Abstract
Changes in strain distribution across the vertebrate skeleton induce modelling and remodelling of bone structure. This relationship, like many in biomedical science, has been recognised since the 1800s, but it is only the recent development of in vivo and in vitro models that is allowing detailed investigation of the cellular mechanisms involved. A number of secondary messenger pathways have been implicated in load transduction by bone cells, and many of these pathways are similar to those proposed for other load-responsive cell types. It appears that load transduction involves interaction between several messenger pathways, rather than one specific switch. Interaction between these pathways may result in a cascade of responses that promote and maintain bone cell activity in remodelling of bone. The paper outlines research on the early rapid signals for load transduction and, in particular, activation of membrane channels in osteoblasts. The involvement of calcium channels in the immediate load response and the modulation of intra-cellular calcium as an early signal are discussed. These membrane channels present a possible target for manipulation in the engineering of bone tissue repair.
Similar content being viewed by others
References
Allen, F. D., Hung, C. T., Pollack, S. R., andBrighton, C. T. (1996): ‘Comparison of [Ca2+]i response to fluid flow of MC3T3-E1, ROS 17/2.8 and cultured primary osteoblast cells’,Cell. Eng.,1, pp. 117–124
Amagai, Y., andKasai, S. (1989): ‘A voltage-dependent calcium current in mouse MC3T3-E1 osteogenic cells’,J. Physiol. (London),398, pp. 291–311
Bean, B. P. (1989): ‘Classes of calcium channels in vertebrate cells’,Ann. Rev. Physiol.,51, pp. 367–384
Binderman, I., Zor, U., Kaye, A., Shimshoni, Z., Harell, A., andSomjen, D. (1988): ‘The transduction of mechanical forces into biochemical events in bone cells may involve activation of Phospholipase A2’,Calcif. Tissue. Int.,42, pp. 261–266.
Brighton, C. T., Stafford, B., Gross, S. B., Leatherwood, D. F., Williams, J. L., andPollack, S. R. (1991): ‘The proliferative and synthetic response of isolated calvarial bone cells of rats to cyclic biaxial mechanical strain’,J. Bone Joint Surg.,73A, (3), pp. 320–331
Brighton, C. T., Sennett, B., Farmer, J. C., Iannotti, J. P., Hansen, C. A., Williams, J. L., andWilliamson, J. (1992): ‘The inositol phosphate pathway as a mediator in the proliferative response of rat calvarial bone cells to cyclical biaxial strain’,J. Orthopaed. Res.,10, pp. 385–393
Buckley, M. J., Banes, A. J., Levin, L. G., Sumpio, B. E., Sato, M., Jordan, R., Gilbert, J., Link, G. W., andTran Son Tay, R. (1988): ‘Osteoblasts increase their rate of division and align in response to cyclic, mechanical tensionin vitro’,Bone Mineral,4, pp. 225–236
Buckley, M. J., Banes, A. J., andJordan, R. D. (1990): ‘The effects of mechanical strain on osteoblastsin vitro’,J. Oral Maxillofac. Surg.,48, pp. 276–282
Caffrey, J. M., andCarson, M. C. F. (1989): ‘Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells’,J. Biol. Chem.,34, pp. 20265–20274
Chesnoy-Marchais, D., andFritsch, J. (1988): ‘Voltage-gated sodium and calcium channels in rat osteoblasts’,J. Physiol. (London),398, pp. 291–311
Chow, J. W. M., andChambers, T. J. (1994): ‘Indomethacin has distinct early and late actions on bone formation induced by mechanical stimulation’,Am. J. Physiol.,267, pp. E287-E292.
Dallas, S. L., Zaman, G., Pead, M. J., andLanyon, L. E. (1993): ‘Early strain related changes in cultured chick tibiotarsi parallel those associated with adaptive modellingin vivo’,J. Bone Miner. Res.,8, pp. 252–259
Davidson, R. M., Tatakis, D. W., andAuerbach, A. L. (1990): ‘Multiple forms of mechanosensitive ion channels in osteoblast-like cells’,Pflugers Arch.,416, pp. 646–651
Dodds, R. A., Ali, N., Pead, M. J., andLanyon, L. E. (1993): ‘Early loading-related changes in the activity of glucose 6-phosphate dehydrogenase and alkaline phosphatase in osteocytes and periosteal osteoblasts in rat fibulaein vivo’,J. Bone Miner. Res.,8, pp. 261–267.
