Abstract
Aging and a sedentary lifestyle conspire to reduce bone quantity and quality, decrease muscle mass and strength, and undermine postural stability, culminating in an elevated risk of skeletal fracture. Concurrently, a marked reduction in the available bone-marrow-derived population of mesenchymal stem cells (MSCs) jeopardizes the regenerative potential that is critical to recovery from musculoskeletal injury and disease. A potential way to combat the deterioration involves harnessing the sensitivity of bone to mechanical signals, which is crucial in defining, maintaining and recovering bone mass. To effectively utilize mechanical signals in the clinic as a non-drug-based intervention for osteoporosis, it is essential to identify the components of the mechanical challenge that are critical to the anabolic process. Large, intense challenges to the skeleton are generally presumed to be the most osteogenic, but brief exposure to mechanical signals of high frequency and extremely low intensity, several orders of magnitude below those that arise during strenuous activity, have been shown to provide a significant anabolic stimulus to bone. Along with positively influencing osteoblast and osteocyte activity, these low-magnitude mechanical signals bias MSC differentiation towards osteoblastogenesis and away from adipogenesis. Mechanical targeting of the bone marrow stem-cell pool might, therefore, represent a novel, drug-free means of slowing the age-related decline of the musculoskeletal system.
Key Points
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Mechanical signals are anabolic to bone while their removal is permissive to osteoporosis
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Mechanical signals need not be large to stimulate bone formation
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Clinical studies suggest that low-magnitude mechanical signals can increase bone mineral density
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Differentiation of mesenchymal stem cells towards osteoblastogenesis simultaneously suppresses adipogenesis
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Mechanical signals can stem osteoporosis and augment and/or accelerate the healing of bone
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References
Kruse, K. & Julicher, F. Oscillations in cell biology. Curr. Opin. Cell Biol. 17, 20–26 (2005).
Zhou, X. L. et al. The transient receptor potential channel on the yeast vacuole is mechanosensitive. Proc. Natl Acad. Sci. USA 100, 7105–7110 (2003).
Neel, P. L. & Harris, R. W. Motion-induced inhibition of elongation and induction of dormancy in liquidambar. Science 173, 58–59 (1971).
Ingber, D. E. Mechanical control of tissue growth: function follows form. Proc. Natl Acad. Sci. USA 102, 11571–11572 (2005).
Orr, A. W., Helmke, B. P., Blackman, B. R. & Schwartz, M. A. Mechanisms of mechanotransduction. Dev. Cell 10, 11–20 (2006).
Frost, H. M. Bone “mass” and the “mechanostat”: a proposal. Anat. Rec. 219, 1–9 (1987).
Lang, T. et al. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J. Bone Miner. Res. 19, 1006–1012 (2004).
Jones, H. H., Priest, J. D., Hayes, W. C., Tichenor, C. C. & Nagel, D. A. Humeral hypertrophy in response to exercise. J. Bone Joint Surg. Am. 59, 204–208 (1977).
Heinonen, A. et al. Bone mineral density in female athletes representing sports with different loading characteristics of the skeleton. Bone 17, 197–203 (1995).
Leichter, I. et al. Gain in mass density of bone following strenuous physical activity. J. Orthop. Res. 7, 86–90 (1989).
McKay, H. A. et al. “Bounce at the Bell”: a novel program of short bouts of exercise improves proximal femur bone mass in early pubertal children. Br. J. Sports Med. 39, 521–526 (2005).
Heinonen, A., Sievanen, H., Kannus, P., Oja, P. & Vuori, I. Effects of unilateral strength training and detraining on bone mineral mass and estimated mechanical characteristics of the upper limb bones in young women. J. Bone Miner. Res. 11, 490–501 (1996).
Judex, S., Garman, R., Squire, M., Donahue, L. R. & Rubin, C. Genetically based influences on the site-specific regulation of trabecular and cortical bone morphology. J. Bone Miner. Res. 19, 600–606 (2004).
