Osteocytes: Master orchestrators of bone

Calcified Tissue International

Volumn 94, Issue 1, 2014, Pages 5-24

  Schaffler, Mitchell B ^a   Cheung, Wing Yee ^a   Majeska, Robert ^a   Kennedy, Oran ^b  

^a City College of the City University of New York   (United States)

^b NEW YORK UNIVERSITY   (United States)

Author keywords

Biomechanics; Intercellular communication; Mechanotransduction; Osteocyte

Indexed keywords

MINERAL;

BONE; CELL COMMUNICATION; CELL INTERACTION; CELLULAR PARAMETERS; HOMEOSTASIS; HUMAN; MACROMOLECULE; MECHANOTRANSDUCTION; METABOLITE; MINERAL BALANCE; MOLECULAR SENSOR; NONHUMAN; OSTEOBLAST; OSTEOCYTE; PARACRINE SIGNALING; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW;

ANIMALS; BONE AND BONES; CELL COMMUNICATION; HUMANS; OSTEOCLASTS; OSTEOCYTES; OSTEOGENESIS; STRESS, MECHANICAL;

EID: 84893759022     PISSN: 0171967X     EISSN: 14320827     Source Type: Journal    
DOI: 10.1007/s00223-013-9790-y     Document Type: Review

References (195)

1. Franz-Odendaal TA, Hall BK, Witten PE (2006) Buried alive: how osteoblasts become osteocytes. Dev Dyn 235:176-190
2. Palumbo C (1986) A three-dimensional ultrastructural study of osteoid-osteocytes in the tibia of chick embryos. Cell Tissue Res 246:125-131
3. Palumbo C, Palazzini S, Zaffe D, Marotti G (1990) Osteocyte differentiation in the tibia of newborn rabbit: an ultrastructural study of the formation of cytoplasmic processes. Acta Anat 137:350-358
4. Doty SB, Morey-Holton ER, Durnova GN, Kaplansky AS (1990) Cosmos 1887: morphology, histochemistry, and vasculature of the growing rat tibia. FASEB J 4:16-23
5. Dallas SL, Veno PA (2012) Live imaging of bone cell and organ cultures. Methods Mol Biol 816:425-457
6. Zhang K, Barragan-Adjemian C, Ye L, Kotha S, Dallas M, Lu Y, Zhao S, Harris M, Harris SE, Feng JQ, Bonewald LF (2006) E11/gp38 selective expression in osteocytes: regulation by mechanical strain and role in dendrite elongation. Mol Cell Biol 26:4539-4552
7. Holmbeck K, Bianco P, Pidoux I, Inoue S, Billinghurst RC, Wu W, Chrysovergis K, Yamada S, Birkedal-Hansen H, Poole AR (2005) The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone. J Cell Sci 118:147-156
8. Inoue K, Mikuni-Takagaki Y, Oikawa K, Itoh T, Inada M, Noguchi T, Park JS, Onodera T, Krane SM, Noda M, Itohara S (2006) A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism. J Biol Chem 281:33814-33824
9. Bloch SL, Kristensen SL, Sorensen MS (2012) The viability of perilabyrinthine osteocytes: a quantitative study using bulk-stained undecalcified human temporal bones. Anat Rec 295:1101-1108
10. McNamara LM, Majeska RJ, Weinbaum S, Friedrich V, Schaffler MB (2009) Attachment of osteocyte cell processes to the bone matrix. Anat Rec 292:355-363
11. Kamioka H, Kameo Y, Imai Y, Bakker AD, Bacabac RG, Yamada N, Takaoka A, Yamashiro T, Adachi T, Klein-Nulend J (2012) Microscale fluid flow analysis in a human osteocyte canaliculus using a realistic high-resolution image-based three-dimensional model. Integr Biol (Camb) 4:1198-1206
12. Doty SB (1981) Morphological evidence of gap junctions between bone cells. Calcif Tissue Int 33:509-512
13. You LD, Weinbaum S, Cowin SC, Schaffler MB (2004) Ultrastructure of the osteocyte process and its pericellular matrix. Anat Rec A 278:505-513
14. Thompson WR, Modla S, Grindel BJ, Czymmek KJ, Kirn-Safran CB, Wang L, Duncan RL, Farach-Carson MC (2011) Perlecan/Hspg2 deficiency alters the pericellular space of the lacunocanalicular system surrounding osteocytic processes in cortical bone. J Bone Miner Res 26:618-629
15. Noonan KJ, Stevens JW, Tammi R, Tammi M, Hernandez JA, Midura RJ (1996) Spatial distribution of CD44 and hyaluronan in the proximal tibia of the growing rat. J Orthop Res 14:573-581
16. Busse B, Djonic D, Milovanovic P, Hahn M, Puschel K, Ritchie RO, Djuric M, Amling M (2010) Decrease in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of remodeling in aged human bone. Aging Cell 9:1065-1075