Dolphin, A. C. (1995): ‘Voltage-dependent calcium channels and their modulation by neurotransmitters and G-proteins’,Exp. Physiol.,80, pp. 1–36
Donahue, H. J., Fryer, M. J., Eriksen, E. F., andHeath, H. (1988): ‘Differential effects of parathyroid hormone and its analogues on cytosolic calcium ion and cAMP levels in cultured rat osteoblast like cells’,J. Biol. Chem.,263, pp. 13522–13526
Duncan, R. L., andMisler, S. (1989): ‘Voltage-activated and stretch activated Ba2+conducting channels in an osteoblast-like cell line (UMR-106)’,FEBS Lett.,251, pp. 17–21.
Duncan, R. L., andHruska, K. A. (1994): ‘Chronic intermittent loading alters mechanosenstive channel characteristics in osteoblast-like cells’,Am. J. Physiol.,267, pp. F909-F916.
Duncan, R. L., andTurner, C. H. (1995): ‘Mechanotransduction and the functional response of bone to mechanical strain’,Calcif. Tissue. Int.,57, pp. 344–358
Dunlap, K., Luebke, J. I., andTurner, T. J. (1995): ‘Exocytotic Ca2+ channels in mammalian central neurons’,TINS,18, pp. 89–98.
El Haj, A. J., Minter, S. L., Rawlinson, S. C. F., Suswillo, R., andLanyon, L. E. (1990): ‘Cellular responses to mechanical loadingin vitro’,J. Bone Miner. Res.,5, pp. 923–932
El Haj, A. J., andThomas, G. P. (1994): ‘Cellular modelling of mechanical interactions with the skeleton biomechanics and cells’, Part Two: Hard tissue,Lyall, F., andEl Haj, A. J. (Eds.) pp. 147–163
Fox, A. P., Nowycky, M. C., andTsein, R. W. (1987): ‘Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones’,J. Physiol. (London),394, pp. 149–172
Grygorczyk, C., Grygorczyk, R., andFerrier, J. (1989): ‘Osteo-blastic cells have L-type calcium channels’,Bone Mineral,7, pp. 137–148.
Guggino, S. E., Lajeunesse, D., Wagner, J. A., andSynder, S. H. (1989): ‘Bone remodelling signalled by a dihydropryidine-phenylalkylamine-sensitive calcium channel’,Proc. Nat. Acad. Sci. USA,86, pp. 2957–2960
Harter, L. V., Hruska, K. A., andDuncan, R. L. (1995): ‘Human oesteoblast-like cells respond to mechanical strain with increased bone matrix protein production independent of hormonal regulation’,Endocrinology,136, (2), pp. 528–535
Hasegawa, S., Sato, S., Saito, S., Suzuki, Y., andBrunette, D. M. (1985): ‘Mechanical stretching increases the number of cultured bone cells synthesising DNA and alters their pattern of protein synthesis’,Calcif. Tissue Int.,37, pp. 431–436
Hung, C. T., Allen, F. D., Pollack, S. R., andBrighton, C. T. (1996): ‘Intracellular Ca2+ stores and extracellular Ca2+ are required in the real time Ca2+ response of bone cells experiencing fluid flow’,J. Biomech.,29, pp. 1411–1417
Jones, D. B., Nolte, H., Scholubbers, J.-G., Turner, E., andVeltel, D. (1991): ‘Biochemical signal transduction of mechanical strain in osteoblast-like cells’,Biomaterials,12, pp. 101–109
Jones, D. B., andBingmann, D. (1991): ‘How do osteoblasts respond to mechanical stimulation?’,Cells Meterials,1, pp. 329–340
Karpinski, E., Wu, L., Civitelli, R., Avioli, L. V., Hruska, K. A., andPang, P. K. T. (1989): ‘A dihydropyridine-sensitive channel in rodent osteoblastic cells’,Calcif. Tissue Int.,45, pp. 54–57