Peacock, M. et al. Sex-specific and non-sex-specific quantitative trait loci contribute to normal variation in bone mineral density in men. J. Clin. Endocrinol. Metab. 90, 3060–3066 (2005).
Qiu, S., Rao, D. S., Palnitkar, S. & Parfitt, A. M. Differences in osteocyte and lacunar density between Black and White American women. Bone 38, 130–135 (2006).
Heaney, R. P. et al. Peak bone mass. Osteoporos. Int. 11, 985–1009 (2000).
Weaver, C. M. The role of nutrition on optimizing peak bone mass. Asia Pac. J. Clin. Nutr. 17 (Suppl. 1), 135–137 (2008).
Rosen, C. J. & Bouxsein, M. L. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2, 35–43 (2006).
Zayzafoon, M., Gathings, W. E. & McDonald, J. M. Modeled microgravity inhibits osteogenic differentiation of human mesenchymal stem cells and increases adipogenesis. Endocrinology 145, 2421–2432 (2004).
Lee, N. K. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456–469 (2007).
Lanyon, L. E. & Rubin, C. T. Static vs dynamic loads as an influence on bone remodelling. J. Biomech. 17, 897–905 (1984).
Judex, S., Lei, X., Han, D. & Rubin, C. Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J. Biomech. 40, 1333–1339 (2007).
Knothe Tate, M. L. & Knothe, U. An ex vivo model to study transport processes and fluid flow in loaded bone. J. Biomech. 33, 247–254 (2000).
Pollack, S. R., Salzstein, R. & Pienkowski, D. The electric double layer in bone and its influence on stress-generated potentials. Calcif. Tissue Int. 36 (Suppl. 1), S77–S81 (1984).
Fritton, S. P., McLeod, K. J. & Rubin, C. T. Quantifying the strain history of bone: spatial uniformity and self–similarity of low-magnitude strains. J. Biomech. 33, 317–325 (2000).
Huang, R. P., Rubin, C. T. & McLeod, K. J. Changes in postural muscle dynamics as a function of age. J. Gerontol. A Biol. Sci. Med. Sci. 54, B352–B357 (1999).
Rubin, C. T. & Lanyon, L. E. Regulation of bone mass by mechanical strain magnitude. Calcif. Tissue Int. 37, 411–417 (1985).
Rubin, C. T. & Lanyon, L. E. Regulation of bone formation by applied dynamic loads. J. Bone Joint Surg. Am. 66, 397–402 (1984).
Lanyon, L. E., Goodship, A. E., Pye, C. J. & MacFie, J. H. Mechanically adaptive bone remodelling. J. Biomech. 15, 141–154 (1982).
O'Connor, J. A., Lanyon, L. E. & MacFie, H. The influence of strain rate on adaptive bone remodelling. J. Biomech. 15, 767–781 (1982).
Bacabac, R. G. et al. Nitric oxide production by bone cells is fluid shear stress rate dependent. Biochem. Biophys. Res. Commun. 315, 823–829 (2004).
Srinivasan, S., Weimer, D. A., Agans, S. C., Bain, S. D. & Gross, T. S. Low-magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J. Bone Miner. Res. 17, 1613–1620 (2002).
O'Connell-Rodwell, C. E. Keeping an “ear” to the ground: seismic communication in elephants. Physiology (Bethesda) 22, 287–294 (2007).
Qin, Y. X., Rubin, C. T. & McLeod, K. J. Nonlinear dependence of loading intensity and cycle number in the maintenance of bone mass and morphology. J. Orthop. Res. 16, 482–489 (1998).
Rubin, C., Turner, A. S., Bain, S., Mallinckrodt, C. & McLeod, K. Anabolism: Low mechanical signals strengthen long bones. Nature 412, 603–604 (2001).
