Genetic polymorphism of miR-196a-2 is associated with bone mineral density (BMD)

MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate the translation of messenger RNAs. Given the crucial role of miRNAs in gene expression, genetic variants within miRNA-related sequences may affect miRNA function and contribute to disease risk. Osteoporosis is characterized by reduced bone mass, and bone mineral density (BMD) is a major diagnostic proxy to assess osteoporosis risk. Here, we aimed to identify miRNAs that are involved in BMD using data from recent genome-wide association studies (GWAS) on femoral neck, lumbar spine and forearm BMD. Of 242 miRNA-variants available in the GWAS data, we found rs11614913:C > T in the precursor miR-196a-2 to be significantly associated with femoral neck-BMD (p-value = 9.9 × 10-7, β = −0.038) and lumbar spine-BMD (p-value = 3.2 × 10-11, β = −0.061). Furthermore, our sensitivity analyses using the Rotterdam study data showed a sex-specific association of rs11614913 with BMD only in women. Subsequently, we highlighted a number of miR-196a-2 target genes, expressed in bone and associated with BMD, that may mediate the miRNA function in BMD. Collectively, our results suggest that miR-196a-2 may contribute to variations in BMD level. Further biological investigations will give more insights into the mechanisms by which miR-196a-2 control expression of BMD-related genes

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

Helical networks of π‐conjugated rods – a robust design concept for bicontinuous cubic liquid crystalline phases with Ia3d and chiral I23 lattice

Bicontinuous cubic liquid crystalline phases of π‐conjugated molecules, representing self‐assembled 3D‐ordered interpenetrating networks with cubic symmetry, are receiving increasing attention due to their capacity for charge transport in all three dimensions and their inherent spontaneous helicity. Herein, a robust general design concept for creating bicontinuous cubic phases is reported. It is based on a nonsymmetric‐substituted π‐conjugated 5,5′‐diphenyl‐2,2′‐bithiophene platform with one end containing three out‐fanning flexible chains and with a range of substituents at the other end (the apex). The cubic phases are stable over broad temperature ranges, often down to ambient temperature, and tolerate a wide range of apex substitution patterns, allowing structural diversity and tailoring of the cubic phase type and application‐relevant properties. With an increasing number and size of apex substituents, a sequence of three different modes of cubic self‐assembly is observed, following an increasing helical twist. Thus, two ranges of the achiral double network Ia 3d phase range can be distinguished, a long pitch and a short pitch, with the chiral triple network I23 cubic phase in the intermediate pitch range. The findings provide a new prospect for the directed design of cubic phase‐forming functional materials based on spontaneously formed helical network liquid crystals with tunable application specific properties

MskAge—An Epigenetic Biomarker of Musculoskeletal Age Derived From a Genetic Algorithm Islands Model

\ua9 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.Age is a significant risk factor for functional decline and disease of the musculoskeletal system, yet few biomarkers exist to facilitate ageing research in musculoskeletal tissues. Multivariate models based on DNA methylation, termed epigenetic clocks, have shown promise as markers of biological age. However, the accuracy of existing epigenetic clocks in musculoskeletal tissues are no more, and often less accurate than a randomly sampled baseline model. We developed a highly accurate epigenetic clock, MskAge, that is specific to tissues and cells of the musculoskeletal system. MskAge was built using a penalised genetic algorithm islands model that addresses multi-tissue clock bias. The final model was trained on the transformed principal components of CpGs selected by the genetic algorithm. We show that MskAge tracks epigenetic ageing ex vivo and in vitro. Epigenetic age estimates are rejuvenated with cellular reprogramming and are accelerated at a rate of 0.45 years per population doubling. MskAge explains more variance associated with in vitro ageing of fibroblasts than the purpose-developed skin and blood clock. The precision of MskAge and its ability to capture perturbations in biological ageing make it a promising research tool for musculoskeletal and ageing biologists

Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ~4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20-0.24). To explore the basis fo

The DLEU2–miR-15a–16-1 Cluster Is a Determinant of Bone Microarchitecture and Strength in Postmenopausal Women and Mice

