Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity

• Published in: Nature reviews. Endocrinology 2019-06, Vol.15 (6), p.339-355
• Main Authors: Pagnotti, Gabriel M., Styner, Maya, Uzer, Gunes, Patel, Vihitaben S., Wright, Laura E., Ness, Kirsten K., Guise, Theresa A., Rubin, Janet, Rubin, Clinton T.
• Format: Article
• Language: English
• Subjects: 692/163/2743/316/801; 692/163/2743/393; 692/308/575; 692/700/459/284; Adaptations; Adipocytes; Adipocytes - metabolism; Adipogenesis; Adipose tissue; Aging; Aging - metabolism; Aging - pathology; Animals; Body fat; Body Weight - physiology; Bone marrow; Bone mass; Bone Resorption - metabolism; Bone Resorption - pathology; Bone Resorption - therapy; Care and treatment; Cellular signal transduction; Children; Cytoskeleton; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Endocrinology; Exercise - physiology; Exercise therapy; Humans; Mechanical stimuli; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Mesenchyme; Metabolic disorders; Metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Obesity; Obesity - metabolism; Obesity - pathology; Obesity - therapy; Osteoblasts; Osteoblasts - metabolism; Osteoporosis; Osteoporosis - metabolism; Osteoporosis - pathology; Osteoporosis - therapy; Phenotypes; Physiological aspects; Quality of life; Review Article; Signal transduction; Stem cells; Stem Cells - metabolism; Type 2 diabetes
• ISSN: 1759-5029; 1759-5037; 1759-5037
• DOI: 10.1038/s41574-019-0170-1

Osteoporosis, a condition of skeletal decline that undermines quality of life, is treated with pharmacological interventions that are associated with poor adherence and adverse effects. Complicating efforts to improve clinical outcomes, the incidence of obesity is increasing, predisposing the population to a range of musculoskeletal complications and metabolic disorders. Pharmacological management of obesity has yet to deliver notable reductions in weight and debilitating complications are rarely avoided. By contrast, exercise shows promise as a non-invasive and non-pharmacological method of regulating both osteoporosis and obesity. The principal components of exercise — mechanical signals — promote bone and muscle anabolism while limiting formation and expansion of fat mass. Mechanical regulation of bone and marrow fat might be achieved by regulating functions of differentiated cells in the skeletal tissue while biasing lineage selection of their common progenitors — mesenchymal stem cells. An inverse relationship between adipocyte versus osteoblast fate selection from stem cells is implicated in clinical conditions such as childhood obesity and increased marrow adiposity in type 2 diabetes mellitus, as well as contributing to skeletal frailty. Understanding how exercise-induced mechanical signals can be used to improve bone quality while decreasing fat mass and metabolic dysfunction should lead to new strategies to treat chronic diseases such as osteoporosis and obesity. This Review discusses how signals arising from activity are perceived by cell populations and how the cells respond to them, with particular emphasis on the musculoskeletal and adipose systems. The potential of exercise as a non-invasive and non-pharmacological method of regulating osteoporosis and obesity is also outlined. Key points Ageing and inactivity each contribute towards a local and systemic environment conducive to poor bone quality, increased systemic adiposity, marrow adipogenesis and inflammation. Mesenchymal stem cells and their lineage-differentiated progeny (for example, osteoblasts) are mechanosensitive, such that increased mechanical signals (such as exercise) stimulate muscle and bone anabolism. Mechanical signals suppress obesity end points, including fat gain, adipocyte lipid acquisition, chronic inflammation and indices associated with type 2 diabetes mellitus. Transduction of mechanical signals across the plasma membrane of stem cells into the nucleus activates sig