Rosenberg, I. H. Sarcopenia: origins and clinical relevance. J. Nutr. 127 (Suppl. 5), S990–S991 (1997).
Lee, W. S., Cheung, W. H., Qin, L., Tang, N. & Leung, K. S. Age-associated decrease of type IIA/B human skeletal muscle fibers. Clin. Orthop. Relat. Res. 450, 231–237 (2006).
Rubin, C. T., Bain, S. D. & McLeod, K. J. Suppression of the osteogenic response in the aging skeleton. Calcif. Tissue Int. 50, 306–313 (1992).
Vico, L. et al. Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet 355, 1607–1611 (2000).
Burr, D. B. et al. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J. Bone Miner. Res. 12, 6–15 (1997).
Augat, P., Simon, U., Liedert, A. & Claes, L. Mechanics and mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporos. Int. 16 (Suppl. 2), S36–S43 (2005).
Rubin, C. et al. Transmissibility of 15-hertz to 35-hertz vibrations to the human hip and lumbar spine: determining the physiologic feasibility of delivering low-level anabolic mechanical stimuli to skeletal regions at greatest risk of fracture because of osteoporosis. Spine 28, 2621–2627 (2003).
Xie, L., Rubin, C. & Judex, S. Enhancement of the adolescent murine musculoskeletal system using low-level mechanical vibrations. J. Appl. Physiol. 104, 1056–1062 (2008).
Rubin, C. et al. Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention. J. Bone Miner. Res. 17, 349–357 (2002).
Rubin, C. T. & Lanyon, L. E. Dynamic strain similarity in vertebrates; an alternative to allometric limb bone scaling. J. Theor. Biol. 107, 321–327 (1984).
Rubin, C., Xu, G. & Judex, S. The anabolic activity of bone tissue, suppressed by disuse, is normalized by brief exposure to extremely low-magnitude mechanical stimuli. FASEB J. 15, 2225–2229 (2001).
Garman, R., Rubin, C. & Judex, S. Small oscillatory accelerations, independent of matrix deformations, increase osteoblast activity and enhance bone morphology. PLoS ONE 2, e653 (2007).
Bacabac, R. G. et al. Bone cell responses to high-frequency vibration stress: does the nucleus oscillate within the cytoplasm? FASEB J. 20, 858–864 (2006).
Ozcivici, E., Garman, R. & Judex, S. High-frequency oscillatory motions enhance the simulated mechanical properties of non-weight bearing trabecular bone. J. Biomech. 40, 3404–3411 (2007).
Rubin, C. T. et al. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc. Natl Acad. Sci. USA 104, 17879–17884 (2007).
Luu, Y. K. et al. In vivo quantification of subcutaneous and visceral adiposity by micro-computed tomography in a small animal model. Med. Eng. Phys. 31, 34–41 (2009).
Luu, Y. K. et al. Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J. Bone Miner. Res. 24, 50–61 (2009).
Akune, T. et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846–855 (2004).
Liu, J., Wang, H., Zuo, Y. & Farmer, S. R. Functional interaction between peroxisome proliferator-activated receptor gamma and beta-catenin. Mol. Cell Biol. 26, 5827–5837 (2006).
Krishnan, V., Bryant, H. U. & MacDougald, O. A. Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209 (2006).
Rosen, C. J. & Klibanski, A. Bone, fat, and body composition: evolving concepts in the pathogenesis of osteoporosis. Am. J. Med. 122, 409–414 (2009).
Taes, Y. E. et al. Fat mass is negatively associated with cortical bone size in young healthy male siblings. J. Clin. Endocrinol. Metab. 94, 2325–2331 (2009).
Rubin, J., Murphy, T., Nanes, M. S. & Fan, X. Mechanical strain inhibits expression of osteoclast differentiation factor by murine stromal cells. Am. J. Physiol. Cell Physiol. 278, C1126–C1132 (2000).
