Osteocyte mechanobiology and pericellular mechanics

Annual Review of Biomedical Engineering

Volumn 12, Issue , 2010, Pages 369-400

  Jacobs, Christopher R ^a   Temiyasathit, Sara ^b   Castillo, Alesha B ^c  

^a Columbia University ^*  (United States)

^b STANFORD UNIVERSITY   (United States)

^c VA PALO ALTO HEALTH CARE SYSTEM   (United States)

Author keywords

bone mass; mechanosignaling; mechanotransduction; osteoblast

Indexed keywords

BIOLOGICAL RESPONSE; BONE MASS; DISEASE PROCESS; EXCITABLE CELLS; MECHANICAL EFFECTS; MECHANICAL LOADING; MECHANO-BIOLOGY; MECHANOSENSING; MECHANOSIGNALING; MECHANOTRANSDUCTION; MOLECULAR LEVELS; NASCENT FIELD; OSTEOCYTES; PHYSIOLOGICAL FUNCTIONS;

BIOLOGICAL ORGANS; BONE; MECHANICS;

MECHANISMS;

GAP JUNCTION PROTEIN; GUANINE NUCLEOTIDE BINDING PROTEIN; NITRIC OXIDE; NUCLEOTIDE; STROMAL CELL DERIVED FACTOR 1; ION CHANNEL;

BIOMECHANICS; BONE DEFORMATION; BONE REMODELING; BONE STRESS; BONE TISSUE; CALCIUM CELL LEVEL; CALCIUM SIGNALING; CELL INTERACTION; CELL MEMBRANE; CYTOSKELETON; ELECTROMAGNETIC FIELD; EUKARYOTIC FLAGELLUM; FLUID FLOW; FOCAL ADHESION; GAP JUNCTION; IN VIVO STUDY; MECHANOTRANSDUCTION; MEMBRANE CHANNEL; MESENCHYMAL STEM CELL; MOLECULAR DYNAMICS; MOLECULAR MECHANICS; OSTEOCYTE; REVIEW; SIGNAL TRANSDUCTION; TISSUE INJURY; TISSUE PRESSURE; TRACTION THERAPY; VIBRATION; BONE; CELL COMMUNICATION; HUMAN; MECHANICAL STRESS; PHYSIOLOGY; PRESSURE;

BIOMECHANICS; BONE AND BONES; CELL COMMUNICATION; CELL MEMBRANE; CILIA; CYTOSKELETON; ELECTROMAGNETIC FIELDS; FOCAL ADHESIONS; HUMANS; ION CHANNELS; MECHANOTRANSDUCTION, CELLULAR; OSTEOCYTES; PRESSURE; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; VIBRATION; BIOMECHANICAL PHENOMENA;

EID: 77955632905     PISSN: 15239829     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev-bioeng-070909-105302     Document Type: Review

References (140)

