Abstract
Bone formation responds to mechanical loading, which is believed to be mediated by osteocytes. Previous theories assumed that loading stimulates osteocytes to secrete signals that stimulate bone formation. In computer simulations this ‘stimulatory’ theory successfully produced load-aligned trabecular structures. In recent years, however, it was discovered that osteocytes inhibit bone formation via the protein sclerostin. To reconcile this with strain-induced bone formation, one must assume that sclerostin secretion decreases with mechanical loading. This leads to a new ‘inhibitory’ theory in which loading inhibits osteocytes from inhibiting bone formation. Here we used computer simulations to show that a sclerostin-based model is able to produce a load-aligned trabecular architecture. An important difference appeared when we compared the response of the stimulatory and inhibitory models to loss of osteocytes, and found that the inhibitory pathway prevents the loss of trabeculae that is seen with the stimulatory model. Further, we demonstrated with combined stimulatory/inhibitory models that the two pathways can work side-by-side to achieve a load-adapted bone architecture.
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Bentolila V, Boyce TM, Fyhrie DP, Drumb R, Skerry TM, Schaffler MB (1998) Intracortical remodeling in adult rat long bones after fatigue loading. Bone 23: 275–281
Brown TD, Pedersen DR, Gray ML, Brand RA, Rubin CT (1990) Toward an identification of mechanical parameters initiating periosteal remodeling: a combined experimental and analytic approach. J Biomech 23: 893–905
Burger EH, Klein-Nulend J (1999) Mechanotransduction in bone—role of the lacuno-canalicular network. FASEB J 13 Suppl: 101–112
Cheng B, Kato Y, Zhao S, Luo J, Sprague E, Bonewald LF, Jiang JX (2001) PGE 2 is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. Endocrinology 142: 3464–3473
Chow JW, Chambers TJ (1994) Indomethacin has distinct early and late actions on bone formation induced by mechanical stimulation. Am J Physiol Endocrinol Metab 267: E287–E292
Cox LGE, van Rietbergen B, van Donkelaar CC, Ito K (2011) The turnover of mineralized growth plate cartilage into bone may be regulated by osteocytes. J Biomech (accepted)
Currey JD (1988) The effect of porosity and mineral content on the Young’s modulus of elasticity of compact bone. J Biomech 21: 131–191
Heino TJ, Hentunen TA, Väänänen HK (2004) Conditioned medium from osteocytes stimulates the proliferation of bone marrow mesenchymal stem cells and their differentiation into osteoblasts. Exp Cell Res 294: 458–468
Huiskes R (2000) If bone is the answer, then what is the question?. J Anat 197: 145–156
Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD (2000) Effects of mechanical forces on maintenance and adaptation of form in trabecular bone. Nature 405: 704–706
Imai S, Heino TJ, Hienola A, Kurata K, Büki K, Matsusue Y, Väänänen HK, Rauvala H (2009) Osteocyte-derived HB-GAM (pleiotrophin) is associated with bone formation and mechanical loading. Bone 44: 785–794
Lancaster J (1996) Diffusion of free nitric oxide. Methods Enzymol 268: 31–50
Liu XS, Huang AH, Zhang XH, Sajda P, Baohua J, Guo XE (2008) Dynamic simulation of three dimensional architecture and mechanical alterations in human trabecular bone during menopause. Bone 43: 292–301
Papanicolaou SE, Phipps RJ, Fyhrie DP, Genetos DC (2009) Modulation of sclerostin expression by mechanical loading and bone morphogenetic proteins in osteogenic cells. Biorheology 46: 389–399
Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283: 5866–5875
Ruimerman R, Hilbers PAJ, van Rietbergen B, Huiskes R (2005) A theoretical framework for strain-related trabecular bone maintenance and adaptation. J Biomech 38: 931–941
Ruimerman R, Huiskes R, van Lenthe GH, Janssen JD (2001) A computer-simulation model relating bone-cell metabolism to mechanical adaptation of trabecular architecture. Comput Methods Biomech Biomed Eng 4: 433–448
Skerry TM, Bitensky L, Chayen J, Lanyon LE (1989) Early strain-related changes in enzyme activity in osteocytes following bone loading in vivo. J Bone Miner Res 4: 783–788
Suponitzky I, Weinreb M. (1998) Differential effects of systemic prostaglandin E 2 on bone mass in rat long bones and calvariae. J Endocrinol 156: 51–57
Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K (2007) Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 5: 464–475
Taylor AF, Saunders MM, Shingle DL, Cimbala JM, Zhou Z, Donahue HJ (2007) Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions. Am J Physiol Cell Physiol 292: 545–552
van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P, Löwik CW (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22: 19–28
van Oers RFM, Ruimerman R, Tanck E, Hilbers PAJ, Huiskes R (2008) A unified theory for osteonal and hemi-osteonal remodeling. Bone 42: 250–259
Verborgt O, Gibson GJ, Schaffler MB (2000) Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 15: 60–67
Vezeridis PS, Semeins CM, Chen Q, Klein-Nulend J (2006) Osteocytes subjected to pulsating fluid flow regulate osteoblast proliferation and differentiation. Biochem Biophys Res Commun 348: 1082–1088
Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22: 6267–6276
Wolff J (1892) Das Gesetz der Transformation der Knochen. Hirschwald, Berlin; translated as: Wolff J (1986) The law of bone remodeling. Springer, Berlin
Acknowledgments
This work was supported by the Netherlands Organization for Scientific Research, section Computational Life Sciences (NWO/CLS, grant number 635.100.014).
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Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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van Oers, R.F.M., van Rietbergen, B., Ito, K. et al. A sclerostin-based theory for strain-induced bone formation. Biomech Model Mechanobiol 10, 663–670 (2011). https://doi.org/10.1007/s10237-010-0264-0
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DOI: https://doi.org/10.1007/s10237-010-0264-0