Klein-Nulend, J., Van Der Plas, A., Semeins, C. M., Ajubi, N. E., Frangos, J. A., Nijweide, P. J., andBurger, E. H. (1995): ‘Sensitivity of osteocytes to biochemical stressin vitro’,FASEB,9, pp. 441–445
Klein-Nulend, J., Burger, E. H., Semeins, C. M., Raizz, L. G., andPilbeam, C. C. (1997): ‘Pulsating fluid flow stimulates prostaglandin release and inducible prostaglandin G/H synthase mRNA expression in primary mouse bone cells’,J. Bone Miner. Res.,1, pp. 45–51
Kodama, H. A., Amagi, Y., Sudo, H., Kasai, S., andYamamoto, S. (1981): ‘Establishment of a clonal osteogenic cell line from newborn mouse calvaria’,Jpn. J. Oral Biol.,23, pp. 899–901
Lean, J. M., Jagger, C. J., Chambers, T. J., andChow, J. W. M. (1995): ‘Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation’,Am. J. Physiol.,268, pp. E318-E327
Leblanc, A. D., Schneider, V. S., Evans, H. J., Englebertson, D. A., andKrebs, J. M. (1990): ‘Bone mineral loss and recovery after 17 weeks of bed rest’,J. Bone Miner Res.,5 pp. 843–850
Lee, H. M., andWong, B. S. (1994): ‘Stretch-activated increases in intracellular calcium in osteoblast-like cells’,J. Dent. Res.,73, pp. 419–423
Loza, J., Stephan, J., Dolce, E., Dziak, C., andSimasko, R. (1994): ‘Calcium currents in osteoblastic cells-dependence on cellular growth stage’,Calcif. Tissue Int.,55, pp. 128–133
McClesky, E. W. (1994): ‘Calcium channels: cellular roles and molecular mechanisms’,Curr. Opinion Neurobiol.,4, pp. 304–312
McDonald, F., Somasundaram, B., McCann, T. J., Mason, W. T., andMeikle, M. C. (1996): ‘Calcium waves in fluid-flow stimulated osteoblasts are G-protein mediated’,Arch. Biochem. Biophys.,326, pp. 31–38
Morain, P., Peglion, J. L., andGiesen-Crouse, E. (1992): ‘Ca2+ channel inhibition in a rat osteoblast-like cell line, UMR 106, by a new dihydropyridine derivative, S11568’,Eur. J. Pharmacol.,220, pp. 1–17
Murray, D. W., andRushton, N. (1990): ‘The effect of strain on bone cell prostaglandin E2 release: a new experimental method’,Calcif. Tissue. Int.,47, pp. 35–39
Neidlinger-Wilke, C., Stalla, I., Claes, L., Brand, R., Hoellen, I., Rubenacher, S., Arand, M., andKinzi, L. (1995): ‘Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF-b release in response to cyclic strain’,J. Biomech.,28, (12), pp. 1411–1418
Nishioka, S., Fukuda, K., andPanaka, S. (1993): ‘Cyclic stretch increases alkaline phosphatase activity of osteoblast-like cells: a role for prostaglandin E2’,Bone Mineral,21, pp. 141–150
Nowycky, M., Fox, A. P., andTsein, R. Y. (1985): ‘Three types of neuronal calcium channels with different calcium agonist snesitivity’,Nature,316, pp. 440–443
Pead, M. J., andLanyon, L. E. (1989) ‘Indomethacin modulation of load-related stimulation of new bone formationin-vivo’,Calcif. Tissue Int.,45, pp. 34–40
Pitsillides, A. A., Rawlinson, S. C. F., Suswillo, R. F. L., Bourrin, S., Zaman, G., andLanyon, L. E. (1995): ‘Mechanical strain-induced NO production by bone cells: A possible role in adaptive bone (re)modelling?’,FASEB,9, pp. 1614–1622
Preston, M. R., El Haj, A. J., andPublicover, S. J. (1996): ‘Expression of voltage-operated Ca2+ channels in rat bone marrow stromal cellsin vitro’,Bone,19, pp. 101–106
