Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA.
Department of Internal Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic, Rochester, MN 55902, USA.
Int J Mol Sci. 2021 Mar 29;22(7):3553. doi: 10.3390/ijms22073553.
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.
骨骼是一个由紧密调控机制维持的动态器官。随着年龄的增长，骨骼的动态平衡（由骨形成和骨吸收之间的精细平衡维持）会失调。氧化应激诱导的 DNA 损伤、细胞凋亡和细胞衰老都导致了组织功能障碍和骨动态平衡失衡。这些细胞机制已成为治疗与年龄相关的骨质疏松症的治疗靶点。遗传小鼠模型表明，清除衰老细胞对于缓解与年龄相关的骨质疏松症至关重要。此外，我们和其他人已经表明，通过药理学靶向细胞衰老，是缓解年龄和辐射诱导的骨质疏松症的有效工具。衰老细胞还具有一种改变的分泌组，称为衰老相关分泌表型（SASP），其可能具有自分泌、旁分泌或内分泌功能。本综述讨论了导致老年骨骼衰老特征的当前和潜在途径，以及在与年龄相关的骨质疏松症期间骨动态平衡是如何受到影响的。该综述还讨论了治疗骨质疏松症的现有疗法，并基于细胞衰老和 SASP 作为衰老骨骼的潜在发病机制，为新的治疗选择提供了合理化建议。
