Calcified Tissue International最新文献

This study aims to identify novel loci associated with sarcopenia-related traits in UK Biobank (UKB) through multi-trait genome-wide analysis. To identify novel loci associated with sarcopenia, we integrated the genome-wide association studies (GWAS) of usual walking pace (UWP) and hand grip strength (HGS) to conduct a joint association study known as multi-trait analysis of GWAS (MTAG). We performed a transcriptome-wide association study (TWAS) to analyze the results of MTAG in relation to mRNA expression data for genes identified in skeletal muscle. Additionally, we utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to explore the relationships between the identified genes and hub genes related to sarcopenia. We identified 15 novel loci associated with UWP and 5 novel loci associated with HGS at the genome wide significance level (GWS, $p<5\times {10}^{-8}$ ). After TWAS ( $p_{\mathrm{TWAS}}<6.659\times {10}^{-6},0.05/7509$ ), we found two significant genes: PPP1R3A, located at 7q31.1 and associated with HGS, and ZBTB38, located at 3q23 and associated with UWP. 11 identified genes associated with hub genes for sarcopenia were obtained through WGCNA. Our findings offer new insights into biological mechanisms underlying sarcopenia and identify several novel genes related to sarcopenia that warrant in-depth study.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an uncommon hereditary form of rickets characterised by chronic renal phosphate loss and impaired bone mineralisation. This results from compound heterozygous or homozygous pathogenic variants in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), a key producer of extracellular inorganic pyrophosphate (PPi) and an inhibitor of fibroblast growth factor23 (FGF23). ENPP1 deficiency impacts FGF23 and increases its activity. Inactivating ENPP1 variants are associated with both Generalised Arterial Calcification of Infancy (GACI) and ARHR2, even within the same family. Both conditions share a deficiency of ENPP1, displaying clinical variability without a clear genotype-phenotype correlation. Whilst pathogenic ENPP1 variants are known to be associated with various phenotypes, including vascular calcification, hearing loss, ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum (PXE), skull changes have not been reported to our knowledge. We present herein a case of a 10-year-old girl with ARHR2, due to compound heterozygous pathogenic ENPP1 variants, who was found to have papilledema on a routine eye test. Neuroimaging revealed enlarged lateral ventricles, compression of the spinal cord at the foramen magnum with Chiari 1 malformation and a retroverted odontoid peg. She underwent two endoscopic third ventriculostomy procedures to manage the hydrocephalus and a further foramen magnum decompression procedure to alleviate her headaches and neck pain concerns. Individuals with ARHR2 may experience alterations at the base of the skull, potentially leading to base of skull narrowing, chronic hydrocephalus, and Chiari malformation.

Osteogenesis imperfecta (OI) is a group of rare genetic disorders most commonly caused by reduced amount of biologically normal collagen type I, a structural component of the gastrointestinal tract and abdominal wall. The risk of gastrointestinal (GI) disease in individuals with OI is not well understood, despite GI complaints being frequently reported by the OI population. To investigate the risk of GI diseases in individuals with OI. A Danish nationwide register-based cohort study utilizing data from the Danish National Patient Register and the Danish National Prescription Register. All individuals registered with an OI diagnosis in Denmark from 1995 through 2018, along with a reference population matched 1:5 based on sex, birth year, and month. Sub-hazard ratios (SHR) for peptic ulcer disease, diverticular disease, gastrointestinal cancers, intestinal obstruction with ileus, constipation, abdominal wall hernia, and other reasons for abdominal discomfort. The study included 864 individuals with OI (472 women) and 4,276 in the reference population (2,332 women). The SHR was significantly increased for ulcer (3.28 [95% CI 2.21-4.28]), constipation (2.67 [1.91-3.74]), and hernia (among women: 1.85 [1.22-2.80]). Higher SHRs were also observed for inflammatory bowel disease, biliary and pancreatic diseases, appendicitis, and unspecified abdominal pain. SHRs were not statistically significantly increased for diverticular disease, gastrointestinal cancers, intestinal obstruction with ileus, kidney stones or hemorrhoid disease. Individuals with OI have a higher risk of peptic ulcer disease, constipation, hernia among women, inflammatory bowel diseases, biliary and pancreatic diseases, appendicitis, and unspecified abdominal pain, compared with the general population.

Human dentin performs its function throughout life, even though it is not remodeled like bone. Therefore, dentin must have extreme durability against daily repetitive loading. Elucidating its durability requires a comprehensive understanding of its shape, structure, and anisotropy at various levels of its structure. However, few studies have examined the nanostructure of dentin as a whole and not much is known about its age-related changes. Our aim is to characterize the mineral particle characteristics of human dentin and age-related changes using synchrotron scanning small- and wide-angle X-ray scattering. 30 molar and premolar teeth extracted from 16 to 77-year-old individuals for orthodontic or periodontal reasons were used. Synchrotron-based X-ray scattering was employed to acquire two-dimensional maps of nanostructural features. These maps revealed a negative gradient of particle size toward the pulp chamber. The preferential orientation of particles was position-dependent, with a higher orientation in the area from the pulp horn to the cusp tip and root region. These patterns were maintained in different tooth types. The mineral particle thickness of the inner crown increased significantly with age. This increase could relate to the filling of tubules and, therefore, likely contribute to the deterioration of the mechanical performance of teeth with age.

