Calcified Tissue International最新文献

Fibroblast Growth Factor (FGF) receptor signalling is important for skeletal development. The FGF19 subfamily which includes FGF19 and FGF21 are involved in bone metabolism, although their effects on bone mineral density (BMD) and bone strength remain unclear. To further characterise the influence of these two factors on the skeleton, we studied the association between circulating concentrations of FGF19 and 21 with BMD and parameters of hip geometry and strength in post-menopausal osteoporosis (PMO). The study cohort consisted of 374 women aged (mean [SD]) 68.7[12.3] years with PMO. FGF19 and FGF21 were measured in serum by ELISA. BMD was measured at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) by dual energy X-ray absorptiometry (DXA) and hip structural analysis (HSA) parameters (n = 263) at the narrow neck of the femur (NN), Intertrochanter (IT) and Femoral shaft (FS) were derived from DXA scans. FGF19 and 21 were not associated with prevalent fractures or BMD when corrected for covariates; age, BMI, smoking habits and alcohol intake. Log-transformed FGF 21 was negatively associated with HSA parameters including Outer Diameter (OD) (p = 0.019), Cross-sectional area (CSA) (p = 0.01), cross-sectional moment of inertia (CSMI) (p = 0.011), Section modulus (Z) (p = 0.002) and cortical thickness (Co Th) (p = 0.026) at the IT only. CSA, CSMI, Z and Co Th were significantly lower (p < 0.05) in women with FGF21 concentrations greater than the median (> 103.5 pg/ml). Our data suggest that FGF 21 may have potentially adverse effects on the skeleton. Further characterisation is needed, particularly as FGF 21 analogues or agonists may be used to treat obesity-related metabolic disorders.

There is important variation in the occurrence of Paget's disease in different regions and populations. There are though few data concerning the occurrence of clinically diagnosed disease in black and ethnic minority groups in the United Kingdom (UK). We undertook an anonymised search using an integrated primary and secondary care-based database in Greater Manchester, covering a population of over 3 million people. We looked also among those with a first positive COVID test, the influence of Paget's disease on subsequent admission to hospital within 28 days. Within our database, there were 534,571 people aged 60 years and over alive on 1 January 2020. The majority were white (84%) with 4.7% identifying as Asian or Asian British, and 1.27% Black or Black British. There were 931 with clinically diagnosed Paget's disease. Overall prevalence in the greater Manchester area was 0.174%. Prevalence was higher in men than women (0.195 vs 0.155%). Compared to the prevalence of Paget's in whites (0.179%) the prevalence was lower among those identifying as Asian or Asian British (0.048%) and higher among those identifying as Black or Black British (0.344%). Prevalence increased with increasing deprivation. Clinically diagnosed Paget's disease is uncommon affecting 0.174% of men and women aged 60 or more years. Within Greater Manchester, it was more common in those identifying as Black or Black British and less common in those identifying as Asian or Asian British.

Bone formation is tightly modulated by genetically encoded molecular proteins that interact to regulate cellular differentiation and secretion of bony matrix. Many transcription factors are known to coordinate these events by controlling gene transcription within networks. However, not all factors involved are known. Here, we identified a novel function for Zinc Finger Homeobox 3 (Zfhx3), a gene encoding a transcription factor, as a regulator of bone metabolism. We knocked out Zfhx3 conditionally in mice in either chondrocytes or osteoblasts and characterized their bones by micro-CT in 12-week-old mice. We observed a negative effect in linear bone growth in both knockout mice but reduced bone mass only in mice with Zfhx3 deleted in osteoblasts. Loss of Zfhx3 expression in osteoblasts affected trabecular bone mass in femurs and vertebrae in both sexes but influenced cortical bone volume fraction only in females. Moreover, transcriptional analysis of femoral bones in osteoblast Zfhx3 conditional knockout mice revealed a reduced expression of osteoblast genes, and histological evaluation of trabecular bones suggests that Zfhx3 causes changes in bone formation and not resorption. The loss of Zfhx3 causes reductions in trabecular bone area and osteoid volume, but no changes in the expression of osteoclast differentiation markers or number of TRAP stained osteoclasts. These studies introduce Zfhx3 as a relevant factor toward understanding gene regulatory networks that control bone formation and development of peak bone mass.

Renin-angiotensin-aldosterone system plays a crucial role in the regulation of blood pressure and fluid homeostasis. It is reported to be involved in mediating osteoclastogenesis and bone loss in diseases of inflammatory bone resorption such as osteoporosis. Angiotensin-(1-7), a product of Angiotensin I and II (Ang I, II), is cleaved by Angiotensin-converting enzyme 2 and then binds to Mas receptor to counteract inflammatory effects produced by Ang II. However, the mechanism by which Ang-(1-7) reduces bone resorption remains unclear. Therefore, we aim to elucidate the effects of Ang-(1-7) on lipopolysaccharide (LPS)-induced osteoclastogenesis. In vivo, mice were supracalvarial injected with Ang-(1-7) or LPS ± Ang-(1-7) subcutaneously. Bone resorption and osteoclast formation were compared using micro-computed tomography, tartrate-resistant acid phosphatase (TRAP) stain, and real-time PCR. We found that Ang-(1-7) attenuated tumor necrosis factor (TNF)-α, TRAP, and Cathepsin K expression from calvaria and decreased osteoclast number along with bone resorption at the suture mesenchyme. In vitro, RANKL/TNF-α ± Ang-(1-7) was added to cultures of bone marrow-derived macrophages (BMMs) and osteoclast formation was measured via TRAP staining. The effect of Ang-(1-7) on LPS-induced osteoblasts RANKL expression and peritoneal macrophages TNF-α expression was also investigated. The effect of Ang-(1-7) on the MAPK and NF-κB pathway was studied by Western blotting. As a result, Ang-(1-7) reduced LPS-stimulated macrophages TNF-α expression and inhibited the MAPK and NF-κB pathway activation. However, Ang-(1-7) did not affect osteoclastogenesis induced by RANKL/TNF-α nor reduce osteoblasts RANKL expression in vitro. In conclusion, Ang-(1-7) alleviated LPS-induced osteoclastogenesis and bone resorption in vivo via inhibiting TNF-α expression in macrophages.