Publicover, S. J., Thomas, G. P., andEl Haj, A. J. (1994): ‘Induction of a low voltage-activated, fast-inactivating Ca2+ channel in cultured bone marrow stromal cells by dexamethasone’,Calcif. Tissue Int.,54, pp. 125–132
Publicover, S. J., Preston, M. R., andEl Haj, A. J. (1995): ‘Voltage-dependent potentiation of low-voltage activated Ca2+ channel currents in cultured rat bone marrow cells’,J. Physiol.,489, pp. 649–661
Raab-Cullen, D. M., Thiede, M. A., Peterson, D. N., Kimmel, D. B., andRecker, R. R. (1994): ‘Mechanical loading stimulates rapid changes in periosteal gene expression’,Calcif. Tissue Int.,55, pp. 473–478
Rawlinson, S., El Haj, A., Minter, S., Tavares, I., Bennett, A., andLanyon, L. (1991). ‘Load-related increases of prostaglandin production in cores of adult canine cancellous bonein-vitro-a role for prostacyclin in adaptive bone remodelling’,J. Bone Miner. Res.,6, pp. 1345–1351
Rawlinson, S. C. F., Mosley, J. R. B., Suswillo, R. F. L., Pitsillides, A. A., andLanyon, L. E. (1995): ‘Calvarial and limb bone cells in organ and monolayer culture do not show the same early responses to dynamic mechanical strain’,J. Bone Miner. Res.,10, pp. 1225–1232
Rawlinson, S. C. F., Pitsillides, A. A., andLanyon, L. E. (1996): ‘Involvement of different ion channels in osteoblasts and osteocytes early response to mechanical strain’,Bone,19, pp. 609–614
Rodan, G., Bourret, L., Harvey, A., andMensi, T. (1975): ‘Cyclic AMP and cyclic GMP mediators of the mechanical effects on bone remodelling’,Science189, pp. 467–499
Roelofsen, J., Klein-Nulend, J., andBurger, E. H. (1995): ‘Mechanical stimulation by intermittent hydrostatic compression promotes bone specific gene expressionin vitro’,J. Biomech.,28, (12), pp. 1493–1503
Rubin, C. T., andLanyon, L. E. (1984): ‘Regulation of bone formation by applied dynamic loads’,J. Bone Joint Surg.,66A, pp. 397–402
Sammons, R. L., El Haj, A. J., andMarquis, P. M. (1994): ‘A novel culture which permits the synthesis of proteins by rat calvarial cells cultured on hydroxyapatite particles to be quantified’,Biomaterials,15 (7), pp. 536–542
Schofield, J., Tangtrongskadi, N., Hughes-Fulford, M., andSnowdowne, K. (1994): ‘Increased [Ca2+]i through stretch-acti-vated channels in MC3T3-E1 osteoblast-like cells’,J. Dent. Res.,73, p. 419
Shelton, R., andEl Haj, A. J. (1992): ‘A novel carrier bead model to investigate bone cell responses to mechanical compressionin vitro’,J. Bone Miner. Res.,7, (supp. 2), pp. S403-S405
Simkin, A., Ayalon, J., andLeichter, I. (1987): ‘Increased trabecular bone density due to bone-loading exercises in postmenopausal osteoporotic women’,Calcif. Tissue Int.,40, pp. 50–63
Skerry, T. M., Bitensky, L., Chayen, J., andLanyon, L. E. (1989): ‘Early strain related changes in enzyme activity in osteocytes following bone loadingin-vivo’,J. Bone Min. Res.,4, pp. 783–788
Snutch, T. P., andReiner, P. B. (1992): ‘Ca2+ channels: diversity of form and function’,Curr. Opinion Neurobiol.,2, pp. 247–253
Somjen, D., Binderman, I., Berger, E., andHarell, A. (1980): ‘Bone remodelling induced by physical stress in prostaglandin E2 mediated’,Biochem. Biophys. Acta,627, pp. 91–100
