RESUMO
BACKGROUND: It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates in this pathological process remains unknown. Here, we report that platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts in the bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), a nonspecific transcytosis marker, was upregulated during HFD challenge. MAIN BODY: Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations in the circulation recapitulated the HFD-induced neuroinflammation and transcytosis shift. Preosteoclast-specific Pdgfb knockout mice were partially rescued from hippocampal neuroinflammation and transcytosis shifts in HFD-challenged mice. HFD-induced PDGF-BB elevation aggravated microglia-associated neuroinflammation and interleukin-1ß (IL-1ß) secretion, which increased ALPL expression and transcytosis shift through enhancing protein 1 (SP1) translocation in endothelial cells. CONCLUSION: Our findings confirm the role of bone-secreted PDGF-BB in neuroinflammation and the transcytosis shift in the hippocampal region during HFD challenge and identify a novel mechanism of microglia-endothelial crosstalk in HFD-induced metabolic syndrome.
Assuntos
Becaplermina , Dieta Hiperlipídica , Células Endoteliais , Hipocampo , Síndrome Metabólica , Microglia , Transcitose , Animais , Camundongos , Becaplermina/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Transcitose/fisiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Microglia/metabolismo , Microglia/patologia , Dieta Hiperlipídica/efeitos adversos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Masculino , Osso e Ossos/metabolismo , Osso e Ossos/patologiaRESUMO
OBJECTIVE: To analyze the effects of the angle between dynamic hip screw (DHS) and anti-rotation screw (AS) on vertically oriented femoral neck fractures (VOFNFs) and investigate the clinical results of them. METHODS: Eighteen synthetic femurs were simulated and divided into 3 groups. The angle between DHS and AS in anteroposterior-view was marked as α, and in lateral-view was marked as ß, thus the total angle (TA) was defined as the summation of α and ß. The groups were categorized as group A (TA ≤ 5°), B (5° < TA ≤ 10°), and C (TA > 10°), respectively. All samples were tested under incremental, cyclical loading, and loading to failure. In clinic, 80 consecutive VOFNFs in 78 patients were treated with DHS plus AS. The patients were divided into 2 groups, including 48 fractures in parallel group (TA ≤10°) and 32 in angular group (TA >10°). RESULTS: Group A and B survived during incremental and cyclical loading and endured longer than group C. Axial stiffness and failure loads were not different between group A and B, and greater than group C. Fracture gaps compressive stress was highest in group A, followed by group B and C. Forty-one fractures in parallel group and 23 in angular group healed at final follow-up. Nonunion and osteonecrosis occurred in 3 and 4 of parallel group, and 4 and 5 of angular group. CONCLUSION: The construction with TA ≤10° between DHS and AS showed superior biomechanical performance and clinical results than those with TA >10°.
Assuntos
Fraturas do Colo Femoral , Fixação Interna de Fraturas , Humanos , Fixação Interna de Fraturas/métodos , Fraturas do Colo Femoral/cirurgia , Parafusos Ósseos , Fêmur , Fenômenos BiomecânicosRESUMO
Osteoporosis and its related fractures are common causes of morbidity and mortality in older adults, but its underlying molecular and cellular mechanisms remain largely unknown. In this study, we found that lipoteichoic acid (LTA) treatment could ameliorate age-related bone degeneration and attenuate intramedullary macrophage senescence. FOXO1 signaling, which was downregulated and deactivated in aging macrophages, played a key role in the process. Blocking FOXO1 signaling caused decreased REDD1 expression and increased phosphorylation level of mTOR, a major driver of aging, as well as aggravated bone loss and deteriorated macrophage senescence. Moreover, LTA elevated FOXO1 signaling through ß-catenin pathway while ß-catenin inhibition significantly suppressed FOXO1 signaling, promoted senescence-related protein expression, and accelerated bone degeneration and macrophage senescence. Our findings indicated that ß-catenin/FOXO1/REDD1 signaling plays a physiologically significant role that protecting macrophages from senescence during aging.