17. Addison WN, Masica DL, Gray JJ, McKee MD (2010) Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Miner Res 25:695-705
18. Gericke A, Qin C, Sun Y, Redfern R, Redfern D, Fujimoto Y, Taleb H, Butler WT, Boskey AL (2010) Different forms of DMP1 play distinct roles in mineralization. J Dent Res 89:355-359
19. Tami AE, Schaffler MB, Knothe Tate ML (2003) Probing the tissue to subcellular level structure underlying bone's molecular sieving function. Biorheology 40:577-590
20. Thompson WR, Majid AS, Czymmek KJ, Ruff AL, Garcia J, Duncan RL, Farach-Carson MC (2011) Association of the alpha(2)delta(1) subunit with Ca(v)3.2 enhances membrane expression and regulates mechanically induced ATP release in MLO-Y4 osteocytes. J Bone Miner Res 26:2125-2139
21. Wang L, Wang Y, Han Y, Henderson SC, Majeska RJ, Weinbaum S, Schaffler MB (2005) In situ measurement of solute transport in the bone lacunar-canalicular system. Proc Natl Acad Sci USA 102:11911-11916
22. Piekarski K, Munro M (1977) Transport mechanism operating between blood supply and osteocytes in long bones. Nature 269:80-82
23. 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
24. Wang L, Ciani C, Doty SB, Fritton SP (2004) Delineating bone's interstitial fluid pathway in vivo. Bone 34:499-509
25. 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
26. Knothe Tate ML, Niederer P, Knothe U (1998) In vivo tracer transport through the lacunocanalicular system of rat bone in an environment devoid of mechanical loading. Bone 22:107-117
27. Li W, You L, Schaffler MB, Wang L (2009) The dependency of solute diffusion on molecular weight and shape in intact bone. Bone 45:1017-1023
28. Price C, Zhou X, Li W, Wang L (2011) Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: direct evidence for load-induced fluid flow. J Bone Miner Res 26:277-285
29. Wang B, Zhou X, Price C, Li W, Pan J, Wang L (2013) Quantifying load-induced solute transport and solute-matrix interactions within the osteocyte lacunar-canalicular system. J Bone Miner Res 28:1075-1086
30. Weinstein RS, O'Brien CA, Almeida M, Zhao H, Roberson PK, Jilka RL, Manolagas SC (2011) Osteoprotegerin prevents glucocorticoid-induced osteocyte apoptosis in mice. Endocrinology 152:3323-3331
31. Knothe Tate ML (2003) "Whither flows the fluid in bone?" an osteocyte's perspective. J Biomech 36:1409-1424
32. Wolff J (1986) The law of bone remodelling. Springer-Verlag, New York
33. Takai E, Mauck RL, Hung CT, Guo XE (2004) Osteocyte viability and regulation of osteoblast function in a 3D trabecular bone explant under dynamic hydrostatic pressure. J Bone Miner Res 19:1403-1410
34. Liu C, Zhao Y, Cheung WY, Gandhi R, Wang L, You L (2010) Effects of cyclic hydraulic pressure on osteocytes. Bone 46:1449-1456
35. Adachi T, Aonuma Y, Ito S, Tanaka M, Hojo M, Takano-Yamamoto T, Kamioka H (2009) Osteocyte calcium signaling response to bone matrix deformation. J Biomech 42:2507-2512
36. Rubin CT, Lanyon LE (1984) Regulation of bone formation by applied dynamic loads. J Bone Joint Surg Am 66:397-402
37. Fritton SP, McLeod KJ, Rubin CT (2000) Quantifying the strain history of bone: spatial uniformity and self-similarity of low-magnitude strains. J Biomech 33:317-325
38. 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
39. Burger E, Veldhuijzen JP (1993) Influence of mechanical factors on bone formation, resorption and growth in vitro. In: Hall BK (ed) Bone. Vol 7: Bone growth. CRC Press, Boca Raton, pp 37-56
40. Martin RB, Burr DB, Sharkey NA (1998) Mechanical properties of bone. In: Martin RB, Burr DB, Sharkey NA (eds) Skeletal tissue mechanics. Springer-Verlag, New York
41. 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
42. 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
43. Lu XL, Huo B, Park M, Guo XE (2012) Calcium response in osteocytic networks under steady and oscillatory fluid flow. Bone 51:466-473
44. Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, Jiang JX (2005) Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell 16:3100-3106
45. Anderson EJ, Kaliyamoorthy S, Iwan J, Alexander D, Knothe Tate ML (2005) Nano-microscale models of periosteocytic flow show differences in stresses imparted to cell body and processes. Ann Biomed Eng 33:52-62
46. Han Y, Cowin SC, Schaffler MB, Weinbaum S (2004) Mechanotransduction and strain amplification in osteocyte cell processes. Proc Natl Acad Sci USA 101:16689-16694
47. 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
48. Nakamura H, Kenmotsu S, Sakai H, Ozawa H (1995) Localization of CD44, the hyaluronate receptor, on the plasma membrane of osteocytes and osteoclasts in rat tibiae. Cell Tissue Res 280:225-233
49. Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM (2003) Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res 93:e136-e142
50. Bellin RM, Kubicek JD, Frigault MJ, Kamien AJ, Steward RL Jr, Barnes HM, Digiacomo MB, Duncan LJ, Edgerly CK, Morse EM, Park CY, Fredberg JJ, Cheng CM, LeDuc PR (2009) Defining the role of syndecan-4 in mechanotransduction using surface-modification approaches. Proc Natl Acad Sci USA 106:22102-22107
51. 2 release by bone cells is reduced by glycocalyx degradation whereas calcium signals are not. Biorheology 40:591-603
52. Wang Y, McNamara LM, Schaffler MB, Weinbaum S (2008) Strain amplification and integrin based signaling in osteocytes. J Musculoskelet Neuronal Interact 8:332-334
53. McKee MD, Nanci A (1995) Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein. Ann N Y Acad Sci 760:177-189
54. Nakamura I, Pilkington MF, Lakkakorpi PT, Lipfert L, Sims SM, Dixon SJ, Rodan GA, Duong LT (1999) Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone. J Cell Sci 112(Pt 22):3985-3993
55. Roca-Cusachs P, Gauthier NC, Del Rio A, Sheetz MP (2009) Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction. Proc Natl Acad Sci USA 106:16245-16250
56. Tzima E, del Pozo MA, Shattil SJ, Chien S, Schwartz MA (2001) Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J 20:4639-4647
57. Miyauchi A, Gotoh M, Kamioka H, Notoya K, Sekiya H, Takagi Y, Yoshimoto Y, Ishikawa H, Chihara K, Takano-Yamamoto T, Fujita T, Mikuni-Takagaki Y (2006) AlphaVbeta3 integrin ligands enhance volume-sensitive calcium influx in mechanically stretched osteocytes. J Bone Miner Metab 24:498-504
58. Wu D, Ganatos P, Spray DC, Weinbaum S (2011) On the electrophysiological response of bone cells using a Stokesian fluid stimulus probe for delivery of quantifiable localized piconewton level forces. J Biomech 44:1702-1708
59. Radel C, Carlile-Klusacek M, Rizzo V (2007) Participation of caveolae in beta1 integrin-mediated mechanotransduction. Biochem Biophys Res Commun 358:626-631
60. Friedland JC, Lee MH, Boettiger D (2009) Mechanically activated integrin switch controls alpha5beta1 function. Science 323:642-644
61. Phillips JA, Almeida EA, Hill EL, Aguirre JI, Rivera MF, Nachbandi I, Wronski TJ, van der Meulen MC, Globus RK (2008) Role for beta1 integrins in cortical osteocytes during acute musculoskeletal disuse. Matrix Biol 27:609-618
62. Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J (2006) Osteocyte lacunae tissue strain in cortical bone. J Biomech 39:1735-1743
63. Lancaster MA, Gleeson JG (2009) The primary cilium as a cellular signaling center: lessons from disease. Curr Opin Genet Dev 19:220-229
64. Malone AM, Anderson CT, Tummala P, Kwon RY, Johnston TR, Stearns T, Jacobs CR (2007) Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism. Proc Natl Acad Sci USA 104:13325-13330
65. Wann AK, Knight MM (2012) Primary cilia elongation in response to interleukin-1 mediates the inflammatory response. Cell Mol Life Sci 69:2967-2977
66. Wheatley DN (2005) Landmarks in the first hundred years of primary (9+0) cilium research. Cell Biol Int 29:333-339
