, transplantation of GM adapted to ovariectomy induced bone loss. However, GM depletion reversed ovariectomy-induced gene expression in the tibia and increased periosteal bone formation. Furthermore, bioinformatics analysis revealed that the G-protein-coupled bile acid receptor (TGR5) and systemic inflammatory factors play key roles in bone metabolism. Silencing TGR5 expression through small interfering RNA (siRNA) in the local tibia and knockout of TGR5 attenuated the effects of GM depletion in ovariectomized mice, confirming these findings. Thus, this study highlights the critical role of the GM in inducing bone loss in ovariectomized mice and suggests that targeting TGR5 within the GM may have therapeutic potential for postmenopausal osteoporosis. [Display omitted] [ABSTRACT FROM AUTHOR]