Kuhnkloster0309
The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. EPZ005687 in vitro In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8 kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson's r = 0.991, p = 0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.
Cross-sectional studies have shown that patients with type 2 diabetes mellitus (T2DM) have low circulating levels of osteocalcin (OC) and undercarboxylated OC (ucOC). This longitudinal study aimed to examine whether low OC or ucOC levels at baseline are associated with the risk of incident T2DM.
We examined 1700 community-dwelling Japanese men (≥65years) after excluding those with history of diseases (other than T2DM) or medications that affect bone and glucose metabolism. T2DM was defined as fasting plasma glucose (FPG) ≥126mg/dl or glycated hemoglobin A
(HbA1c) ≥6.5%. Participants without prevalent T2DM at baseline were invited to follow-up surveys 5 and 10years after baseline.
Among the participants, 309 with prevalent T2DM showed significantly lower serum OC and ucOC levels at baseline than those without. After excluding these participants, 46 and 57 participants with incident T2DM were identified in the first and second follow-up surveys, respectively. These participants did not show significantly different OC and ucOC levels at baseline relative to those without T2DM, although their FPG and HbA1c levels at baseline were significantly higher compared to those without incident T2DM. Increase in glycemic indices preceded decrease in OC and ucOC levels. OC and ucOC levels at baseline were not significantly associated with the risk of incident T2DM identified in the follow-up surveys.
OC and ucOC levels at baseline were not significantly associated with the risk of incident T2DM. Our results do not support the findings of animal studies that ucOC is a hormone regulating glucose metabolism.
OC and ucOC levels at baseline were not significantly associated with the risk of incident T2DM. Our results do not support the findings of animal studies that ucOC is a hormone regulating glucose metabolism.
The relative contribution of genetic and clinical factors for bone loss is not well known. This study aimed to investigate the annualized percentage change in total hip bone mineral density (BMD) and the genetic and clinical risk factors for bone loss in a Korean prospective cohort study over a 6-year period.
We included 645 men aged ≥50years and 683 postmenopausal women who had repeated BMD testing between 2007 and 2014. The association between covariates and annualized percentage change in hip BMD was analyzed through the multivariate linear regression analysis. A total of 2614 single-nucleotide polymorphisms (SNPs) from 23 known BMD-related candidate genes and genome-wise association study were investigated.
Hip bone loss increased more rapidly in women than in men with advancing age. Hip bone loss in men increased with lean mass (LM) loss (%/year) (P<0.001) and current smoking (P=0.024) and decreased with increasing waist circumference (WC) (P<0.001), alcohol consumption (P=0.049), and increasactors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.
In this study, decreasing WC and LM were significant risk factors for hip bone loss in both men and women. Those factors were also identified that had sex-specific or age-specific effects on hip bone loss. None of the SNPs were associated with hip bone loss after multiple testing adjustments. The understanding of the modifiable factors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why her that presents a treatment target in OI, remains to be established.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by impaired bone quality and quantity. Established imaging techniques have limited reliability in OI. The TX-Analyzer™ is a new, fractal-based software allowing a non-invasive assessment of bone structure based on conventional radiographs. We explored whether the TX-Analyzer™ can discriminate OI patients and healthy controls. Furthermore, we investigated the correlation between TX-Analyzer™ parameters and (i) bone mineral density (BMD) by Dual Energy X-ray Absorptiometry (DXA), (ii) trabecular bone score (TBS), and (iii) bone microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT).
Data of 29 adult OI patients were retrospectively analyzed. Standard radiographs of the thoracic and lumbar spine were evaluated using the TX-Analyzer™. Bone Structure Value (BSV), Bone Variance Value (BVV), and Bone Entropy Value (BEV) were measured at the vertebral bodies T7 to L5. Data were compared to a healthy, age- and gele to discriminate patients with OI from healthy controls. ROC curves of BEV values suggest a suitable clinical applicability. Low to no correlations with conventional methods suggest, that the TX-Analyzer™ may indicate a new and independent examination tool in OI.
The software TX-Analyzer™ is able to discriminate patients with OI from healthy controls. ROC curves of BEV values suggest a suitable clinical applicability. Low to no correlations with conventional methods suggest, that the TX-Analyzer™ may indicate a new and independent examination tool in OI.
Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown.
Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and toll-like receptor (TLR)-3 stimulation in human lung macrophages.
Low doses of RT (0.5-1 Gray) decreased LPS-induced pneumonia, and increased the percentage of nerve- and airway-associated macrophages producing interleukin (IL) 10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses of RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased interferon γ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased.
Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS.
Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS.
As the association between insulin resistance and ischaemic stroke is conflicting, our study aimed to examine the association between triglyceride-glucose (TyG), a surrogate marker of insulin resistance, and incident ischaemic stroke, and also to further assess the potential effect of modification by several known risk factors of stroke.
The Rural Chinese Cohort Study enrolled 11,777 participants, aged ≥40 years, who were free of stroke and cardiovascular disease at baseline during 2007-2008, and who were then followed during 2013-2014. TyG was determined using the following formula Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The relative risk (RR) and 95% confidence interval (CI) of incident ischaemic stroke associated with TyG were estimated using modified Poisson regression models.
During a median follow-up duration of 6 years, 677 new ischaemic stroke cases were identified. After multivariate adjustment, RR (95% CI) values for ischaemic stroke were 1.33 (1.01-1.75), 1.57 (1.17-2.10) and 1.95 (1.34-2.82) in TyG quartile (Q) 2, 3 and 4 groups, respectively, compared with Q1. A significant interaction between TyG index and age for risk of ischaemic stroke (P
< 0.001) was also observed. However, no significant interaction was found between TyG index and other potential risk factors of risk for ischaemic stroke, although there were significant positive associations with female, non-smoker, non-drinker, low or moderate physical activity, non-obese and non-type 2 diabetes mellitus groups.
Elevated TyG index is an independent predictor of ischaemic stroke in the general population, and insulin resistance may be positively associated with future stroke risk.
Elevated TyG index is an independent predictor of ischaemic stroke in the general population, and insulin resistance may be positively associated with future stroke risk.