Hyperparathyroidism-jaw tumor syndrome is a rare form of syndromic primary hyperparathyroidism. We describe a young female with a history of common precursor B acute lymphoblastic leukaemia who was diagnosed with overt primary hyperparathyroidism due to a pathogenic CDC73 variant (c.25C > T). This patient posed several challenging management aspects: the development of nephrocalcinosis, the risk for parathyroid carcinoma, and persistent hyperparathyroidism after two selective parathyroidectomies, leading to the decision to perform a total parathyroidectomy. The latter resulted in permanent complete hypoparathyroidism, with subsequent difficult medical therapy. This case report illustrates the challenge to identify the optimal treatment of parathyroid disease in the context of hyperparathyroidism-jaw tumor syndrome, balancing the risks of hyperparathyroidism and parathyroid carcinoma against the burden of permanent hypoparathyroidism at young age.

Patients with radiographic axial spondyloarthritis (r-axSpA) experience a higher prevalence of fragility fractures, though the pathophysiology of osteoporosis associated with this disease remains poorly understood. The objective of this study was to evaluate the histomorphometric data in r-axSpA patients. Male r-axSpA patients up to 55 years old were enrolled in this cross-sectional study. Clinical, lab, and imaging data, including spine X-Ray to evaluate vertebral fractures and new bone formation, as well as dual-energy X-ray absorptiometry (DXA) at spine, hip, and forearm and trabecular bone score (TBS), were performed in all patients. Transiliac histomorphometry was also underwent in all patients, and data were compared with 21 male cadavers' material. A total of 21 patients were included, with a mean age of 45.8 years, long disease duration (median 17.5 years), mostly white (66.7%) and positive for HLA-B27 (90.5%). The prevalence of DXA abnormalities and low TBS (≤ 1.338) was 42.8% and 57.1%, respectively. There was higher osteoid trabecular thickness (p = 0.027) and cortical bone changes, including reduced thickness (p = 0.031) and increased porosity (p = 0.015) in r-axSpA patients. In addition, a pattern of cortical trabecularization was observed in 52.3%. Dynamic evaluation revealed a longer mineralization lag time (p = 0.0074) and lower mineralized surface (p = 0.0029) and bone formation rate (p = 0.0074) in patients compared to reference values. Our results showed a pattern of low trabecular remodeling, bone mineralization impairment, as well as cortical thickness and porosity abnormalities in men with r-axSpA. These findings may impact future treatment of bone fragility in this disease.

Rett syndrome (RS) is a rare neurodevelopmental disorder primarily caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene, responsible for encoding MECP2 which plays a pivotal role in regulating gene expression. The neurological and non-neurological manifestations of RS vary widely in severity depending on the specific mutation type. Bone complications, mostly scoliosis but also osteoporosis, hip displacement, and a high rate of fractures, are among the most prevalent non-neurological comorbidities observed in girls with RS. Low bone mineral density (BMD) is primarily due to a slow rate of bone formation due to dysfunctional osteoblast activity. The use of anticonvulsants, immobilization, low physical activity, poor nutrition, and inadequate vitamin D intake all significantly hamper skeletal maturation and the accumulation of bone mass in RS girls, making them more susceptible to fragility fractures. In RS patients, the upper and lower limbs are the most common sites for fractures which are due to both a reduced BMD and a diminished bone size. This review summarizes the knowledge on risk factors for fragility fracture in patients with RS and proposes a potential diagnostic and therapeutic pathway to enhance low BMD and mitigate the risk of fragility fractures. In particular, this review focused on the importance of clinical and instrumental evaluation of bone status as a basis for adequate planning of nutritional, pharmacological, and surgical interventions to be undertaken. Additionally, the management of bone defects in individuals with RS should be customized to meet each person's specific needs, abilities, and general health.

This study assessed the feasibility of miR17 ~ 92-based antiresorptive strategy by determining the effects of conditional transgenic (cTG) overexpression of miR17 ~ 92 in myeloid cells on bone and osteoclasts. Osteoclasts of male and female cTG mutant mice each showed 3- to fivefold overexpression of miR17 ~ 92 cluster genes compared to those of age- and sex-matched wildtype (WT) littermates. Male but not female cTG mutant mice had more trabecular and cortical bones as well as lower bone resorption reflected by reduction in osteoclast number and resorbing surface. Osteoclasts of male but not female cTG mutants showed decreased bone resorption activity. Consistent with suppression of osteoclast maturation, osteoclasts of male cTG mutants were smaller, contained less nuclei, showed reduced levels of mRNA of genes associated with osteoclast differentiation and fusion, and formed more diffused actin ring. Osteoclastic overexpression of miR17 ~ 92 also increased bone formation, but the increase was much larger in males than in females. The increase in male mutants was due to higher mineral apposition rate, and conversely, it was caused by increasing bone-forming surface in female mutants. In summary, osteoclastic overexpression of miR17 ~ 92 increased bone mass through reduction in bone resorption along with coupled increase in bone formation in male-specific manner. Although the osteoclastic overexpression of miR17 ~ 92-induced suppression of bone resorption and increases in bone formation support the feasibility of miR17 ~ 92-based antiresorptive strategies, the male-specific sexual disparity in skeletal responses to osteoclastic overexpression of miR17 ~ 92 could limit its clinical utility as it may not be used in women with postmenopausal osteoporosis.