1. Jacobs CR. 2000. The mechanobiology of cancellous bone structural adaptation. J. Rehabil. Res. Dev. 37:209-216
2. Stoltz JF, Wang X. 2002. From biomechanics to mechanobiology. Biorheology 39:5-10
3. Castillo AB, Jacobs CR. 2010. Skeletal mechanobiology. In Mechanobiology Handbook, ed. J Nagatomi. Boca Raton, FL: CRC Press. In press
4. Temiyasathit S, Jacobs CR. 2010. The osteocyte primary cilium and its role in bone mechanotransduc-tion. Ann. NY Acad. Sci. 1192:422-428
5. Rubin J, Rubin C, Jacobs CR. 2006. Molecular pathways mediating mechanical signaling in bone. Gene 367:1-16
6. Friedenberg ZB, Brighton CT. 1966. Bioelectric potentials in bone. J. Bone Joint Surg. Am. 48:915-923
7. Riddle RC, Donahue HJ. 2009. From streaming-potentials to shear stress: 25 years of bone cell mechan-otransduction. J. Orthop. Res. 27:143-149
8. Burr DB, Milgrom C, Fyhrie D, Forwood M, Nyska M, et al. 1996. In vivo measurement of human tibial strains during vigorous activity. Bone 18:405-410
9. Zhang D, Weinbaum S, Cowin SC. 1998. Estimates of the peak pressures in bone pore water. J. Biomech. Eng. 120:697-703
10. Cowin SC, Gailani G, Benalla M. 2009. Hierarchical poroelasticity: movement of interstitial fluid between porosity levels in bones. Philos. Trans. A Math. Phys. Eng. Sci. 367:3401-3444
11. Piekarski K, Munro M. 1977. Transport mechanism operating between blood supply and osteocytes in long bones. Nature 269:80-82
12. Ciani C, Doty SB, Fritton SP. 2005. Mapping bone interstitial fluid movement: displacement of ferritin tracer during histological processing. Bone 37:379-387
13. Dillaman RM, Roer RD, Gay DM. 1991. Fluid movement in bone: theoretical and empirical. J. Biomech. 24(Suppl. 1):163-177
14. Qin YX, Kaplan T, Saldanha A, Rubin C. 2003. 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
15. Bergula AP, Haidekker MA, Huang W, Stevens HY, Frangos JA. 2004. Venous ligation-mediated bone adaptation is NOS 3 dependent. Bone 34:562-569
16. Stevens HY, Meays DR, Frangos JA. 2006. Pressure gradients and transport in the murine femur upon hindlimb suspension. Bone 39:565-572
17. Ciani C, Doty SB, Fritton SP. 2009. An effective histological staining process to visualize bone interstitial fluid space using confocal microscopy. Bone 44:1015-1017
18. Castillo AB, Alam I, Tanaka SM, Levenda J, Li J, et al. 2006. Low-amplitude, broad-frequency vibration effects on cortical bone formation in mice. Bone 39:1087-1096
19. Judex S, Lei X, Han D, Rubin C. 2007. 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
20. Rittweger J, Beller G, Armbrecht G, Mulder E, Buehring B, et al. 2010. Prevention of bone loss during 56 days of strict bed rest by side-alternating resistive vibration exercise. Bone 46(1):137-147
21. Maddalozzo GF, Iwaniec UT, Turner RT, Rosen CJ, Widrick JJ. 2008. Whole-body vibration slows the acquisition of fat in mature female rats. Int. J. Obes. (Lond.) 32:1348-1354
22. O'Brien FJ, Hardiman DA, Hazenberg JG, Mercy MV, Mohsin S, et al. 2005. The behavior of microc-racks in compact bone. Eur. J. Morphol. 42:71-79
23. Burr DB, Martin RB, Schaffler MB, Radin EL. 1985. Bone remodeling in response to in vivo fatigue microdamage. J. Biomech. 18:189-200
24. Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP. 2000. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26:375-380
25. Fazzalari NL, Forwood MR, Manthey BA, Smith K, Kolesik P. 1998. Three-dimensional confocal images of microdamage in cancellous bone. Bone 23:373-378
26. Vander Molen MA, Donahue HJ, Rubin CT, McLeod KJ. 2000. Osteoblastic networks with deficient coupling: differential effects of magnetic and electric field exposure. Bone 27:227-231
27. Owan I, Burr DB, Turner CH, Qiu J, Tu Y, et al. 1997. Mechanotransduction in bone: osteoblasts are more responsive to fluid forces than mechanical strain. Am. J. Physiol. 273:C810-15
