The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgAmut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgAmut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgAmut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgAmut/mut cells. Finally, application of an exercise intervention to a subset of PolgAmut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.

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Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss.

Bones as an alive organ consist of about 70% mineral and 30% organic component. About 200 million people are suffering from osteopenia and osteoporosis around the world. There are multiple ways of protecting bone from endogenous and exogenous risk factors. Planned physical activity is another useful way for protecting bone health. It has been investigated that arranged exercise would effectively regulate bone metabolism. Until now, a number of systems have discovered how exercise could help bone health. Previous studies reported different mechanisms of the effect of exercise on bone health by modulation of bone remodeling. However, the regulation of RANKL/RANK/OPG pathway in exercise and physical performance as one of the most important remodeling systems is not considered comprehensive in previous evidence. Therefore, the aim of this review is to clarify exercise influence on bone modeling and remodeling, with a concentration on its role in regulating RANKL/RANK/OPG pathway.

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RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling.

Osteoporosis is a very common bone disorder characterized by low bone mass and signs of deterioration, responsible for bone fragility typical in this pathology. The risk factors for the onset of osteoporosis are many and different from each other. Some of them cannot be modified, such as age, hereditary diseases and endocrine diseases. Others are modifiable, so that prevention is an advisable tool to reduce the incidence of osteoporosis. Among preventive tools, physical activity is certainly a valid instrument of prevention, in fact physical activity contributes to a healthy energy balance and increases muscle mass and bone mass. In the present narrative review, we wanted to pay attention to the possible influence of physical activity on the pathophysiological molecular pathways of osteoporosis and to the use of different exercise training in treatment of osteoporosis. From the literature analyzed, in relation to the effects of physical activity on bone metabolism, it is shown that exercise acts on molecular pathways of bone remodeling involving all cellular types of bone tissue. In relation to clinical trials adopted in patients with osteoporosis, it is evident that a multi-component training, including aerobic activity and other types of training (resistance and/or strength exercises), is the best kind of exercise in improving bone mass and bone metabolism in older adults and especially osteopoenic and osteoporotic women. With regard to whole-body-vibration training, it seems to be a valid alternative to current methods due to its greater adaptability to patients. In conclusion, physical activity, whatever the adopted training, always has beneficial effects on patients suffering from osteoporosis, and not only on bone homeostasis but on the whole skeletal muscle system.

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The importance of physical activity in osteoporosis. From the molecular pathways to the clinical evidence

Physical activity or appropriate exercise prevents the development of osteoporosis. However, the exact mechanism remains unclear although it is well accepted that exercise or mechanical loading regulates the hormones, cytokines, signaling pathways, and noncoding RNAs in bone. Accumulating evidence has shown that bone is a highly vascularized tissue, and dysregulation of vasculature is associated with many bone diseases such as osteoporosis or osteoarthritis. In addition, exercise or mechanical loading regulates bone vascularization in bone microenvironment via the modulation of angiogenic mediators, which play a crucial role in maintaining skeletal health. This review discusses the effects of exercise and its underlying mechanisms for osteoporosis prevention, as well as an angiogenic and osteogenic coupling in response to exercise.

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The Effect of Exercise on the Prevention of Osteoporosis and Bone Angiogenesis

Impacts of exercise interventions on different diseases and organ functions in mice

With a rapid increase in the aging population, osteoporosis has become a global health problem. Although anti-resorption and anabolic drugs are available, osteoporosis cannot be completely cured. Exercise is an economical, efficacious, and safe way to prevent the development of osteoporosis. Recent studies have investigated the mechanisms by which exercise affects bone remodeling. Here we update the progress made on the effects of exercise on bone cells, including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts, as well as on bone mass, bone strength, and geometry, hoping to provide a theoretical basis to improve osteoporosis prevention and treatment with exercise.

The roles of exercise in bone remodeling and in prevention and treatment of osteoporosis.

Physical exercise is beneficial to bone health. However, little is known how different intensities of exercise affect bone mass and strength. In the present study, we used young mice to study the effects of different intensities of exercise on bone mass and bone strength in comparison to pharmacological doses of active vitamin D (calcitriol). We found that only the medium level of exercise tested showed a positive effect on bone mineral density, trabecular bone volume, and bone strength, which are attributable to a decrease in bone resorption and an increase in bone formation, with the latter being accompanied by an increase in the number of osteogenic mesenchymal stem cells in the bone marrow. Calcitriol increases bone volume and bone strength, yet the combination of calcitriol and medium-intensity exercise did not further improve bone mass or strength. Moreover, calcitriol also showed some protective effect on the bone in mice with high levels of exercise. These results indicate that exercise at medium intensity increases bone mass and strength via affecting both bone formation and resorption and that its beneficial effects on bone mass cannot be further improved by calcitriol.

Juanni Wu

Papers

The roles of exercise in bone remodeling and in prevention and treatment of osteoporosis.

The effects of different intensities of exercise and active vitamin D on mouse bone mass and bone strength