Stanford, C., Stevens, J., andBrand, R. (1995): ‘Cellular deformation reversibly depresses RT-PCR detectable levels of bone related mRNA’,J. Biomech.,28, (12), pp. 1419–1427
Sudo, H., Kodama, H. A., Amagi, Y., Yamamoto, S., andKasai, S. (1983): ‘In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria’,J. Cell Biol.,96, pp. 191–198
Sun, Y. Q., McLeod, K. J., andRubin, C. T. (1995): ‘Mechanically induced periosteal bone formation is paralleled by the upregulation of collagen type one mRNA in osteocytes as measured byin situ reverse transcript-polymerase chain reaction’,Calcif. Tissue Int.,57, pp. 456–462
Thomas, G. P., andEl Haj, A. J. (1996): ‘Bone marrow stromal cells are load responsivein-vitro’,Calcif. Tissue Int.,58, pp. 101–108
Triggle, D. J. (1990): ‘Calcium, calcium channels and calcium channel antagonists’,Can. J. Physiol. Pharmacol.,68, pp. 1474–1481
Turner, C. H., Forwood, M. R., Rho, J., andYoskikawa, T. (1994): ‘Mechanical loading thresholds for lamellar and woven bone formation’,J. Bone Miner.9, pp. 87–97
Turner, C. H., andForwood, M. R. (1995): ‘What role does the osteocyte network play in bone adaptation?’,Bione,16, pp. 283–285
Vadiakias, G. P., andBanes, A. J. (1992). ‘Verapamil decreases cyclic load-induced calcium incorporation in ROS 17/2.8 Osteosarcoma cell cultures’,Matrix,12, pp. 439–447
Walker, L. M., Said Ahmed, M. A. A., Publicover, S. J., andEl Haj, A. J. (1997): ‘Mechanical load transduction pathways: intra-cellular calcium fluxes and calcium channels’,J. Bone Miner. Res.,17, p. 19
Xia, S. L., andFerrier, J. (1995): ‘Calcium signal induced by mechanical perturbation of osteoclasts’,J. Cell Physiol.,163, pp. 493–501
Xia, S. L., andFerrier, J. (1996): ‘Localised calcium signalling in multinucleated osteoclasts’,J. Cell Physiol.,163, pp. 148–155
Yamaguchi, D. T., Green, J., Merritt, B. S., Kleeman, C. R., andMuallem, S. (1989): ‘Properties of the depolarization activated calcium and barium entry in osteoblast-like cells’,J. Biol. Chem.,264, pp. 197–204
Yeh, C. K., andRodan, G. A. (1984): ‘Tensile forces enhance prostaglandin E synthesis in osteoblastic cells grown on collagen ribbons’,Calcif. Tissue Int.,36, pp. 567–571
Ypey, D. L., Weidema, A. F., Hold, K. M., Van Der Laarse, A., Ravesloot, J. H., Van Der Plas, A., andNijweide, P. J., (1992): ‘Voltage, calcium, and stretch activated ionic channels and intra-cellular calcium in bone cells’,J. Bone Miner. Res.,7, (Suppl. 2), pp. S377-S387
Zaman, G., Dallas, S. L., andLanyon, L. E. (1992): ‘Cultured embryonic bone shafts show osteogenic responses to mechanical loading’,Calcif. Tissue Int.,51, pp. 132–136
Zaman, G., Suswillo, R. F. L., Cheng, M. Z., Tavares, I. A., andLanyon, L. E. (1997): ‘Early responses to dynamic strain changes and prostaglandins in bone-derived cells in culture’,J. Bone Miner. Res.,12, (5), pp. 769–777
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
El Haj, A.J., Walker, L.M., Preston, M.R. et al. Mechanotransduction pathways in bone: calcium fluxes and the role of voltage-operated calcium channels. Med. Biol. Eng. Comput. 37, 403–409 (1999). https://doi.org/10.1007/BF02513320
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02513320