28. Smalt R, Mitchell FT, Howard RL, Chambers TJ. 1997. Mechanotransduction in bone cells: induction of nitric oxide and prostaglandin synthesis by fluid shear stress, but not by mechanical strain. Adv. Exp. Med. Biol. 433:311-314
29. You J, Yellowley CE, Donahue HJ, Zhang Y, Chen Q, Jacobs CR. 2000. Substrate deformation levels associated with routine physical activity are less stimulatory to bone cells relative to loading-induced oscillatory fluid flow. J. Biomech. Eng. 122:387-393
30. Boutahar N, Guignandon A, Vico L, Lafage-Proust MH. 2004. Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 tyrosine sites involved in ERK activation. J. Biol. Chem. 279:30588-30599
31. Brown TD, Bottlang M, Pedersen DR, Banes AJ. 1998. Loading paradigms\intentional and unintentional\for cell culture mechanostimulus. Am. J. Med. Sci. 316:162-168
32. Bonivtch AR, Bonewald LF, Nicolella DP. 2007. Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J. Biomech. 40:2199-2206
33. You L, Cowin SC, Schaffler MB, Weinbaum S. 2001. A model for strain amplification in the actin cytoskeleton of osteocytes due to fluid drag on pericellular matrix. J. Biomech. 34:1375-1386
34. Kwon RY, Jacobs CR. 2007. Time-dependent deformations in bone cells exposed to fluid flow in vitro: investigating the role of cellular deformation in fluid flow-induced signaling. J. Biomech. 40:3162-3168
35. Reilly GC, Haut TR, Yellowley CE, Donahue HJ, Jacobs CR. 2003. Fluid flow-induced PGE2 release by bone cells is reduced by glycocalyx degradation whereas calcium signals are not. Biorheology 40:591-603
36. Malone AM, Anderson CT, Tummala P, Kwon RY, Johnston TR, et al. 2007. Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism. Proc. Natl. Acad. Sci. USA 104:13325-13330
37. Kufahl RH, Saha S. 1990. A theoretical model for stress-generated fluid flow in the canaliculi-lacunae network in bone tissue. J. Biomech. 23:171-180
38. Weinbaum S, Cowin SC, Zeng Y. 1994. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J. Biomech. 27:339-360
39. McNamara LM, Majeska RJ, Weinbaum S, Friedrich V, Schaffler MB. 2009. Attachment of osteocyte cell processes to the bone matrix. Anat. Rec. (Hoboken) 292:355-363
40. Wang Y, McNamara LM, Schaffler MB, Weinbaum S. 2007. A model for the role of integrins in flow induced mechanotransduction in osteocytes. Proc. Natl. Acad. Sci. USA 104:15941-15946
41. Wang Y, McNamara LM, Schaffler MB, Weinbaum S. 2008. Strain amplification and integrin based signaling in osteocytes. J. Musculoskelet. Neuronal Interact. 8:332-334
42. Fornells P, Garcia-Aznar JM, Doblare M. 2007. A finite element dual porosity approach to model deformation-induced fluid flow in cortical bone. Ann. Biomed. Eng. 35:1687-1698
43. Hayward LN, Morgan EF. 2009. Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation. Biomech. Model Mechanobiol. 8(6):447-455
44. Khayyeri H, Checa S, Tagil M, Prendergast PJ. 2009. Corroboration of mechanobiological simulations of tissue differentiation in an in vivo bone chamber using a lattice-modeling approach. J. Orthop. Res. 27:1659-1666
45. Goulet GC, Coombe D, Martinuzzi RJ, Zernicke RF. 2009. Poroelastic evaluation of fluid movement through the lacunocanalicular system. Ann. Biomed. Eng. 37:1390-1402
46. Gururaja S, Kim HJ, Swan CC, Brand RA, Lakes RS. 2005. Modeling deformation-induced fluid flow in cortical bone's canalicular-lacunar system. Ann. Biomed. Eng. 33:7-25
47. Gailani G, Benalla M, Mahamud R, Cowin SC, Cardoso L. 2009. Experimental determination of the permeability in the lacunar-canalicular porosity of bone. J. Biomech. Eng. 131:101007
48. Donahue SW, Jacobs CR, Donahue HJ. 2001. Flow-induced calcium oscillations in rat osteoblasts are age, loading frequency, and shear stress dependent. Am. J. Physiol. Cell Physiol. 281:C1635-41
49. Rodan GA, Bourret LA, Harvey A, Mensi T. 1975. Cyclic AMP and cyclic GMP: mediators of the mechanical effects on bone remodeling. Science 189:467-469
