Renal Kallikrein Excretion and Epigenetics in Human Acute Kidney Injury: Expression, Mechanisms and Consequences

Abstract

Bone is a complex connective tissue characterized by a calcified extracellular matrix. This mineralized matrix is constantly being formed and resorbed throughout life, allowing the bone to adapt to daily mechanical loads and maintain skeletal properties and composition. The imbalance between bone formation and bone resorption leads to changes in bone mass. This is the case of osteoporosis and osteoarthritis, two common skeletal disorders. While osteoporosis is characterized by a decreased bone mass and, consequently, higher susceptibly to fractures, bone mass tends to be higher in patients with osteoarthritis, especially in the subchondral bone region. It is known that these diseases are influenced by heritable factors. However, the DNA polymorphisms identified so far in GWAS explain less than 10% of the genetic risk, suggesting that other factors, and specifically epigenetic mechanisms, are involved in the pathogenesis of these disorders. This review summarizes current knowledge about the influence of epigenetic marks on bone homeostasis, paying special attention to the role of DNA methylation in the onset and progression of osteoporosis and osteoarthritis.

DNA methylation and the social gradient of osteoporotic fracture: A conceptual model

“…This may have important implications for diseases such as osteoporosis that have slower progression compared to cancers, as there may be a greater likelihood of negative side effects. Understanding the role played by DNAm in osteoporosis not only has much potential to enhance lifestyle interventions, but also the development of novel osteoporotic drug treatment [9]. Furthermore, knowledge of these associations also has the potential to reduce the social gradient of osteoporotic fracture by enhancing the current evidence base regarding why interventions should be targeted toward socially disadvantaged individuals as the most at risk group.…”

“…To advance understanding of the aetiology and pathogenesis of osteoporosis, there are now large-scale efforts to identify genes associated with fracture risk via genome-wide association studies (GWAS) of BMD [5][6][7][8]. The maintenance of BMD is not static, rather osteoblast and osteoclast differentiation processes are highly organized and driven by modifications in gene expression patterns throughout the life course [9]. Indeed, it is argued that the risk of developing osteoporosis occurs over the life course, with potential mechanisms involving epigenetic processes [10].…”

“…These processes include DNA methylation (DNAm), histone modification and non-coding RNA (ncRNA) activity [12], with much interest recently directed toward the modulation of epigenetic pathways via DNAm [9]. A seminal review by Delgado-Calle et al [9] argued that DNAm plays a role in the onset and progression of musculoskeletal disorders including osteoporosis; a role similarly reported in other non-communicable diseases such as obesity [13], cancer [14], cardiovascular [15] and metabolic diseases [12,13]. Furthermore, recent data have suggested that patients with fractures have differentially methylated genes that are related to skeletal development [16].…”

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

“…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 .…”

Low protein intake compromises the recovery of lactation-induced bone loss in female mouse dams without affecting skeletal muscles

“…Epigenetic mechanisms are potential therapeutic targets due to their reversible nature. Several studies have suggested that methylome changes play an important role in osteoblast differentiation and activity (27)(28)(29)(30). Hypomethylation of the promoters of the runt-related transcription factor-2 (Runx-2), bone gamma-carboxyglutamate protein (Bglap, the coding gene for osteocalcin) and osterix (Osx) genes is involved in osteogenic differentiation of adiposederived mesenchymal stromal cells (MSCs) (31).…”