The decline of tissue function in ageing is a consequence of many changes in the gene expression and other extrinsic factors. The molecular mechanisms underlying these changes are heavily investigated with focus on regulation of time-lapse gene expression. microRNAs, short non-coding RNA molecules are among the major regulators of gene expression. microRNAs have been shown to control ageing-related mechanisms and several evidence suggest age-related changes in microRNA transcriptome. However, the source regulator of time-lapse gene expression control still remains unknown. Here we reviewed microRNA molecules related to the ageing of bones and studies that investigated age-related bone tissue gene expression. We identified 41 microRNAs molecules from the literature that correlate with bone mineral density or fractures and one recent study demonstrated how a combination of several microRNAs can be used for better prediction of the fractures in osteoporotic patients. The personalised diagnostic algorithms in the future should be therefore based on the combination of multiple biomarkers. Until now little is known about the regulatory mechanisms of microRNA expression and genes in agening. We propose a link between telomere length and gene expression profiles, however this now needs to be further investigated
COBISS.SI-ID: 4298353
Background: Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mineral density and microarchitectural deterioration of bone tissue, resulting in bone fragility and low trauma fractures. Imaging techniques are used routinely to detect low bone mass; however, they are unable to identify deterioration of bone quality. Recently, microRNAs have emerged as regulators of bone remodelling and potentially also as a new class of sensitive biomarkers of bone health to aid in diagnosis and treatment monitoring of osteoporosis. Methods: To identify new plasma-based biomarkers associated with osteoporosis we analysed microRNAs isolated from plasma samples of 74 postmenopausal women divided into osteoporotic (N=17) and control groups (N=57). A prior microRNA screening was performed where a few showed promise for further analysis. Quantitative polymerase chain reaction was used to investigate differences in expression of let-7d-5p, let-7e-5p, miR-30d-5p, miR-30e-5p, miR-126-3p, miR-148a-3p, miR-199a-3p, miR-423-5p and miR-574-5p, between the two groups. Furthermore, correlation analysis between miRNA expression levels and patient bone mineral density measurements and FRAX as well as trabecular bone scores were performed. Results: Expression of miR-148a-3p was significantly higher (p = 0.042) in the osteoporotic patient group compared to the control. In addition, we identified a correlation between miR-126-3p (% = 0.253, p = 0.032) and 423-5p (% = %0.230, p = 0.049) and parameters of bone quality and quantity. Conclusion: Results from our study, together with the functional role of miR-148a-3p in bone suggest, that this miRNA could be considered as a potential new plasma-based biomarker for pathological changes associated with osteoporosis.
COBISS.SI-ID: 4247153
Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through [alpha]2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of [alpha]2A-AR in bone. The aim of this study was to investigate the presence of [alpha]2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate [alpha]2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in [alpha]2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-timePCR, genetic association study between rs553668 A)G and rs1800544 C)GSNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. [alpha2A-AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on [alpha]2A-AR mRNA level in human bone samples through the stability of mRNA. [alpha]2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that [alpha]2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in [alpha]2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis.
COBISS.SI-ID: 3887217
Purpose of the study: Sufficient oxygen supply to bone tissue is essential for normal bone development and efficient bone repair. Hypoxia and hypoxia-inducible factor 1Ž (HIF1Ž) signaling pathway have been shown to exhibit profound effects on proliferation, differentiation as well as gene and protein expression in osteoblasts, osteoclasts and mesenchymal stem cells; however, as epigenetic mechanisms also perform an important regulatory role in these cells, our aim was to elucidate whether hypoxia mimetic deferoxamine could influence epigenetic mechanisms in bone cells by modulating the gene expression levels of chromatin-modifying enzymes. Materials and methods: Osteoblast cell line HOS was exposed to deferoxamine, a widely used hypoxia mimetic, and expression profile of 40 genes associated with histone acetylation, deacetylation and DNA methylation was determined using quantitative real time polymerase chain reaction (qPCR) array followed by individual qPCR analyses. In addition, genes associated with hypoxia response,RANK/RANKL/OPG system, WNT/Ž-catenin signaling pathway and oxidative stress were also analyzed. Results: We observed induced expression of histone deacetylase 9 (HDAC9) and suppressed expression of K(lysine) acetyltransferase 5 (KAT5) and DNA methyltransferase 3A (DNMT3A) demonstrating for the first time that expression of genes encoding chromatin-modifying enzymes could be influenced by hypoxia mimetic in HOS cells. Conclusions: Based on our results we can conclude that hypoxia mimetic deferoxamine influences expression of histone acetylation- and DNA methylation-associated genes in osteoblasts and that further studies of hypoxia-induced epigenetic changes in bone cells should be undertaken.
COBISS.SI-ID: 3879793
Epigenetics refers to the study of mechanisms able to influence gene expression in a stable and potentially heritable manner without altering the DNA sequence. These mechanisms include posttranslational histone modifications, miRNA-mediated post-transcriptional regulation and DNA methylation. The accumulation of molecular errors over time resulting, at least partly, in the alteration of normal epigenetic patterns is being widely associated with aging. Epigenetic processes are also considered important mechanisms through which environmental and stochastic stressors promote numerous pathologies in humans. It is, therefore, reasonable to expect that several complex multi-factorial late-onset disorders, like osteoporosis and osteoarthritis, could have a strong epigenetic component. The focal point of all skeletal pathologies is the deregulation of bone remodeling, mediated by bone-forming osteoblasts and boneresorbing osteoclasts. In order to keep both processes in balance, the activity, differentiation and apoptosis of both cell types have to be tightly regulated. In particular, the differentiation of osteoblasts and osteoclasts is accompanied by profound changes in gene expression. It has been shown that histone deacetylation and DNA methylation negatively regulate the expression of several genes associated with different stages of osteoblast differentiation; however, several miRNAs promote osteoblastogenesis. Furthermore, inactivating mutations in the miRNA coding regions could be associated with the pathogenesis of osteoporosis. The aim of this review is to highlight the role of epigenetic mechanisms in bone remodeling and bone homeostasis, so as to implicate their diagnostic and therapeutic potential in skeletal diseases.
COBISS.SI-ID: 3604593