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.

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.

Mesenchymal stem cell lineage selection as a function of mechanical signals drives osteogenic differentiation. Here, exercise is directly responsible for augmenting bone and muscle mass while suppressing the accumulation of fat. By contrast, sedentary lifestyles (the absence of mechanical stimuli, often accompanied by poor diet) increase adipogenic programmes, resulting in increased marrow adiposity that can obstruct the persistence of bone-remodelling cells. In the absence of mechanical load, osteoclast-mediated resorption is accelerated, in part, by the secretion of inflammatory adipokines released into the marrow, which results in the resorption of abnormal levels of bone that are not reciprocated by bone formation, as is the case in normal bone remodelling. Chronic destruction of bone matrix releases transforming growth factor-β (TGFβ), an inflammatory cytokine that leads to an impairment in the calcium gradient across muscle fibres. Therefore, mechanical signals are critical in regulating the dynamic between bone, muscle and fat. Depriving the body of mechanical stimuli in combination with a high-fat diet perpetuates extensive bone loss, muscle weakness and fatty-tissue accumulation around vital organs, which are tissue phenotypes that are conducive to the advancement of osteoporosis, impairments in glucose metabolism and chronic inflammation. NOX4, NADPH oxidase 4; RANKL, receptor activator of nuclear factor-κB ligand; ROS, reactive oxygen species; RUNX2, Runt-related transcription factor 2.

Fig. 2 |. Exercise suppresses expansion of marrow adipocytes and strengthens bone in obese mice.

a | Obese (diet-induced obesity (DIO)) and lean (low-fat diet (LFD)) mice were allocated to running exercise (DIO-E and LFD-E, respectively) or sedentary groups for 6 weeks (n = 6 per group). The images are a visualization of femoral marrow adipose tissue (MAT) in mice measured by MRI with advanced image analysis. Each image represents six images superimposed on each other. The heat map demonstrates the relative lipid quantity. b | Schematic representation of marrow adipocytes in the setting of obesity with or without exercise. DIO increases adipocyte size and number and expression of the lipid droplet marker PLIN5, resulting in expansion of cortical endosteal and periosteal bone surfaces. By contrast, exercise increases bone quantity and quality relying on β-oxidation of lipids in the marrow, as supported by a reduced number of adipocytes in the marrow and their cross-sectional area and increased expression of oxidation and lipolysis markers (for example, PLIN3). Part a reproduced with permission from REF.,Wiley-VCH.

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.

a | The absence of mechanical forces prevents the polymerization of actin fibres, preventing the dephosphorylation of β-catenin, which remains bound to GSK3β. As such, β-catenin does not translocate to the nucleus, resulting in the expression of PPARγ-driven adipogenic pathways. b | By contrast, mechanical stimuli recruit actin fibres to the interface of the cell membrane and the substrate surface. These focal adhesions become stronger and denser in response to dynamic mechanical stimuli, permitting the movement of β-catenin into the nucleus and an ensuing osteogenic response. FHOD1, FH1/FH2 domain-containing protein 1; LINC, linker of nucleoskeleton and cytoskeleton.