Epigenetic mechanisms guiding articular cartilage regeneration and age‐related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age‐patterned transcription factor highly active in fetal and OA chondrocytes, but the context‐specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor‐like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post‐traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor‐like phenotype. However, it is likely that chronic activation of this pathway, induced by IL‐6 cytokines, is detrimental and leads to tissue degeneration.

BackgroundThe urinary system serves as a crucial pathway for eliminating metallic substances from the body, making it susceptible to the effects of metal exposure. However, limited research has explored the association between metal mixtures and bladder function. This study aims to investigate the relationship between urinary metal mixtures (specifically barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten) and urine flow rate (UFR) in the general population, utilizing multiple mixture analysis models.MethodsThis study utilizes data obtained from the National Health and Nutrition Examination Survey. After adjusting for relevant covariates, we assessed the correlations between metal mixtures and UFR using three distinct analysis models: weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). Additionally, a gender-stratified analysis was conducted. Finally, we also performed sensitivity analyses.ResultsA total of 7,733 subjects were included in this study, with 49% being male. The WQS regression model, when fitted in the positive direction, did not yield any significant correlations in the overall population or in the male and female subgroups. However, when analyzed in the negative direction, the WQS index exhibited a negative correlation with UFR in the overall group (β = −0.078; 95% CI: −0.111, −0.045). Additionally, a significant negative correlation between the WQS index and UFR was observed in the female group (β = −0.108; 95% CI: −0.158, −0.059), while no significant correlation was found in the male group. The results obtained from the qgcomp regression model were consistent with those of the WQS regression model. Similarly, the BKMR regression model revealed a significant negative correlation trend between metal mixtures and UFR, with cadmium and antimony potentially playing key roles.ConclusionOur study revealed a significant negative correlation between urinary metal mixture exposure and mean UFR in US adults, with notable gender differences. Specifically, higher urinary levels of cadmium and antimony were identified as potential key factors contributing to the decrease in mean UFR. These findings significantly contribute to the existing knowledge on the impact of metal mixtures on bladder function and provide valuable insights for safeguarding bladder health and preventing impaired bladder function.

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Summary The traditional H-κ stacking technique is often used to determine the crustal thickness (H) and Vp/Vs (κ) using multiple Moho converted P-to-S phases, but weak crustal multiples and variation of arrival time of crustal multiples in receiver function resulting from complex crustal structure, such as dipping interface and/or crustal anisotropy, can cause bias estimates leading to erroneous interpretations. In this study, we overcome these problems by combining the Ps arrival times in receiver functions and independent constraint from gravity data, providing a complementary to the H-κ method for estimating H and κ with the advantage of not relying on the crustal multiples which are commonly hardly identified. Harmonic corrections are only made to arrival time variations of Ps phase before H-κ stacking. Independent gravity data can help constrain the trade-off between the H and κ when using Ps times only. Stacking these two complementary datasets allows us to yield a more accurate estimation of H and κ. The reliability and validity of our method to constrain the crustal properties are confirmed using synthetic data from multiple types of models and real data recorded by two permanent seismic stations belonging to different geological regions.