AbstractFragile bone is the root cause of osteoporosis. For inherited or acquired reasons, the fragile bone does not provide sufficient fracture resistance to withstand the physical strains of a normal lifestyle. Accordingly, clinical characteristics consist of fragility fractures that occur during daily life activities or low energy trauma. Hip fractures and vertebral fractures are so called "major osteoporotic fractures”, that also cause the highest burden of disease. Although the clinical osteoporosis manifestations are relatively uniform, there is a vast spectrum of underlying molecular causes. Impaired bone formation, accelerated bone loss, and impaired lifetime adaptive regeneration according to physical impact characterize the cruder facets of osteoporosis. The signaling cascades that govern bone formation and metabolism may be altered by genetically or epigenetically inherited defects or acquired epigenetic changes due to tissue aging and/or underlying diseases. While molecular genetics and mechanisms and specific osteoporosis treatments have made impressive progress over the last three decades, there is still an urgent need to better understand the role of epigenetics in this disease.Epigenetic mechanisms such as covalent modifications of DNA, histones, or essential core factors like the osteogenic transcription factors (e. g., RUNX2) and inhibitory modulators of osteogenic WNT-signaling (e. g., Dickkopf-1 (DKK-1), sclerostin (SOST)) are all intricately implicated in developmental bone formation and adaptive regeneration and remodeling processes throughout adult life. These mechanisms are accompanied by chromatin architecture and gene expression changes of small (e. g., microRNAs (miRs)) and long, noncoding RNAs (lncRNAs). The timely execution of these mechanisms either facilitates or inhibits bone formation and remodeling. Together, epigenetic mechanisms controlling bone homeostasis widen the spectrum of potential dysregulations that can cause osteoporosis and open new avenues for therapeutic interventions.Apart from the core mechanisms of bone formation and regeneration, recent research revealed that tissue-resident cells of the immune system such as tissue-specific macrophages, myeloid precursors, and lymphocytes have surprisingly fundamental influence on tissue regeneration, including bone. Those tissue resident cells are also subject to epigenetic changes and may substantially contribute to the development of disease. Epigenetic constellations can be inherited, but the dynamic epigenetic mechanisms involved in physiological processes of tissue regeneration may also be affected by pathologies such as cellular aging and senescence. Recently, several studies aimed at identifying DNA methylation signatures in peripheral blood leukocytes from osteoporosis patients that reveal novel disease mechanisms and potential targets for diagnosis and treatment. Overall, these studies rendered, however, yet inconclusive results.By contrast, studies using bone marrow-derived skeletal progenitors identified transcriptome changes in osteoporosis patients, which could have epigenetic reasons in the absence of genetic causes. Respective changes may be related to the local milieu in bone and bone marrow as a kind of segmental attitude of a specific tissue acquired through tissue aging and/or supported by underlying aging-associated diseases such as arteriosclerosis or aging of cells of the immune system.In summary, there is cumulating evidence linking epigenetic factors to the pathogenesis of aging-associated osteoporosis. However, we are currently still limited in our knowledge with respect to the causal traits that are common, inherited, or acquired in a lifetime in the respective tissues and cells involved in bone formation and regeneration. During the following years, the field will most certainly learn more about molecular processes and factors that can be targeted therapeutically and/or used as biomarkers for risk assessment.
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Apr 12, 2022
Amrilmaen Badawi + 6
Open Access