50. Saito S, Ngan P, Rosol T, Saito M, Shimizu H, et al. 1991. Involvement of PGE synthesis in the effect of intermittent pressure and interleukin-1 beta on bone resorption. J. Dent. Res. 70:27-33
51. Goulet GC, Cooper DM, Coombe D, Zernicke RF. 2008. Influence of cortical canal architecture on lacunocanalicular pore pressure and fluid flow. Comput. Methods Biomech. Biomed. Eng. 11:379-387
52. Buechner PM, Lakes RS, Swan C, Brand RA. 2001. A broadband viscoelastic spectroscopic study of bovine bone: implications for fluid flow. Ann. Biomed. Eng. 29:719-728
53. Swan CC, Lakes RS, Brand RA, Stewart KJ. 2003. Micromechanically based poroelastic modeling of fluid flow in Haversian bone. J. Biomech. Eng. 125:25-37
54. Karjalainen HM, Sironen RK, Elo MA, Kaarniranta K,Takigawa M, et al. 2003. Gene expression profiles in chondrosarcoma cells subjected to cyclic stretching and hydrostatic pressure. A cDNA array study. Biorheology 40:93-100
55. Noble B. 2005. Microdamage and apoptosis. Eur. J. Morphol. 42:91-98
56. Hazenberg JG, Freeley M, Foran E, Lee TC, Taylor D. 2006. Microdamage: a cell transducing mechanism based on ruptured osteocyte processes. J. Biomech. 39:2096-2103
57. Tami AE, Nasser P, Verborgt O, Schaffler MB, Knothe Tate ML. 2002. The role of interstitial fluid flow in the remodeling response to fatigue loading. J. Bone Miner. Res. 17:2030-2037
58. Waldorff EI, Christenson KB, Cooney LA, Goldstein SA. 2009. Microdamage repair and remodeling requires mechanical loading. J. Bone Miner. Res. 25(4):734-745
59. Federman M, Nichols G Jr. 1974. Bone cell cilia: vestigial or functional organelles? Calcif. Tissue Res. 17:81-85
60. Poole CA, Flint MH, Beaumont BW. 1985. Analysis of the morphology and function of primary cilia in connective tissues: a cellular cybernetic probe? Cell Motil. 5:175-193
61. Ong AC, Wheatley DN. 2003. Polycystic kidney disease\the ciliary connection. Lancet 361:774-776
62. Malone AM, Anderson CT, Stearns T, Jacobs CR. 2007. Primary cilia in bone. J. Musculoskelet. Neuronal Interact. 7:301
63. Whitfield JF. 2003. Primary cilium\isitan osteocyte's strain-sensing flowmeter? J. Cell Biochem. 89:233-237
64. Olsen B. 2005. Nearly all cells in vertebrates and many cells in invertebrates contain primary cilia. Matrix Biol. 24:449-450
65. DeRouen MC, Oro AE. 2009. The primary cilium: a small yet mighty organelle. J. Invest. Dermatol. 129:264-265
66. Gurkan UA, Akkus O. 2008. The mechanical environment of bone marrow: a review. Ann. Biomed. Eng. 36:1978-1991
67. Guilak F, Cohen DM, Estes BT, Gimble JM, Liedtke W, Chen CS. 2009. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5:17-26
68. Sen B, Xie Z, Case N, Ma M, Rubin C, Rubin J. 2008. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable beta-catenin signal. Endocrinology 149:6065-6075
69. Simmons CA, Matlis S, Thornton AJ, Chen S, Wang CY, Mooney DJ. 2003. Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. J. Biomech. 36:1087-1096
70. Arnsdorf EJ, Tummala P, Kwon RY, Jacobs CR. 2009. Mechanically induced osteogenic differentiation\the role of RhoA, ROCKII and cytoskeletal dynamics. J. Cell Sci. 122:546-553
71. Bao G. 2009. Protein mechanics: a new frontier in biomechanics. Exp. Mech. 49:153-164
72. Mofrad MR, Golji J, Abdul Rahim NA, Kamm RD. 2004. Force-induced unfolding of the focal adhesion targeting domain and the influence of paxillin binding. Mech. Chem. Biosyst. 1:253-265
73. Forman JR, Qamar S, Paci E, Sandford RN, Clarke J. 2005. The remarkable mechanical strength of polycystin-1 supports a direct role in mechanotransduction. J. Mol. Biol. 349:861-871
74. Johnson CP, Tang HY, Carag C, Speicher DW, Discher DE. 2007. Forced unfolding of proteins within cells. Science 317:663-666
75. Malone AM, Batra NN, Shivaram G, Kwon RY, You L, et al. 2007. The role of actin cytoskeleton in oscillatory fluid flow-induced signaling in MC3T3-E1 osteoblasts. Am. J. Physiol. Cell Physiol. 292:C1830-36
76. Myers KA, Rattner JB, Shrive NG, Hart DA. 2007. Osteoblast-like cells and fluid flow: cytoskeleton-dependent shear sensitivity. Biochem. Biophys. Res. Commun. 364:214-219
