Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1ß (IL-1ß) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1ß and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target.

Autoimmune diseases are a group of heterogeneous diseases with diverse clinical manifestations that can be divided into systemic and organ-specific. The common etiology of autoimmune diseases is the destruction of immune tolerance and the production of autoantibodies, which attack specific tissues and/or organs in the body. The pathogenesis of autoimmune diseases is complicated, and genetic, environmental, infectious, and even psychological factors work together to cause aberrant innate and adaptive immune responses. Although the exact mechanisms are unclear, recently, excessive exacerbation of pyroptosis, as a bond between innate and adaptive immunity, has been proven to play a crucial role in the development of autoimmune disease. Pyroptosis is characterized by pore formation on cell membranes, as well as cell rupture and the excretion of intracellular contents and pro-inflammatory cytokines, such as IL-1ß and IL-18. This overactive inflammatory programmed cell death disrupts immune system homeostasis and promotes autoimmunity. This review examines the molecular structure of classical inflammasomes, including NLRP3, AIM2, and P2X7-NLRP3, as the switches of pyroptosis, and their molecular regulation mechanisms. The sophisticated pyroptosis pathways, including the canonical caspase-1-mediated pathway, the noncanonical caspase-4/5/11-mediated pathway, the emerging caspase-3-mediated pathway, and the caspase-independent pathway, are also described. We highlight the recent advances in pyroptosis in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome and dermatomyositis, and attempt to identify its potential advantages as a therapeutic target or prognostic marker in these diseases.

Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway.

Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.