67. Wassermann FYJ (1965) Fine structure of the osteocyte capsule and of the wall of the lacunae in bone. Cell Tissue Res 67:636-652
68. Mochizuki T, Tsuchiya K, Nitta K (2013) Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies. Clin Exp Nephrol 17:317-326
69. Harris PC, Torres VE (2002) Polycystic kidney disease, autosomal dominant. In: GeneReviews. University of Washington, Seattle
70. Torres VE, Harris PC (2007) Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities. J Intern Med 261:17-31
71. Xiao Z, Dallas M, Qiu N, Nicolella D, Cao L, Johnson M, Bonewald L, Quarles LD (2011) Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB J 25:2418-2432
72. (2004) Syncytium. In: The Merriam-Webster's Collegiate Dictionary, Merriam Webster, Springfield, MA
73. Palazzini S, Palumbo C, Ferretti M, Marotti G (1998) Stromal cell structure and relationships in perimedullary spaces of chick embryo shaft bones. Anat Embryol (Berl) 197:349-357
74. Stains JP, Civitelli R (2005) Cell-to-cell interactions in bone. Biochem Biophys Res Commun 328:721-727
75. 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
76. Cheng B, Zhao S, Luo J, Sprague E, Bonewald LF, Jiang JX (2001) Expression of functional gap junctions and regulation by fluid flow in osteocyte-like MLO-Y4 cells. J Bone Miner Res 16:249-259
77. 2 is essential for gap junction-mediated intercellular communication between osteocyte-like MLO-Y4 cells in response to mechanical strain. Endocrinology 142:3464-3473
78. D'Hondt C, Ponsaerts R, De Smedt H, Bultynck G, Himpens B (2009) Pannexins, distant relatives of the connexin family with specific cellular functions? BioEssays 31:953-974
79. Castro CH, Stains JP, Sheikh S, Szejnfeld VL, Willecke K, Theis M, Civitelli R (2003) Development of mice with osteoblast-specific connexin43 gene deletion. Cell Commun Adhes 10:445-450
80. Zhang Y, Paul EM, Sathyendra V, Davison A, Sharkey N, Bronson S, Srinivasan S, Gross TS, Donahue HJ (2011) Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS One 6:e23516
81. Grimston SK, Goldberg DB, Watkins M, Brodt MD, Silva MJ, Civitelli R (2011) Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis. J Bone Miner Res 26:2151-2160
82. Grimston SK, Brodt MD, Silva MJ, Civitelli R (2008) Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the connexin43 gene (Gja1). J Bone Miner Res 23:879-886
83. Lloyd SA, Lewis GS, Zhang Y, Paul EM, Donahue HJ (2012) Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading. J Bone Miner Res 27:2359-2372
84. Scemes E, Dermietzel R, Spray DC (1998) Calcium waves between astrocytes from Cx43 knockout mice. Glia 24:65-73
85. Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R (2000) Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 151:931-944
86. Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, DeSimone D, Bonewald LF, Lafer EM, Sprague E, Schwartz MA, Jiang JX (2012) Mechanical stress-activated integrin alpha5beta1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci USA 109:3359-3364
87. Reddy KV, Mangale SS (2003) Integrin receptors: the dynamic modulators of endometrial function. Tissue Cell 35:260-273
88. Spray DC, Ye ZC, Ransom BR (2006) Functional connexin "hemichannels": a critical appraisal. Glia 54:758-773
89. 2+ signaling in wild-type and Cx43-null neonatal mouse cardiac myocytes. Am J Physiol Heart Circ Physiol 279:H3076-H3088
90. Iglesias R, Dahl G, Qiu F, Spray DC, Scemes E (2009) Pannexin 1: the molecular substrate of astrocyte "hemichannels". J Neurosci 29:7092-7097
91. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born TL, Usman N, Staroverov D, Lukyanov S, Panchin Y (2004) The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics 83:706-716
92. Thi MM, Islam S, Suadicani SO, Spray DC (2012) Connexin43 and pannexin1 channels in osteoblasts: who is the "hemichannel"? J Membr Biol 245:401-409
93. Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G (2011) Pannexin channels are not gap junction hemichannels. Channels (Austin) 5:193-197
94. Bao L, Locovei S, Dahl G (2004) Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett 572:65-68
95. Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21-32
96. Lau KH, Baylink DJ, Zhou XD, Rodriguez D, Bonewald LF, Li Z, Ruffoni D, Muller R, Kesavan C, Sheng MH (2013) Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. Am J Physiol Endocrinol Metab 305:E271-E281
97. Marotti G, Ferretti M, Muglia MA, Palumbo C, Palazzini S (1992) A quantitative evaluation of osteoblast-osteocyte relationships on growing endosteal surface of rabbit tibiae. Bone 13:363-368
98. 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
99. 2 mediated. Biochim Biophys Acta 627:91-100
100. Forwood MR, Kelly WL, Worth NF (1998) Localisation of prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2 in bone following mechanical loading in vivo. Anat Rec 252:580-586
101. Forwood MR (1996) Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo. J Bone Miner Res 11:1688-1693
102. 2: involvements of cyclooxygenase (COX)-1 and COX-2 in human and rat systems. J Pharmacol Exp Ther 303:1001-1006
103. Li J, Rose E, Frances D, Sun Y, You L (2012) Effect of oscillating fluid flow stimulation on osteocyte mRNA expression. J Biomech 45:247-251
104. 2. Cell Commun Adhes 8:283-288
105. Mikuni-Takagaki Y (1999) Mechanical responses and signal transduction pathways in stretched osteocytes. J Bone Miner Metab 17:57-60
106. Fortier I, Patry C, Lora M, Samadfan R, de Brum-Fernandes AJ (2001) Immunohistochemical localization of the prostacyclin receptor (IP) human bone. Prostaglandins Leukot Essent Fatty Acids 65:79-83
107. Nakalekha C, Yokoyama C, Miura H, Alles N, Aoki K, Ohya K, Morita I (2010) Increased bone mass in adult prostacyclin-deficient mice. J Endocrinol 204:125-133
108. 2 receptor subtypes in human bone tissue: differences in foetal, adult normal, osteoporotic and pagetic bone. Prostaglandins Leukot Essent Fatty Acids 70:431-439
109. Zaman G, Pitsillides AA, Rawlinson SC, Suswillo RF, Mosley JR, Cheng MZ, Platts LA, Hukkanen M, Polak JM, Lanyon LE (1999) Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res 14:1123-1131
110. Knowles RG, Moncada S (1994) Nitric-oxide synthases in mammals. Biochem J 298:249-258
111. Caballero-Alias AM, Loveridge N, Lyon A, Das-Gupta V, Pitsillides A, Reeve J (2004) NOS isoforms in adult human osteocytes: multiple pathways of NO regulation? Calcif Tissue Int 75:78-84
112. Mancini L, Moradi-Bidhendi N, Becherini L, Martineti V, MacIntyre I (2000) The biphasic effects of nitric oxide in primary rat osteoblasts are cGMP dependent. Biochem Biophys Res Commun 274:477-481
113. Bakker AD, Huesa C, Hughes A, Aspden RM, van't Hof RJ, Klein-Nulend J, Helfrich MH (2013) Endothelial nitric oxide synthase is not essential for nitric oxide production by osteoblasts subjected to fluid shear stress in vitro. Calcif Tissue Int 92:228-239
114. van't Hof RJ, MacPhee J, Libouban H, Helfrich MH, Ralston SH (2004) Regulation of bone mass and bone turnover by neuronal nitric oxide synthase. Endocrinology 145:5068-5074
115. Hakim TS, Sugimori K, Camporesi EM, Anderson G (1996) Half-life of nitric oxide in aqueous solutions with and without haemoglobin. Physiol Meas 17:267-277
116. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D (2002) Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771-781
117. Sheng MH, Zhou XD, Bonewald LF, Baylink DJ, Lau KH (2013) Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone 52:133-144
118. Lean JM, Jagger CJ, Chambers TJ, Chow JW (1995) Increased insulin-like growth factor I mRNA expression in rat osteocytes in response to mechanical stimulation. Am J Physiol Endocrinol Metab 268:E318-E327