77. Norvell SM, Ponik SM, Bowen DK, Gerard R, Pavalko FM. 2004. Fluid shear stress induction of COX-2 protein and prostaglandin release in cultured MC3T3-E1 osteoblasts does not require intact microfilaments or microtubules. J. Appl. Physiol. 96:957-966
78. Ponik SM, Pavalko FM. 2004. Formation of focal adhesions on fibronectin promotes fluid shear stress induction of COX-2 and PGE2 release in MC3T3-E1 osteoblasts. J. Appl. Physiol. 97:135-142
79. Young SR, Gerard-O'Riley R, Kim JB, Pavalko FM. 2009. Focal adhesion kinase is important for fluid shear stress-induced mechanotransduction in osteoblasts. J. Bone Miner. Res. 24:411-424
80. Tong L, Buchman SR, Ignelzi MA Jr, Rhee S, Goldstein SA. 2003. Focal adhesion kinase expression during mandibular distraction osteogenesis: evidence for mechanotransduction. Plast. Reconstr. Surg. 111:211-22; discuss. 23-24
81. Litzenberger JB, Tang WJ, Castillo AB, Jacobs CR. 2009. Deletion of beta 1 integrins from cortical osteocytes reduces load-induced bone formation. Cell. Mol. Bioeng. 2:416-424
82. 2+ channels. J. Bone Miner. Res. 16:240-248
83. You J, Reilly GC, Zhen X, Yellowley CE, Chen Q, et al. 2001. Osteopontin gene regulation by oscillatory fluid flow via intracellular calcium mobilization and activation of mitogen-activated protein kinase in MC3T3-E1 osteoblasts. J. Biol. Chem. 276:13365-13371
84. Haut Donahue TL, Genetos DC, Jacobs CR, Donahue HJ, Yellowley CE. 2004. Annexin V disruption impairs mechanically induced calcium signaling in osteoblastic cells. Bone 35:656-663
85. Markoff A, Bogdanova N, Knop M, Ruffer C, Kenis H, et al. 2007. Annexin A5 interacts with polycystin-1 and interferes with the polycystin-1 stimulated recruitment of E-cadherin into adherens junctions. J. Mol. Biol. 369:954-966
86. Cherian PP, Xia X, Jiang JX. 2008. Role of gap junction, hemichannels, and connexin 43 in mineralizing in response to intermittent and continuous application of parathyroid hormone. Cell Commun. Adhes. 15:43-54
87. Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ. 2007. Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J. Cell Physiol. 212:207-214
88. Xia X, Batra N, Shi Q, Bonewald LF, Sprague E, Jiang JX. 2009. Prostaglandin promotion of osteo-cyte gap junction function through transcriptional regulation of connexin 43 by GSK-3/beta-catenin signaling. Mol. Cell Biol. 30(1):206-219
89. Haidekker MA, L'Heureux N, Frangos JA. 2000. Fluid shear stress increases membrane fluidity in endothelial cells: a study with DCVJ fluorescence. Am. J. Physiol. Heart Circ. Physiol. 278:H1401-6
90. Rubin J, Murphy TC, Rahnert J, Song H, Nanes MS, et al. 2006. Mechanical inhibition of RANKL expression is regulated by H-Ras-GTPase. J. Biol. Chem. 281:1412-1418
91. Rubin J, Schwartz Z, Boyan BD, Fan X, Case N, et al. 2007. Caveolin-1 knockout mice have increased bone size and stiffness. J. Bone Miner. Res. 22:1408-1418
92. Pavalko FM, Norvell SM, Burr DB, Turner CH, Duncan RL, Bidwell JP. 2003. A model for mechan-otransduction in bone cells: the load-bearing mechanosomes. J. Cell Biochem. 88:104-112
93. Arnsdorf EJ, Tummala P, Jacobs CR. 2009. Non-canonical Wnt signaling and N-cadherin related beta-catenin signaling play a role in mechanically induced osteogenic cell fate. PLoS One 4:e5388
94. Case N, Ma M, Sen B, Xie Z, Gross TS, Rubin J. 2008. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J. Biol. Chem. 283:29196-29205
95. Marszalek JR, Ruiz-Lozano P, Roberts E, Chien KR, Goldstein LS. 1999. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc. Natl. Acad. Sci. USA 96:5043-5048
96. Haycraft CJ, Serra R. 2008. Cilia involvement in patterning and maintenance of the skeleton. Curr. Top. Dev. Biol. 85:303-332
97. Praetorius HA, Spring KR. 2003. Removal of the MDCK cell primary cilium abolishes flow sensing. J. Membr. Biol. 191:69-76
