Abstract
Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.
Highlights
Bone as a tissue has its own complexities with one of the largest pools of diverse cell types
DNMT3A were downregulated at gene expression level in women with post-menopausal osteoporosis and osteoarthritis, with superior quantity and quality of bone being directly associated with HAT1, HDAC6, and MBD1 expression [82]
Mitochondrial DNA is another focus of research in aging and its associated comorbidities. mtDNA polymerase gamma (Polg), a lone DNA polymerase found in mitochondria, when mutated, showed accelerated age-related osteoporosis with reduced osteogenic potential and increased osteoclasts activity [116]
Summary
Bone as a tissue has its own complexities with one of the largest pools of diverse cell types. Together with tight regulations from hormones such as Vitamin D (cholecalciferol), parathyroid hormone (PTH), and calcitonin, and supported by several organ systems, these minerals are maintained in a homeostasis This perfect harmony of minerals is supported by various cells in the bone compartment, which may have altered functions due to a familial genetic alteration (associated with mechanisms underlying primary osteoporosis), hormonal changes (loss of estrogen in post-menopausal women, and loss of androgens in men), physiological aging, and pathological changes (disease or treatment related), leading to other forms of osteoporosis. Proteostasis, either by impairment in the ubiquitin or the autophagy pathway, allows aggregation of unwanted proteins, contributing to senescent profile of theproteasome cell. Il: Interleukin, Irf: Interferon Regulatory Factor 1, Mmp: Matrix metallopeptidase, Pappa: pregnancy-associated plasma protein A, TNF: Tumor necrosis factor, Vcam: Cell Adhesion Molecule 1
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