Epigenetic Regulation of Bone Remodeling and Its Impacts in Osteoporosis

Ghayor, Chafik; Weber, Franz E.

doi:10.3390/ijms17091446

Cited by 103 publications

(62 citation statements)

References 110 publications

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“…It is reported that HDAC inhibition by TSA promotes osteoblast maturation in vitro , inhibits osteoclast differentiation of bone marrow cells4849 and mitigated osteoporotic injuries in animal studies50. Interestingly, previous studies reported that bone expressed low levels of Klotho5152 and we found that TSA also substantially recovered the Klotho loss in adenine mouse femurs, which likely exerting a local protective effects.…”

Section: Discussionsupporting

confidence: 57%

Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice

Lin

Chen

et al. 2017

Sci Rep

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Bone loss and increased fracture are the devastating outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD) resulting from Klotho deficit-related mineral disturbance and hyperparathyroidism. Because Klotho down-regulation after renal injury is presumably affected by aberrant histone deacetylase (HDAC) activities, here we assess whether HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD. Mice fed adenine-containing diet developed the expected renal damage, a substantial Klotho loss and the deregulated key factors causally affecting bone remodeling, which were accompanied by a marked reduction of bone mineral density. Intriguingly, administration of a potent HDAC inhibitor trichostatin A (TSA) impressively alleviated the Klotho deficit and the observed alterations of serum, kidney and bone. TSA prevented Klotho loss by increasing the promoter-associated histone acetylation, therefore increasing Klotho transcription. More importantly the mice lacking Klotho by siRNA interference largely abolished the TSA protections against the serum and renal abnormalities, and the deranged bone micro-architectures. Thus, our study identified Klotho loss as a key event linking HDAC deregulation to the renal and bone injuries in CKD-MBD mice and demonstrated the therapeutic potentials of endogenous Klotho restoration by HDAC inhibition in treating CKD and the associated extrarenal complications.

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Section: Discussionsupporting

confidence: 57%

Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice

Lin

Chen

et al. 2017

Sci Rep

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“…Epigenetic mechanisms, in general, and DNA methylation, in particular, regulate gene expression in several diseases, including critical genes implicated in bone metabolism . A close interaction exists between immune and skeletal systems because of shared expression of several cytokines and transcription factors consistent with a role for osteoimmunology in bone disorders .…”

Section: Introductionmentioning

confidence: 99%

Identification of an Epigenetic Signature of Osteoporosis in Blood DNA of Postmenopausal Women

Cheishvili

Parashar

Mahmood

et al. 2018

Journal of Bone and Mineral Research

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Osteoporosis is one of the most common age-related progressive bone diseases in elderly people. Approximately one in three women and one in five men are predisposed to developing osteoporosis. In postmenopausal women, a reduction in BMD leads to an increased risk of fractures. In the current study, we delineated the DNA methylation signatures in whole blood samples of postmenopausal osteoporotic women. We obtained whole blood DNA from 22 normal women and 22 postmenopausal osteoporotic women (51 to 89 years old) from the Canadian Multicenter Osteoporosis Study (CaMos) cohort. These DNA samples were subjected to Illumina Infinium human methylation 450 K analysis. Illumina 450K raw data were analyzed by Genome Studio software. Analysis of the female participants with early and advanced osteoporosis resulted in the generation of a list of 1233 differentially methylated CpG sites when compared with age-matched normal women. T test, ANOVA, and post hoc statistical analyses were performed, and 77 significantly differentially methylated CpG sites were identified. From the 13 most significant genes, ZNF267, ABLIM2, RHOJ, CDKL5, and PDCD1 were selected for their potential role in bone biology. A weighted polygenic DNA methylation score of these genes predicted osteoporosis at an early stage with high sensitivity and specificity and correlated with measures of bone density. Pyrosequencing analysis of these genes was performed to validate the results obtained from Illumina 450 K methylation analysis. The current study provides proof of principal for the role of DNA methylation in osteoporosis. Using whole blood DNA methylation analysis, women at risk of developing osteoporosis can be identified before a diagnosis of osteoporosis is made using BMD as a screening method. Early diagnosis will help to select patients who might benefit from early therapeutic intervention. © 2018 American Society for Bone and Mineral Research.

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“…There is evidence that DNA methylation at various genes, including cyclin‐dependent kinases such as CDKN2A , plays a role in skeletal development, homeostasis, and bone cell activity. Thus methylation has been implicated in mechanisms of osteoblastic differentiation and osteoclastogenesis, together with the transition from osteoblast to osteocyte . These experimental findings are complemented by data from genome‐wide methylation profiling studies in older patients, demonstrating differential methylation at genes such as the cyclin‐dependent kinase inhibitor CKDN1C and cyclin‐dependent kinase CDK20 is associated with BMD .…”

Section: Introductionmentioning

confidence: 89%

Perinatal DNA Methylation at CDKN2A Is Associated With Offspring Bone Mass: Findings From the Southampton Women's Survey

Curtis

Murray

Titcombe

et al. 2017

Journal of Bone and Mineral Research

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Poor intrauterine and childhood growth has been linked with the risk of osteoporosis in later life, a relationship that may in part be mediated through altered epigenetic regulation of genes. We previously identified a region within the promoter of the long non‐coding RNA ANRIL encoded by the CDKN2A locus, at which differential DNA methylation at birth showed correlations with offspring adiposity. Given the common lineage of adipocytes and osteoblasts, we investigated the relationship between perinatal CDKN2A methylation and bone mass at ages 4 and 6 years. Using sodium bisulfite pyrosequencing, we measured the methylation status of the 9 CpGs within this region in umbilical cord samples from discovery (n = 332) and replication (n = 337) cohorts of children from the Southampton Women's Survey, whose bone mass was assessed by dual‐energy X‐ray absorptiomietry (DXA; Hologic Discovery). Inverse associations were found between perinatal CDKN2A methylation and whole‐body minus head bone area (BA), bone mineral content (BMC), and areal bone mineral density (BMD). This was confirmed in replication and combined data sets (all p < 0.01), with each 10% increase in methylation being associated with a decrease in BMC of 4 to 9 g at age 4 years (p ≤ 0.001). Relationships were similar with 6‐year bone mass. Functional investigation of the differentially methylated region in the SaOS‐2 osteosarcoma cell line showed that transcription factors bound to the identified CpGs in a methylation‐specific manner and that CpG mutagenesis modulated ANRIL expression. In conclusion, perinatal methylation at CDKN2A is associated with childhood bone development and has significance for cell function. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Epigenetic Regulation of Bone Remodeling and Its Impacts in Osteoporosis

Cited by 103 publications

References 110 publications

Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice

Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice

Identification of an Epigenetic Signature of Osteoporosis in Blood DNA of Postmenopausal Women

Perinatal DNA Methylation at CDKN2A Is Associated With Offspring Bone Mass: Findings From the Southampton Women's Survey

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