98. Batra NN, Li YJ, Yellowley CE, You L, Malone AM, et al. 2005. Effects of short-term recovery periods on fluid-induced signaling in osteoblastic cells. J. Biomech. 38:1909-1917
99. Jacobs CR, Yellowley CE, Davis BR, Zhou Z, Cimbala JM, Donahue HJ. 1998. Differential effect of steady versus oscillating flow on bone cells. J. Biomech. 31:969-976
100. Saunders MM, You J, Zhou Z, Li Z, Yellowley CE, et al. 2003. Fluid flow-induced prostaglandin E2 response of osteoblastic ROS 17/2.8 cells is gap junction-mediated and independent of cytosolic calcium. Bone 32:350-356
101. Saunders MM, You J, Trosko JE, Yamasaki H, Li Z, et al. 2001. Gap junctions and fluid flow response in MC3T3-E1 cells. Am. J. Physiol. Cell Physiol. 281:C1917-25
102. Kwon RY, Temiyasathit S, Tummala P, Quah CC, Jacobs CR. 2010. Primary cilium-dependent mechanosensing is medicated by adenylyl cyclase 6. FASEB J. In press, doi:10.1096/fj.09-148007
103. Donahue SW, Donahue HJ, Jacobs CR. 2003. Osteoblastic cells have refractory periods for fluid-flow-induced intracellular calcium oscillations for short bouts of flow and display multiple low-magnitude oscillations during long-term flow. J. Biomech. 36:35-43
104. Li J, Duncan RL, Burr DB, Turner CH. 2002. L-type calcium channels mediate mechanically induced bone formation in vivo. J. Bone Miner. Res. 17:1795-1800
105. Thorsen K, Kristoffersson AO, Lerner UH, Lorentzon RP. 1996. In situ microdialysis in bone tissue. Stimulation ofprostaglandinE2 releaseby weight-bearing mechanical loading.J. Clin. Invest. 98:2446-2449
106. Weinreb M, Rutledge SJ, Rodan GA. 1997. Systemic administration of an anabolic dose of prostaglandin E2 induces early-response genes in rat bones. Bone 20:347-353
107. Gudi S, Nolan JP, Frangos JA. 1998. Modulation of GTPase activity of G proteins by fluid shear stress and phospholipid composition. Proc. Natl. Acad. Sci. USA 95:2515-2519
108. Rubin J, Murphy TC, Zhu L, Roy E, Nanes MS, Fan X. 2003. Mechanical strain differentially regulates endothelial nitric-oxide synthase and receptor activator of nuclear kappa B ligand expression via ERK1/2 MAPK. J. Biol. Chem. 278:34018-34025
109. Yellowley CE, Li Z, Zhou Z, Jacobs CR, Donahue HJ. 2000. Functional gap junctions between osteocytic and osteoblastic cells. J. Bone Miner. Res. 15:209-217
110. Vander Molen MA, Rubin CT, McLeod KJ, McCauley LK, Donahue HJ. 1996. Gap junctional intercellular communication contributes to hormonal responsiveness in osteoblastic networks. J. Biol. Chem. 271:12165-12171
111. Guo XE, Takai E, Jiang X, Xu Q, Whitesides GM, et al. 2006. Intracellular calcium waves in bone cell networks under single cell nanoindentation. Mol. Cell Biomech. 3:95-107
112. Huo B, Lu XL, Hung CT, Costa KD, Xu Q, et al. 2008. Fluid flow induced calcium response in bone cell network. Cell Mol. Bioeng. 1:58-66
113. Alford AI, Jacobs CR, Donahue HJ. 2003. Oscillating fluid flow regulates gap junction communication in osteocytic MLO-Y4 cells by an ERK1/2 MAP kinase-dependent mechanism. Bone 33:64-70
114. Klein-Nulend J, Semeins CM, Ajubi NE, Nijweide PJ, Burger EH. 1995. Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts\correlation with prostaglandin upregulation. Biochem. Biophys. Res. Commun. 217:640-648
115. McGarry JG, Klein-Nulend J, Mullender MG, Prendergast PJ. 2005. A comparison of strain and fluid shear stress in stimulating bone cell responses\a computational and experimental study. FASEB J. 19:482-484
116. Bakker AD, Joldersma M, Klein-Nulend J, Burger EH. 2003. Interactive effects of PTH and mechanical stress on nitric oxide and PGE2 production by primary mouse osteoblastic cells. Am. J. Physiol. Endocrinol. Metab. 285:E608-13
117. Abou Alaiwi WA, Takahashi M, Mell BR, Jones TJ, Ratnam S, et al. 2009. Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ. Res. 104:860-869
118. Jee WS, Ke HZ, Li XJ. 1991. Long-term anabolic effects of prostaglandin-E2 on tibial diaphyseal bone in male rats. Bone Miner. 15:33-55