119. Reijnders CM, Bravenboer N, Tromp AM, Blankenstein MA, Lips P (2007) Effect of mechanical loading on insulin-like growth factor-I gene expression in rat tibia. J Endocrinol 192:131-140
120. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842-1844
121. Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ (2013) Sclerostin is expressed in osteoclasts from aged mice and reduces osteoclast-mediated stimulation of mineralization. J Cell Biochem 114:1901-1907
122. Roudier M, Li X, Niu QT, Pacheco E, Pretorius JK, Graham K, Yoon BR, Gong J, Warmington K, Ke HZ, Black RA, Hulme J, Babij P (2013) Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury. Arthritis Rheum 65:721-731
123. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883-19887
124. Leupin O, Piters E, Halleux C, Hu S, Kramer I, Morvan F, Bouwmeester T, Schirle M, Bueno-Lozano M, Fuentes FJ, Itin PH, Boudin E, de Freitas F, Jennes K, Brannetti B, Charara N, Ebersbach H, Geisse S, Lu CX, Bauer A, Van Hul W, Kneissel M (2011) Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 286:19489-19500
125. Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu Ke H, Li X, Richards WG (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754-766
126. Balemans W, Piters E, Cleiren E, Ai M, Van Wesenbeeck L, Warman ML, Van Hul W (2008) The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif Tissue Int 82:445-453
127. Robling AG, Bellido T, Turner CH (2006) Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J Musculoskelet Neuronal Interact 6:354
128. 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
129. Gaudio A, Pennisi P, Bratengeier C, Torrisi V, Lindner B, Mangiafico RA, Pulvirenti I, Hawa G, Tringali G, Fiore CE (2010) Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 95:2248-2253
130. Moriishi T, Fukuyama R, Ito M, Miyazaki T, Maeno T, Kawai Y, Komori H, Komori T (2012) Osteocyte network: a negative regulatory system for bone mass augmented by the induction of Rankl in osteoblasts and Sost in osteocytes at unloading. PLoS One 7:e40143
131. Moustafa A, Sugiyama T, Prasad J, Zaman G, Gross TS, Lanyon LE, Price JS (2012) Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered. Osteoporos Int 23:1225-1234
132. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578-588
133. Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C (2010) Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 25:948-959
134. Padhi D, Jang G, Stouch B, Fang L, Posvar E (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 26:19-26
135. Shen L, Xie X, Su Y, Luo C, Zhang C, Zeng B (2011) Parathyroid hormone versus bisphosphonate treatment on bone mineral density in osteoporosis therapy: a meta-analysis of randomized controlled trials. PLoS One 6:e26267
136. Hattner R, Epker BN, Frost HM (1965) Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature 206:489-490
137. Frost HM (1967) An introduction to biomechanics. Charles C. Thomas, Springfield
138. Hatori M, Klatte KJ, Teixeira CC, Shapiro IM (1995) End labeling studies of fragmented DNA in the avian growth plate: evidence of apoptosis in terminally differentiated chondrocytes. J Bone Miner Res 10:1960-1968
139. Noble BS, Stevens H, Loveridge N, Reeve J (1997) Identification of apoptotic changes in osteocytes in normal and pathological human bone. Bone 20:273-282
140. 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
141. Elmardi AS, Katchburian MV, Katchburian E (1990) Electron microscopy of developing calvaria reveals images that suggest that osteoclasts engulf and destroy osteocytes during bone resorption. Calcif Tissue Int 46:239-245
142. Cerri PS, Boabaid F, Katchburian E (2003) Combined TUNEL and TRAP methods suggest that apoptotic bone cells are inside vacuoles of alveolar bone osteoclasts in young rats. J Periodontal Res 38:223-226
143. Torrance AG, Mosley JR, Suswillo RF, Lanyon LE (1994) Noninvasive loading of the rat ulna in vivo induces a strain-related modeling response uncomplicated by trauma or periostal pressure. Calcif Tissue Int 54:241-247
