Mechanosensing in Bone and the Role of Glutamate Signalling

  • Tim Skerry


The ability of the skeleton to sense the effects of mechanical loading is necessary to explain the adaptation of bone to the functions imposed upon it by different activities. While initially it appears that such adaptation could be explained by load-induced bone formation and disuse-induced bone resorption, such ideas rapidly become too simplistic to explain many observations of skeletal physiology. When examined in more detail, these require that the skeleton is sensitive to more than simply the amount of force applied to it, and that its responses to changes in loading are not limited to formation or resorption, but must include a much more sophisticated architectural response. Finally, it is clear that the skeleton has the ability to retain some evidence of loading events and to use this in modifying its responses to subsequent events. The mechanisms underlying this “memory” of loading in bone are still not clear. However, the identification of numerous signalling systems in bone cells that have clearly identified functions in learning and memory in the central nervous system point to the possibility that common mechanisms may exist in both bone and brain. Understanding of the complexities of these different aspects of the way the skeleton perceives and responds to loading may have implications on several areas of clinical relevance, including optimisation of exercise regimens, development of artificial loading systems that mimic physiological stimuli, and pharmacological stimulation or potentiation of mechanical events.


Adaptive Change Habitual Activity Strain Magnitude Glutamate Signalling Bone Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The work performed in my lab that I mention here was funded largely by grants from BBSRC, with additional support from ARC, MRC and Conacyt.