\ua9 2024 by the authors. This study explores how select microRNAs (miRNAs) influence bone structure in humans and in transgenic mice. In trabecular bone biopsies from 84 postmenopausal women (healthy, osteopenic, and osteoporotic), we demonstrate that DLEU2 (deleted in lymphocytic leukemia 2)-encoded miR-15a-5p is strongly positively associated with bone mineral density (BMD) at different skeletal sites. In bone transcriptome analyses, miR-15a-5p levels correlated positively with the osteocyte characteristic transcripts SOST (encoding sclerostin) and MEPE (Matrix Extracellular Phosphoglycoprotein), while the related miR-15b-5p showed a negative association with BMD and osteoblast markers. The data imply that these miRNAs have opposite roles in bone remodeling with distinct actions on bone cells. Expression quantitative trait loci (eQTL) variants confirmed earlier DLEU2 associations. Furthermore, a novel variant (rs12585295) showed high localization with transcriptionally active chromatin states in osteoblast primary cell cultures. The supposition that DLEU2-encoded miRNAs have an important regulatory role in bone remodeling was further confirmed in a transgenic mice model showing that miR-15a/16-1-deleted mice had significantly higher percentage bone volume and trabecular number than the wild type, possibly due to prenatal actions. However, the three-point mechanical break force test of mice femurs showed a positive correlation between strength and miR-15a-5p/miR-16-5p levels, indicating differential effects on cortical and trabecular bone. Moreover, these miRNAs appear to have distinct and complex actions in mice prenatally and in adult humans, impacting BMD and microstructure by regulating bone cell transcription. However, detailed interactions between these miRNAs and their downstream mechanisms in health and disease need further clarification

A semi-synthetic oligosaccharide conjugate vaccine candidate confers protection against Streptococcus pneumoniae serotype 3 infection

The identification of immunogenic glycotopes that render glycoconjugate vaccines protective is key to improving vaccine efficacy. Synthetic oligosaccharides are an attractive alternative to the heterogeneous preparations of purified polysaccharides that most marketed glycoconjugate vaccines are based on. To investigate the potency of semi-synthetic glycoconjugates, we chose the least-efficient serotype in the current pneumococcal conjugate vaccine Prevnar 13, Streptococcus pneumoniae serotype 3 (ST3). Glycan arrays containing synthetic ST3 repeating unit oligosaccharides were used to screen a human reference serum for antibodies and to define the recognition site of two ST3-specific protective monoclonal antibodies. The glycan array screens identified a tetrasaccharide that was selected for in-depth immunological evaluation. The tetrasaccharide-CRM197 carrier protein conjugate elicited protective immunity as evidenced by opsonophagocytosis assays and protection against pneumonia caused by ST3 in mice. Formulation of the defined protective lead candidate glycotope has to be further evaluated to elicit optimal long-term immunity

A semisynthetic glycoconjugate provides expanded cross-serotype protection against Streptococcus pneumoniae

Streptococcus pneumoniae (S. pneumoniae) infections are the leading cause of child mortality globally. Current vaccines fail to induce a protective immune response towards a conserved part of the pathogen, resulting in new serotypes causing disease. Therefore, new vaccine strategies are urgently needed. Described is a two-pronged approach combining S. pneumoniae proteins, pneumolysin (Ply) and pneumococcal surface protein A (PspA), with a precisely defined synthetic oligosaccharide, whereby the carrier protein acts as a serotype-independent antigen to provide additional protection. Proof of concept in mice and swine models revealed that the conjugates inhibited colonization of the nasopharynx, decreased the bacterial load and reduced disease severity in the bacteria challenge model. Immunization of piglets provided the first evidence for the immunogenicity and protective potential of synthetic glycoconjugate vaccine in a large animal model. A combination of synthetic oligosaccharides with proteins from the target pathogen opens the path to create broadly cross-protective (“universal”) pneumococcal vaccines

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

A prospective, longitudinal study to assess progression of ocular surface signs, tear cytokines and protein profiles in young adults

PURPOSE: To compare ocular surface characteristics, tear protein profiles, and cytokines in young adults with and without evaporative dry eye disease (DED), exploring any associations with lifestyle factors, and determine any progression after one year. METHODS: Fifty participants, aged 18-25 years, were recruited. Detailed ocular surface parameters were assessed following administration of lifestyle and symptom questionnaires. Tear samples collected by microcapillary tubes were analysed using the Agilent Bioanalyzer (7 proteins between 14–230 kDa); tears collected with Schirmer strips were analysed for ten cytokines using Luminex Assay. RESULTS: 6% of participants fulfilled the TFOS DEWS II criteria for DED. 48% had at least 25% meibomian gland loss in either lid regardless of dry eye status, while over 90% had at least one diagnostic sign. Progression was observed, characterised by significant increases (p<0.05) in ocular redness, lid wiper epitheliopathy and blink rate. Albumin was upregulated (p=0.003) in DED, while zinc-α2-glycoprotein, which showed significant correlations with several meibomian gland parameters, was downregulated. Upregulation of both pro- and anti-inflammatory cytokines was observed, with several significant clinical correlations, including IL-1β with meibomian gland parameters. CONCLUSIONS: Evidence of inflammation and overlap of ocular signs in these young adults reinforces the need for early detection and differentiation of those likely to progress to DED. While upregulation of both pro- and anti-inflammatory cytokines has provided evidence of a mechanism to maintain homeostasis, the subtle progression of ocular surface disease observed suggests that counselling is required around the modifiable risk factors of DED identified, regardless of whether symptoms are present or not