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Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity

Abstract

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.

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 signalling cascades and cytoskeletal adaptations to initiate osteogenic, chondrogenic and myogenic differentiation and inhibit adipocyte differentiation.

  • Mechanical signals, such as those induced through low-intensity vibration, need not be large in magnitude, or long in duration, to influence bone or fat phenotypes.

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Fig. 1: Exercise and mechanical signals are anabolic to skeletal tissue and muscle and slow excessive bone resorption, counteracting the negative effects of a high-fat diet and sedentary lifestyle on bone and fat.
Fig. 2: Exercise suppresses expansion of marrow adipocytes and strengthens bone in obese mice.
Fig. 3: Mechanotransductive responses of mesenchymal stem cells to dynamic mechanical stimuli are achieved through the internal stiffening of the cell via cytoplasmic-bound actin proteins.

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Acknowledgements

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Nature Reviews Endocrinology thanks G. Duque, and other anonymous reviewers, for their contribution to the peer review of this work.

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All authors provided a substantial contribution to the discussion of the material. C.T.R., J.R., G.M.P., T.A.G., M.S. and G.U. contributed to all aspects of this Review. V.S.P., L.E.W. and K.K.N. researched data for the article, contributed to discussion of the content and wrote the article.

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Correspondence to Clinton T. Rubin.

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C.T.R. is a founder of Marodyne Medical, Inc. and BTT Health and has several patents issued and pending related to the ability of mechanical signals to control musculoskeletal and metabolic disorders. The other authors declare no competing interests.

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Glossary

Loading

In terms of mechanical loading, a singular or compound series of static or dynamic (time-varying) forces applied to a system via gravity or direct application from an external body, causing tension, shear or compression.

Unloading

A cell or body is considered mechanically unloaded if no static or dynamic strain is present, such as what might occur with bed rest or spaceflight (that is, microgravity).

Ground-reaction forces

As applicable to biomechanics, ground-reaction forces consist of the normal forces exerted by the ground on the body making contact with it, particularly resulting from a heel strike during walking or running.

Spectral content

Muscle contractive forces, specifically on bone, resonate within a discrete frequency range.

Load sensation

Mechanical loads are ‘sensed’ by cells through transduction of external or internal forces across cytoskeletal proteins into the nucleus.

Tissue senility

The ageing process is associated with the quiescence of regenerative cell populations residing in tissues throughout the body.

Muscle-specific force

Quantification of the contractile forces generated by muscles can be normalized to muscle size ex vivo.

Fluid shear

Fluidic forces applied tangentially across cell membranes or tissues.

Dynamic shear forces

Physiological fluids exert a gradient of pulsatile flow across vessel walls, mineralized bone and cells housed in the bone marrow microenvironment.

Tissue stiffness

In terms of bone, the stiffness of the tissue is correlated to its ability to resist deformation.

Nuclear stiffness

Nuclear stiffness refers to its rigidity and is directly related to polymeric structural proteins (that is, microtubules, intermediate filaments and microfilaments) found across the cytoskeleton, of which actin proteins provide substantial reinforcement.

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Pagnotti, G.M., Styner, M., Uzer, G. et al. Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat Rev Endocrinol 15, 339–355 (2019). https://doi.org/10.1038/s41574-019-0170-1

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