  1. Bliziotes M, Gunness M et al (2002) The role of dopamine and serotonin in regulating bone mass and strength: studies on dopamine and serotonin transporter null mice. J Musculoskelet Neuronal Interact 2(3)  :  291–295PubMedGoogle Scholar
  2. Bradley R, Sandifer C (2009) Cauchy’s Cours d’analyse (sources and studies in the history of mathematics and physical sciences). Springer, New YorkGoogle Scholar
  3. Currey JD (1984) Can strains give adequate information for adaptive bone remodeling? Calcif Tissue Int 36  :  S118–S122PubMedCrossRefGoogle Scholar
  4. Duncan R, Misler S (1989) Voltage-activated and stretch-activated Ba2+ conducting channels in an osteoblast-like cell line (UMR 106). FEBS Lett 251  :  17–21PubMedCrossRefGoogle Scholar
  5. Foldhazy Z, Arndt A et al (2005) Exercise-induced strain and strain rate in the distal radius. J Bone Joint Surg Br 87(2)  :  261–266PubMedCrossRefGoogle Scholar
  6. Frost HM (1987) The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. Bone Miner 2  :  73–85PubMedGoogle Scholar
  7. Gray C, Marie H et al (2001) Glutamate does not play a major role in controlling bone growth. J Bone Miner Res 16  :  742–749PubMedCrossRefGoogle Scholar
  8. Gross TS, Srinivasan S et al (2002) Noninvasive loading of the murine tibia: an in vivo model for the study of mechanotransduction. J Bone Miner Res 17(3)  :  493–501PubMedCrossRefGoogle Scholar
  9. Hillam RA, Skerry TM (1995) Inhibition of bone resorption and stimulation of formation by mechanical loading of the modeling rat ulna in vivo. J Bone Miner Res 10(5)  :  683–689PubMedCrossRefGoogle Scholar
  10. Hillam RA, Jackson M et al (1995) Regional differences in human bone strain in-vivo. J Bone Miner Res 10  :  S443Google Scholar
  11. Hinoi E, Takarada T et al (2004) Glutamate signaling in peripheral tissues. Eur J Biochem 271(1)  :  1–13PubMedCrossRefGoogle Scholar
  12. Hylander WL, Johnson KR (1997) In vivo bone strain patterns in the zygomatic arch of macaques and the significance of these patterns for functional interpretations of craniofacial form. Am J Phys Anthropol 102  :  203–232PubMedCrossRefGoogle Scholar
  13. Igwe JC, Jiang X et al (2009) Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J Cell Biochem 108(3)  :  621–630PubMedCrossRefGoogle Scholar
  14. Itzstein C, Espinosa L et al (2000) Specific antagonists of NMDA receptors prevent osteoclast sealing zone formation required for bone resorption. Biochem Biophys Res Commun 268  :  201–209PubMedCrossRefGoogle Scholar
  15. Laketic-Ljubojevic I, Suva LJ et al (1999) Functional characterization of N-methyl-D-aspartic acid-gated channels in bone cells. Bone 25(6)  :  631–637PubMedCrossRefGoogle Scholar
  16. Lanyon LE (1971) Strain in sheep lumbar vertebrae recorded during life. Acta Orthop Scand 42(1)  :  102–112PubMedCrossRefGoogle Scholar
  17. Lanyon LE (1972) In vivo bone strain recorded from thoracic vertebrae of sheep. J Biomech 5(3)  :  277–281PubMedCrossRefGoogle Scholar
  18. Lanyon LE (1973) Analysis of surface bone strain in the calcaneus of sheep during normal locomotion. Strain analysis of the calcaneus. J Biomech 6(1)  :  41–49PubMedCrossRefGoogle Scholar
  19. Lanyon LE (1987) Functional strain in bone tissue as an objective, and controlling stimulus for adaptive bone remodelling. J Biomech 20  :  1083–1093PubMedCrossRefGoogle Scholar
  20. Lanyon LE, Smith RN (1970) Bone strain in the tibia during normal quadrupedal locomotion. Acta Orthop Scand 41(3)  :  238–248PubMedCrossRefGoogle Scholar
  21. Lanyon LE, Hampson WGJ et al (1975) Bone deformation recorded in vivo from strain gauges attached to the human tibial shaft. Acta Orthop Scand 46  :  256–268PubMedCrossRefGoogle Scholar
  22. Martinez-Bautista S, Wang N et al (2008) Mice lacking NMDA receptor expression in osteoblasts have pronounced vertebral bone abnormalities. J Bone Miner Res 23  :  S87Google Scholar
  23. Mason DJ, Suva LJ et al (1997) Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 20  :  199–205PubMedCrossRefGoogle Scholar
  24. May PR, Fuster JM et al (1979) Woodpecker drilling behavior. An endorsement of the rotational theory of impact brain injury. Arch Neurol 36(6)  :  370–373PubMedCrossRefGoogle Scholar
  25. Milgrom C, Finestone A et al (2000) In-vivo strain measurements to evaluate the strengthening potential of exercises on the tibial bone. J Bone Joint Surg Br 82(4)  :  591–594PubMedCrossRefGoogle Scholar
  26. Mosley JR, Lanyon LE (1998) Strain rate as a controlling influence on adaptive modeling in response to dynamic loading of the ulna in growing male rats. Bone 23(4)  :  313–318PubMedCrossRefGoogle Scholar
  27. Mosley JR, March BM et al (1997) Strain magnitude related changes in whole bone architecture in growing rats. Bone 20(3)  :  191–198PubMedCrossRefGoogle Scholar