Kim, C. H. et al. Trabecular bone response to mechanical and parathyroid hormone stimulation: the role of mechanical microenvironment. J. Bone Miner. Res. 18, 2116–2125 (2003).
Cowin, S. C. & Weinbaum, S. Strain amplification in the bone mechanosensory system. Am. J. Med. Sci. 316, 184–188 (1998).
Wang, L., Fritton, S. P., Cowin, S. C. & Weinbaum, S. Fluid pressure relaxation depends upon osteonal microstructure: modeling an oscillatory bending experiment. J. Biomech. 32, 663–672 (1999).
Han, Y., Cowin, S. C., Schaffler, M. B. & Weinbaum, S. Mechanotransduction and strain amplification in osteocyte cell processes. Proc. Natl Acad. Sci. USA 101, 16689–16694 (2004).
Burger, E. H., Klein-Nulend, J. & Veldhuijzen, J. P. Modulation of osteogenesis in fetal bone rudiments by mechanical stress in vitro. J. Biomech. 24 (Suppl. 1), 101–109 (1991).
Noble, B. S. et al. Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. Am. J. Physiol. Cell Physiol. 284, C934–C943 (2003).
Verborgt, O., Gibson, G. J. & Schaffler, M. B. Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J. Bone Miner. Res. 15, 60–67 (2000).
Frost, H. M. Perspectives: bone's mechanical usage windows. Bone Miner. 19, 257–271 (1992).
Judex, S., Lei, X., Han, D. & Rubin, C. Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J. Biomech. 40, 1333–1339 (2007).
Qin, Y. X., Kaplan, T., Saldanha, A. & Rubin, C. Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity. J. Biomech. 36, 1427–1437 (2003).
Porada, C. D., Zanjani, E. D. & Almeida-Porad, G. Adult mesenchymal stem cells: a pluripotent population with multiple applications. Curr. Stem Cell Res. Ther. 1, 365–369 (2006).
Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).
Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).
Rubin, J., Rubin, C. & Jacobs, C. R. Molecular pathways mediating mechanical signaling in bone. Gene 367, 1–16 (2006).
Garman, R., Gaudette, G., Donahue, L. R., Rubin, C. & Judex, S. Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation. J. Orthop. Res. 25, 732–740 (2007).
Sukharev, S. & Corey, D. P. Mechanosensitive channels: multiplicity of families and gating paradigms. Sci. STKE 2004, re4 (2004).
Morris, C. E. Mechanosensitive ion channels. J. Membr. Biol. 113, 93–107 (1990).
Duncan, R. L., Hruska, K. A. & Misler, S. Parathyroid hormone activation of stretch-activated cation channels in osteosarcoma cells (UMR-106.01). FEBS Lett. 307, 219–223 (1992).
Ferrier, J., Ward, A., Kanehisa, J. & Heersche, J. N. Electrophysiological responses of osteoclasts to hormones. J. Cell Physiol. 128, 23–26 (1986).
Davidson, R. M., Tatakis, D. W. & Auerbach, A. L. Multiple forms of mechanosensitive ion channels in osteoblast-like cells. Pflugers Arch. 416, 646–651 (1990).
Rawlinson, S. C., Pitsillides, A. A. & Lanyon, L. E. Involvement of different ion channels in osteoblasts' and osteocytes' early responses to mechanical strain. Bone 19, 609–614 (1996).
McGarry, J. G., Klein-Nulend, J. & Prendergast, P. J. The effect of cytoskeletal disruption on pulsatile fluid flow-induced nitric oxide and prostaglandin E2 release in osteocytes and osteoblasts. Biochem. Biophys. Res. Commun. 330, 341–348 (2005).
Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).
Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39 (2000).
Rizzo, V., Sung, A., Oh, P. & Schnitzer, J. E. Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae. J. Biol. Chem. 273, 26323–26329 (1998).
Bonewald, L. F. & Johnson, M. L. Osteocytes, mechanosensing and Wnt signaling. Bone 42, 606–615 (2008).
Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).
Robling, A. G. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283, 5866–5875 (2008).
Santos, A., Bakker, A. D., Zandieh-Doulabi, B., Semeins, C. M. & Klein-Nulend, J. Pulsating fluid flow modulates gene expression of proteins involved in Wnt signaling pathways in osteocytes. J. Orthop. Res. 27, 1280–1287 (2009).
Armstrong, V. J. et al. Wnt/beta-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor alpha. J. Biol. Chem. 282, 20715–20727 (2007).
Case, N. et al. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J. Biol. Chem. 283, 29196–29205 (2008).
David, V. et al. Mechanical loading down regulates PPAR gamma in bone marrow stromal cells and favours osteoblastogenesis at the expense of adipogenesis. Endocrinology 148, 2553–2562 (2007).
Sen, B. et al. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable beta-catenin signal. Endocrinology 149, 6065–6075 (2008).
Carmona, R. Bone Health and Osteoporosis: A Report of the Surgeon General. 1–404 10-10-2004. US. Dept of Health and Human Services, Public Health Service.
Rubin, C. et al. Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J. Bone Miner. Res. 19, 343–351 (2004).
Ward, K. et al. Low magnitude mechanical loading is osteogenic in children with disabling conditions. J. Bone Miner. Res. 19, 360–369 (2004).
Gilsanz, V. et al. Low-level, high-frequency mechanical signals enhance musculoskeletal development of young women with low BMD. J. Bone Miner. Res. 21, 1464–1474 (2006).
Cardinale, M. & Bosco, C. The use of vibration as an exercise intervention. Exerc. Sport Sci. Rev. 31, 3–7 (2003).
Verschueren, S. M. et al. Effect of 6-month whole body vibration training on hip density, muscle strength, and postural control in postmenopausal women: a randomized controlled pilot study. J. Bone Miner. Res. 19, 352–359 (2004).
Armbrecht, G. et al. Resistive vibration exercise attenuates bone and muscle atrophy in 56 days of bed rest: biochemical markers of bone metabolism. Osteoporos. Int. doi:10.1007/s00198-009-0985-z.
Kiiski, J., Heinonen, A., Jarvinen, T. L., Kannus, P. & Sievanen, H. Transmission of vertical whole body vibration to the human body. J. Bone Miner. Res. 23, 1318–1325 (2008).
Goodship, A. E., Lawes, T. J. & Rubin, C. T. Low-magnitude high-frequency mechanical signals accelerate and augment endochondral bone repair: preliminary evidence of efficacy. J. Orthop. Res. 27, 922–930 (2009).
Rubin, C. T. & McLeod, K. J. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin. Orthop. 298, 165–174 (1994).
Carter, D. R., Caler, W. E., Spengler, D. M. & Frankel, V. H. Fatigue behavior of adult cortical bone: the influence of mean strain and strain range. Acta Orthop. Scand. 52, 481–490 (1981).
Rubin, C. T., Gross, T. S., McLeod, K. J. & Bain, S. D. Morphologic stages in lamellar bone formation stimulated by a potent mechanical stimulus. J. Bone Miner. Res. 10, 488–495 (1995).
Rubin, C. T. & Lanyon, L. E. Limb mechanics as a function of speed and gait: a study of functional strains in the radius and tibia of horse and dog. J. Exp. Biol. 101, 187–211 (1982).
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This work was supported by National Institutes of Health Grant AR 43498.
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Clinton T. Rubin declares that he is a founder of Marodyne Medical, and that he is a shareholder in, and a holds a patent from, this company.
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Ozcivici, E., Luu, Y., Adler, B. et al. Mechanical signals as anabolic agents in bone. Nat Rev Rheumatol 6, 50–59 (2010). https://doi.org/10.1038/nrrheum.2009.239
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DOI: https://doi.org/10.1038/nrrheum.2009.239
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