Daidzein alleviates osteoporosis by promoting osteogenesis and angiogenesis coupling.

Background: Postmenopausal osteoporosis and osteoporosis-related fractures are world-wide serious public health problem. Recent studies demonstrated that inhibiting caveolin-1 leads to osteoclastogenesis suppression and protection against OVX-induced osteoporosis. This study aimed to explore the mechanism of caveolin-1 mediating bone loss and the potential therapeutic target. Methods: Thirty C57BL/6 female mice were allocated randomly into three groups: sham or bilateral ovariectomy (OVX) surgeries were performed for mice and subsequently daidzein or vehicle was administrated to animals (control, OVX + vehicle and OVX + daidzein). After 8-week administration, femurs were harvested for Micro-CT scan, histological staining including H&E, immunohistochemistry, immunofluorescence, TRAP. Bone marrow endothelial cells (BMECs) were cultured and treated with inhibitors of caveolin-1 (daidzein) or EGFR (erlotinib) and then scratch wound healing and ki67 assays were performed. In addition, cells were harvested for western blot and PCR analysis. Results: Micro-CT showed inhibiting caveolin-1with daidzein alleviated OVX-induced osteoporosis and osteogenesis suppression. Further investigations revealed H-type vessels in cancellous bone were decreased in OVX-induced mice, which can be alleviated by daidzein. It was subsequently proved that daidzein improved migration and proliferation of BMECs hence improved H-type vessels formation through inhibiting caveolin-1, which suppressed EGFR/AKT/PI3K signaling in BMECs. Conclusions: This study demonstrated that daidzein alleviates OVX-induced osteoporosis by promoting H-type vessels formation in cancellous bone, which then promotes bone formation. Activating EGFR/AKT/PI3K signaling could be the critical reason.

Apolipoprotein E deficiency potentiates macrophage against Staphylococcus aureus in mice with osteomyelitis via regulating cholesterol metabolism.

Introduction: Staphylococcus aureus (S. aureus) osteomyelitis causes a variety of metabolism disorders in microenvironment and cells. Defining the changes in cholesterol metabolism and identifying key factors involved in cholesterol metabolism disorders during S. aureus osteomyelitis is crucial to understanding the mechanisms of S. aureus osteomyelitis and is important in designing host-directed therapeutic strategies. Methods: In this study, we conducted in vitro and in vivo experiments to define the effects of S. aureus osteomyelitis on cholesterol metabolism, as well as the role of Apolipoprotein E (ApoE) in regulating cholesterol metabolism by macrophages during S. aureus osteomyelitis. Results: The data from GSE166522 showed that cholesterol metabolism disorder was induced by S. aureus osteomyelitis. Loss of cholesterol from macrophage obtained from mice with S. aureus osteomyelitis was detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS), which is consistent with Filipin III staining results. Changes in intracellular cholesterol content influenced bactericidal capacity of macrophage. Subsequently, it was proven by gene set enrichment analysis and qPCR, that ApoE played a key role in developing cholesterol metabolism disorder in S. aureus osteomyelitis. ApoE deficiency in macrophages resulted in increased resistance to S. aureus. ApoE-deficient mice manifested abated bone destruction and decreased bacteria load. Moreover, the combination of transcriptional analysis, qPCR, and killing assay showed that ApoE deficiency led to enhanced cholesterol biosynthesis in macrophage, ameliorating anti-infection ability. Conclusion: We identified a previously unrecognized role of ApoE in S. aureus osteomyelitis from the perspective of metabolic reprogramming. Hence, during treating S. aureus osteomyelitis, considering cholesterol metabolism as a potential therapeutic target presents a new research direction.