  28. O’Connor JA, Lanyon LE, MacFie H (1982) The influence of strain rate on adaptive bone ­remodelling. J Biomech 15(10)  :  767–781Google Scholar
  29. Patton AJ, Genever PG et al (1998) Expression of an NMDA type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone. Bone 22  :  645–649PubMedCrossRefGoogle Scholar
  30. Peet NM, Grabowski PS et al (1999) The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a mechanism predominantly involving osteoclast differentiation. FASEB J 13  :  2179–2185PubMedGoogle Scholar
  31. Perez-Amodio S, Beertsen W et al (2004) (Pre-)osteoclasts induce retraction of osteoblasts before their fusion to osteoclasts. J Bone Miner Res 19(10)  :  1722–1731PubMedCrossRefGoogle Scholar
  32. Perry MJ, Parry LK et al (2009) Ultrasound mimics the effect of mechanical loading on bone formation in vivo on rat ulnae. Med Eng Phys 31(1)  :  42–47PubMedCrossRefGoogle Scholar
  33. RaabCullen DM, Akhter MP et al (1994) Periosteal bone formation stimulated by externally induced bending strains. J Bone Miner Res 9  :  1143–1152CrossRefGoogle Scholar
  34. Ravosa MJ, Johnson KR et al (2000) Strain in the galago facial skull. J Morphol 245(1)  :  51–66PubMedCrossRefGoogle Scholar
  35. Rawlinson SC, Mosley JR et al (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(8)  :  1225–1232PubMedCrossRefGoogle Scholar
  36. Robling AG, Hinant FM et al (2002) Improved bone structure and strength after long-term mechanical loading is greatest if loading is separated into short bouts. J Bone Miner Res 17(8)  :  1545–1554PubMedCrossRefGoogle Scholar
  37. Ross CF, Hylander WL (1996) In vivo and in vitro bone strain in the owl monkey circumorbital region and the function of the postorbital septum. Am J Phys Anthropol 101(2)  :  183–215PubMedCrossRefGoogle Scholar
  38. Rubin CT, Lanyon LE (1984) Dynamic strain similarity in vertebrates; an alternative to allometric limb bone scaling. J Theor Biol 107  :  321–327PubMedCrossRefGoogle Scholar
  39. Rubin CT, Lanyon LE (1985) Regulation of bone mass by mechanical strain magnitude. Calcif Tissue Int 37  :  411–417PubMedCrossRefGoogle Scholar
  40. Rubin CT, Lanyon LE (1987) Osteoregulatory nature of mechanical stimuli: function as a determinant for adaptive remodeling in bone. J Orthop Res 5  :  300–310PubMedCrossRefGoogle Scholar
  41. Rubin C, Turner AS et al (2001) Anabolism. Low mechanical signals strengthen long bones. Nature 412(6847)  :  603–604PubMedCrossRefGoogle Scholar
  42. Rumsfeldt D (2002) The unknown. Department of Defence News Briefing.Google Scholar
  43. Shivaram GM, Kim CH et al (2010) Novel early response genes in osteoblasts exposed to dynamic fluid flow. Philos Trans A Math Phys Eng Sci 368(1912)  :  605–616CrossRefGoogle Scholar
  44. Skerry TM, Genever PG (2001) Glutamate signalling in non-neuronal tissues. Trends Pharmacol Sci 22(4)  :  174–181PubMedCrossRefGoogle Scholar
  45. Skerry TM, Lanyon LE (1995) Interruption of disuse by short-duration walking exercise does not prevent bone loss in the sheep calcaneus. Bone 16  :  269–274PubMedCrossRefGoogle Scholar
  46. Skerry TM, Peet NM (1997) “Unloading” exercise increases bone formation in rats. J Bone Miner Res 12(9)  :  6Google Scholar
  47. Spencer GJ, Hitchcock IS et al (2004) Emerging neuroskeletal signalling pathways: a review. FEBS Lett 559(1–3)  :  6–12PubMedCrossRefGoogle Scholar
  48. Srinivasan S, Weimer DA et al (2002) Low-magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J Bone Miner Res 17(9)  :  1613–1620PubMedCrossRefGoogle Scholar
  49. Srinivasan S, Ausk BJ et al (2007) Rest-inserted loading rapidly amplifies the response of bone to small increases in strain and load cycles. J Appl Physiol 102(5)  :  1945–1952PubMedCrossRefGoogle Scholar
  50. Swartz SM, Bertram JEA et al (1989) Telemetered in vivo strain analysis of locomotor mechanics of brachiating gibbons. Nature 342(6247)  :  270–272PubMedCrossRefGoogle Scholar
  51. Thomason JJ, Grovum LE et al (2001) In vivo surface strain and stereology of the frontal and maxillary bones of sheep: implications for the structural design of the mammalian skull. Anat Rec 264(4)  :  325–338PubMedCrossRefGoogle Scholar
  52. Torrance AG, Mosley JM et al (1994) Noninvasive loading of the rat ulna in vivo induces a strain related modeling response uncomplicated by trauma of periosteal pressure. Calcif Tissue Int 54(3)  :  241–247PubMedCrossRefGoogle Scholar
  53. Turner C, Owan HI et al (1995a) Mechanotransduction in bone – role of strain-rate. Am J Physiol 269  :  E438–E442PubMedGoogle Scholar
  54. Turner CH, Yoshikawa T et al (1995b) High frequency components of bone strain in dogs measured during various activities. J Biomech 28(1)  :  39–44PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  1. 1.Mellanby Bone CentreSchool of Medicine and Biomedical Sciences, University of SheffieldSheffieldUK

Personalised recommendations