The gut microbiome is linked to osteoporosis. Previous clinical studies showed inconsistent results. This study aimed to characterize the gut microbiota feature and reveal its relation with diet in postmenopausal osteoporosis. Fifty-five postmenopausal women with osteoporosis (Op group) and forty-four age-matched postmenopausal women (normal bone mineral density, Con group) were included in this study. Fecal microbiota was collected and analyzed by shallow shotgun sequencing. Food frequency questionnaires were collected from both groups, and Spearman analysis was used to clarify its correlation with gut microbiota. A total of 2671 species from 29 phyla, 292 families, 152 orders, 80 classes were detected in the study. The two groups had no significant difference in the α and β diversity (p > 0.05). At the genus level, Anaerostipes was enriched in Op group (p < 0.05). At species level, Methanobrevibacter smithii, Bifidobacterium animalis, Rhodococcus defluvii, Lactobacillus plantarum, and Carnobacterium mobile were enriched in the Op group, while Bacillus luciferensis, Acetivibrio cellulolyticus, Citrobacter amalonaticus, and Bifidobacterium breve were differentially enriched in the Con group. Food frequency questionnaire showed that postmenopausal women with osteoporosis intaked more red meat, beer, white and red wine (p < 0.05), and the Con group had more yogurt, fruit, and tea consumption. Red meat consumption had a significant negative correlation with Streptosporangiales (p < 0.01) and Actinomadura (p < 0.05). Fruits intake negatively correlated with Nocardiaceae, Rhodococcus, and Rhodococcus defluvii (p < 0.05). More yogurt intake was consistently correlated with a greater abundance of Streptosporangiales. This study suggests that gut microbiota is significantly altered in the postmenopausal osteoporosis population at genus and species levels, and specific dietary intake might relate to these changes.

Osteoporosis is under-diagnosed while detectable by measuring bone mineral density (BMD) using quantitative computer tomography (QCT). Opportunistic screening for low BMD has previously been suggested using lumbar QCT. However, thoracic QCT also possesses this potential to develop upper and lower cut-off values for low thoracic BMD, corresponding to the current cut-offs for lumbar BMD. In participants referred with chest pain, lumbar and thoracic BMD were measured using non-contrast lumbar- and cardiac CT scans. Lumbar BMD cut-off values for very low (< 80 mg/cm³), low (80-120 mg/cm³), and normal BMD (> 120 mg/cm³) were used to assess the corresponding thoracic values. A linear regression enabled identification of new diagnostic thoracic BMD cut-off values. The 177 participants (mean age 61 [range 31-74] years, 51% women) had a lumbar BMD of 121.6 mg/cm³ (95% CI 115.9-127.3) and a thoracic BMD of 137.0 mg/cm³ (95% CI: 131.5-142.5), p < 0.001. Categorization of lumbar BMD revealed 14%, 35%, and 45% in each BMD category. When applied for the thoracic BMD measurements, 25% of participants were reclassified into a lower group. Linear regression predicted a relationship of Thoracic BMD = 0.85 * Lumbar BMD + 33.5, yielding adjusted thoracic cut-off values of < 102 and > 136 mg/cm³. Significant differences in BMD between lumbar and thoracic regions were found, but a linear relationship enabled the development of thoracic upper and lower cut-off values for low BMD in the thoracic spine. As Thoracic CT scans are frequent, these findings will strengthen the utilization of CT images for opportunistic detection of osteoporosis.

Osteoporosis is a significant health concern for postmenopausal women, necessitating efficient screening methods for bone health. This study explores the potential of muscle function, assessed through the 30-s chair stand test (CS-30), as an indicator for low bone stiffness in this demographic, aiming to establish a practical threshold for large-scale fitness surveillance without the need for specialized tools. We analyzed data from 1055 community-dwelling postmenopausal Japanese women, aged 41-89 years, collected between 2016 and 2019. Participants underwent CS-30 to evaluate muscle function alongside quantitative ultrasound (QUS) measurements to assess bone stiffness. The cohort was divided into two groups for the development and validation of a cutoff point for low bone stiffness, defined as a QUS speed of sound less than 1487.3 m/s. The CS-30 cutoff was determined using receiver operating characteristic (ROC) curve analysis and validated through logistic regression, accounting for age, body mass index, and smoking status. Among 577 postmenopausal women, 16.0% exhibited low bone stiffness. In the development group (n = 382), ROC analysis identified a CS-30 cutoff of 25 repetitions for detecting low bone stiffness, with an area under the curve of 0.744 (P < 0.001). In the validation group (n = 195), participants performing ≥ 25 repetitions had a higher risk of low bone stiffness compared to those performing ≤ 24 repetitions. The CS-30 test is an effective preliminary screening tool for identifying postmenopausal women at risk of low bone stiffness, with a threshold of 25 repetitions. This method could facilitate early detection of individuals at higher osteoporosis risk, promoting timely intervention.