119. Chow JW, Chambers TJ. 1994. Indomethacin has distinct early and late actions on bone formation induced by mechanical stimulation. Am. J. Physiol. 267:E287-92
120. Rawlinson SC, Mohan S, Baylink DJ, Lanyon LE. 1993. Exogenous prostacyclin, but not prostaglandin E2, produces similar responses in both G6PD activity and RNA production as mechanical loading, and increases IGF-II release, in adult cancellous bone in culture. Calcif. Tissue Int. 53:324-329
121. Pitsillides AA, Rawlinson SC, Suswillo RF, Bourrin S, Zaman G, Lanyon LE. 1995. Mechanical strain-induced NO production by bone cells: a possible role in adaptive bone (re)modeling? FASEB J.9:1614-1622
122. Donahue TL, Haut TR, Yellowley CE, Donahue HJ, Jacobs CR. 2003. Mechanosensitivity of bone cells to oscillating fluid flow induced shear stress may be modulated by chemotransport. J. Biomech. 36:1363-1371
123. Searby ND, Steele CR, Globus RK. 2005. Influence of increased mechanical loading by hypergravity on the microtubule cytoskeleton and prostaglandin E2 release in primary osteoblasts. Am. J. Physiol. Cell Physiol. 289:C148-58
124. Ajubi NE, Klein-Nulend J, Alblas MJ, Burger EH, Nijweide PJ. 1999. Signal transduction pathways involved in fluid flow-induced PGE2 production by cultured osteocytes. Am. J. Physiol. 276:E171-78
125. McGarry JG, Klein-Nulend J, Prendergast PJ. 2005. 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
126. Zhu W, Boachie-Adjei O, Rawlins BA, Frenkel B, Boskey AL, et al. 2007. A novel regulatory role for stromal-derived factor-1 signaling in bone morphogenic protein-2 osteogenic differentiation of mes-enchymal C2C12 cells. J. Biol. Chem. 282:18676-18685
127. Jung Y, Wang J, Schneider A, Sun YX, Koh-Paige AJ, et al. 2006. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone 38:497-508
128. Castillo AB, Leucht P, Tang J, Helms JA, Jacobs CR. 2008. SDF-1 is expressed in osteocytes and periosteal cells in response to mechanical loading. Presentedat Annu. Meet. Am. Soc. Bone Miner. Res., 30th, Montréal, Québec
129. You J, Jacobs CR, Steinberg TH, Donahue HJ. 2002. P2Y purinoceptors are responsible for oscillatory fluid flow-induced intracellular calcium mobilization in osteoblastic cells. J. Biol. Chem. 277:48724-48729
130. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, et al. 2008. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283:5866-5875
131. 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
132. Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB. 2009. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J. Bone Miner. Res. 24:597-605
133. Kogianni G, Mann V, Noble BS. 2008. Apoptotic bodies convey activity capable of initiating osteoclas-togenesis and localized bone destruction. J. Bone Miner. Res. 23:915-927
134. Pawlicki R. 1976. Correlation between the structure of the wall of the bone lacuna and the localization of the osteocyte within this lacuna. Electron-microscopic studies. Acta Anat. 95:421-433
135. Xiao Z, Zhang S, Mahlios J, Zhou G, Magenheimer BS, et al. 2006. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J. Biol. Chem. 281:30884-30895
136. Li YJ, Batra NN, You L, Meier SC, Coe IA, et al. 2004. Oscillatory fluid flow affects human marrow stromal cell proliferation and differentiation. J. Orthop. Res. 22:1283-1289
137. Ishijima M,Tsuji K, Rittling SR, Yamashita T, Kurosawa H, et al. 2002. Resistance to unloading-induced three-dimensional bone loss in osteopontin-deficient mice. J. Bone Miner. Res. 17:661-667
138. Saxon LK, Robling AG, Castillo AB, Mohan S, Turner CH. 2007. The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-beta. Am. J. Physiol. Endocrinol. Metab. 293:E484-91
139. Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH. 2005. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146:685-693
140. You LD, Weinbaum S, Cowin SC, Schaffler MB. 2004. Ultrastructure of the osteocyte process and its pericellular matrix. Anat. Rec. 278A:505-513