Role of Epigenomics in Bone and Cartilage Disease

Abstract

Phenotypic variation in skeletal traits and diseases is the product of genetic and environmental factors. Epigenetic mechanisms include information-containing factors, other than DNA sequence, that cause stable changes in gene expression and are maintained during cell divisions. They represent a link between environmental influences, genome features, and the resulting phenotype. The main epigenetic factors are DNA methylation, posttranslational changes of histones, and higher-order chromatin structure. Sometimes non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are also included in the broad term of epigenetic factors. There is rapidly expanding experimental evidence for a role of epigenetic factors in the differentiation of bone cells and the pathogenesis of skeletal disorders, such as osteoporosis and osteoarthritis. However, different from genetic factors, epigenetic signatures are cell-and tissue-specific and can change with time. Thus, elucidating their role has particular difficulties, especially in human studies. Nevertheless, epigenomewide association studies are beginning to disclose some disease-specific patterns that help to understand skeletal cell biology and may lead to development of new epigenetic-based biomarkers, as well as new drug targets useful for treating diffuse and localized disorders. Here we provide an overview and update of recent advances on the role of epigenomics in bone and cartilage diseases.Besides chromatin-related marks and structure, non-coding RNAs (ncRNAs) are also frequently included among the mechanisms of epigenetic control. (8) They are classified as small RNAs (<200 nucleotides) and long RNAs (>200 nucleotides). The best-known subset of small RNAs are microRNAs (miRNAs, 18 to 25 nucleotides), which inhibit protein synthesis by binding to the 3 0 -untranslated region of target mRNAs. Long non-coding RNAs (lncRNAs) modulate the activity of both nearby genes and distant genes by a variety of mechanisms. For instance, they often serve as scaffolds for transcription factors and other molecules involved in initiation of transcription, including Box 1. Epigenomics-Related TermsChromatin: The complex of DNA and its packaging molecules. The core of the chromatin is the nucleosome, which consists of an octamer of 4 histones around which 147 bp of DNA is wrapped around.Chromosome conformation capture and Hi-C: Techniques used to map the spatial (3D) organization of the chromatin in the nucleus. Chromosome conformation capture (3C) quantifies the number of interactions between a given loci and the rest of the genome. In Hi-C, all genomic interaction between all genomic regions are quantified.CTCF: CCCTC-binding factor, highly conserved zinc finger protein involved in diverse genomic regulatory functions, including transcriptional activation/repression, insulation, imprinting, and X-chromosome inactivation, through mediating the formation of chromatin loops. DNA methyl-transferases (DNMTs): Family of enzymes responsible for the methylation of DNA. DNMT1...

Diabetes Mellitus Accelerates Progression of Osteoarthritis in Streptozotocin-induced Diabetic Mice by Deteriorating Bone Microarchitecture, Bone Mineral Composition and Bone Strength of Subchondral Bone

“…Due to mice small size, a 0.8 mm diameter flat-tipped cylindrical punch was fixed to the actuator of the materials testing machine and compressed directly to record the mechanical properties data. Uma Sankar and many studies developed and improved this method to measure the axial compressive strength of the cancellous bone in femur of mice, which is more precise and visual than finite element modeling [38][39][40][41][42][43]. The present result in Sham group was consistent with form studies.…”

Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model

“…Epigenetic modifications in bone cells affect the development and therapeutic sensitivity of osteoporosis [35]. An MSC transplantation study showed that MSC-derived exosomes transfer FAS to BMMSCs of recipient FAS-mutated MRL/lpr mice to modify the DNA methylation status of Notch, bone volume in OVX mice.…”

“…SHED-EVs also rescued the impaired function of recipient BMMSCs by regulating Tert-associated telomerase activity. Thus, SHED-EVs appear to play a crucial role in the biological crosstalk between donor SHED and recipient BMMSCs to achieve therapeutic effects in postmenopausal osteoporosis.Epigenetic modifications in bone cells affect the development and therapeutic sensitivity of osteoporosis [35]. An MSC transplantation study showed that MSC-derived exosomes transfer FAS to BMMSCs of recipient FAS-mutated MRL/lpr mice to modify the DNA methylation status of Notch, bone volume in OVX mice.…”

Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model

“…Epigenetic modi cations in bone cells affect the development and therapeutic sensitivity of osteoporosis [47]. An MSC transplantation study show that MSC-derived exosomes transfer FAS to BMMSCs of recipient FAS-mutated MRL/lpr mice to modify the DNA methylation status of Notch, resulting in the rescue of impaired recipient BMMSC function [15].…”