144. 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
145. 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
146. Emerton KB, Hu B, Woo AA, Sinofsky A, Hernandez C, Majeska RJ, Jepsen KJ, Schaffler MB (2010) Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone 46:577-583
147. Cabahug PCLD, Kennedy O, Majeska RJ, Tuthill A, Judex S, Schaffler MB (2013) Inhibition of osteocyte apoptosis prevents trabecular bone loss after unloading of mouse long bone. Orthopaedic Research Society, San Antonio
148. 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
149. Martin RB (2000) Toward a unifying theory of bone remodeling. Bone 26:1-6
150. Gu G, Mulari M, Peng Z, Hentunen TA, Vaananen HK (2005) Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption. Biochem Biophys Res Commun 335:1095-1101
151. Heino TJ, Hentunen TA, Vaananen HK (2002) Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen. J Cell Biochem 85:185-197
152. Maejima-Ikeda A, Aoki M, Tsuritani K, Kamioka K, Hiura K, Miyoshi T, Hara H, Takano-Yamamoto T, Kumegawa M (1997) Chick osteocyte-derived protein inhibits osteoclastic bone resorption. Biochem J 322(Pt 1):245-250
153. Collin-Osdoby P, Rothe L, Bekker S, Anderson F, Huang Y, Osdoby P (2002) Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro. J Bone Miner Res 17:1859-1871
154. Webber DM, Menton D, Osdoby P (1990) An in vivo model system for the study of avian osteoclast recruitment and activity. Bone Miner 11:127-140
155. Parfitt AM (1998) Osteoclast precursors as leukocytes: importance of the area code. Bone 23:491-494
156. + monocytes that develop with RANKL into functional osteoclasts. J Bone Miner Res 21:193-206
157. McGowan NW, Walker EJ, Macpherson H, Ralston SH, Helfrich MH (2001) Cytokine-activated endothelium recruits osteoclast precursors. Endocrinology 142:1678-1681
158. Formigli L, Fiorelli G, Benvenuti S, Tani A, Orlandini GE, Brandi ML, Zecchi-Orlandini S (1997) Insulin-like growth factor-I stimulates in vitro migration of preosteoclasts across bone endothelial cells. Cell Tissue Res 288:101-110
159. Al-Dujaili SA, Lau E, Al-Dujaili H, Tsang K, Guenther A, You L (2011) Apoptotic osteocytes regulate osteoclast precursor recruitment and differentiation in vitro. J Cell Biochem 112:2412-2423
160. Cheung WY, Liu C, Tonelli-Zasarsky RM, Simmons CA, You L (2011) Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. J Orthop Res 29:523-530
161. Shimizu H, Sakamoto M, Sakamoto S (1990) Bone resorption by isolated osteoclasts in living versus devitalized bone: differences in mode and extent and the effects of human recombinant tissue inhibitor of metalloproteinases. J Bone Miner Res 5:411-418
162. Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ, Nakamura T, Soballe K, O'Keefe RJ, Boyce BF, Schwarz EM (2005) Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med 11:291-297
163. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231-1234
164. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235-1241
165. Zhao S, Zhang YK, Harris S, Ahuja SS, Bonewald LF (2002) MLO-Y4 osteocyte-like cells support osteoclast formation and activation. J Bone Miner Res 17:2068-2079
166. Kennedy OD, Herman BC, Laudier DM, Majeska RJ, Sun HB, Schaffler MB (2012) Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations. Bone 50:1115-1122
167. Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JM, Niforas P, Ng KW, Martin TJ, Gillespie MT (1999) Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 25:525-534
168. Verborgt O, Tatton NA, Majeska RJ, Schaffler MB (2002) Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation? J Bone Miner Res 17:907-914
169. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM (1997) Apoptosis in human acute myocardial infarction. Circulation 95:320-323
170. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431-1568
171. Kogianni G, Mann V, Noble BS (2008) Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res 23:915-927
172. Bidwell JP, Yang J, Robling AG (2008) Is HMGB1 an osteocyte alarmin? J Cell Biochem 103:1671-1680
173. Borde C, Barnay-Verdier S, Gaillard C, Hocini H, Marechal V, Gozlan J (2011) Stepwise release of biologically active HMGB1 during HSV-2 infection. PLoS One 6:e16145
174. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, Armstrong AJ, Penuela S, Laird DW, Salvesen GS, Isakson BE, Bayliss DA, Ravichandran KS (2010) Pannexin 1 channels mediate "find-me" signal release and membrane permeability during apoptosis. Nature 467:863-867
175. Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Spiegel S (2008) Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-get-me" signal. FASEB J 22:2629-2638
176. Peter C, Waibel M, Keppeler H, Lehmann R, Xu G, Halama A, Adamski J, Schulze-Osthoff K, Wesselborg S, Lauber K (2012) Release of lysophospholipid "find-me" signals during apoptosis requires the ATP-binding cassette transporter A1. Autoimmunity 45:568-573
177. Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, Melville L, Melrose LA, Ogden CA, Nibbs R, Graham G, Combadiere C, Gregory CD (2008) CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112:5026-5036
178. Mullender MG, van der Meer DD, Huiskes R, Lips P (1996) Osteocyte density changes in aging and osteoporosis. Bone 18:109-113
179. Belanger LF (1969) Osteocytic osteolysis. Calcif Tissue Res 4:1-12
180. Recklinghausen F (1910) Untersuchungen über Rachitis und Osteomalazie. G. Fischer, Jena
181. Baud CA (1968) Submicroscopic structure and functional aspects of the osteocyte. Clin Orthop Relat Res 56:227-236
182. Teti A, Zallone A (2009) Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone 44:11-16
183. Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jahn K, Kato S, Wysolmerski J, Bonewald LF (2012) Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res 27:1018-1029
184. Sharma D, Ciani C, Marin PA, Levy JD, Doty SB, Fritton SP (2012) Alterations in the osteocyte lacunar-canalicular microenvironment due to estrogen deficiency. Bone 51:488-497
185. McKee MD, Farach-Carson MC, Butler WT, Hauschka PV, Nanci A (1993) Ultrastructural immunolocalization of noncollagenous (osteopontin and osteocalcin) and plasma (albumin and alpha 2HS-glycoprotein) proteins in rat bone. J Bone Miner Res 8:485-496
186. Barros NM, Hoac B, Neves RL, Addison WN, Assis DM, Murshed M, Carmona AK, McKee MD (2013) Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. J Bone Miner Res 28:688-699
187. Thompson DL, Sabbagh Y, Tenenhouse HS, Roche PC, Drezner MK, Salisbury JL, Grande JP, Poeschla EM, Kumar R (2002) Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res 17:311-320
188. Bergwitz C, Juppner H (2012) FGF23 and syndromes of abnormal renal phosphate handling. In: Kuro-o M (ed) Endocrine FGFs and klothos. Advances in experimental medicine and biology 728. Landes Bioscience, Austin, pp 41-64
189. Liu S, Zhou J, Tang W, Menard R, Feng JQ, Quarles LD (2008) Pathogenic role of Fgf23 in Dmp1-null mice. Am J Physiol Endocrinol Metab 295:E254-E261
190. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD (2006) Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 291:E38-E49
191. Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, Quarles LD (2011) Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551-2562
192. Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS (2008) Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 149:1757-1772
193. David V, Martin A, Hedge AM, Drezner MK, Rowe PS (2011) ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol 300:F783-F791
194. Guo R, Rowe PS, Liu S, Simpson LG, Xiao ZS, Quarles LD (2002) Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun 297:38-45
195. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23:1638-1649