Microgravity: The immune response and bone

Immunological Reviews

Volumn 208, Issue , 2005, Pages 267-280

  Zayzafoon, Majd ^a   Meyers, Valerie E ^a   McDonald, Jay M ^a,b  

^a University of Alabama at Birmingham   (United States)

^b UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIN; NITRIC OXIDE SYNTHASE; RHO KINASE;

CYTOSKELETON; EXPERIMENTAL ANIMAL; GENE EXPRESSION; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; MICROGRAVITY; MOLECULAR MECHANICS; NONHUMAN; OSTEOLYSIS; PHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SKELETON; SPACE FLIGHT; STRESS FIBER;

EID: 28544439443     PISSN: 01052896     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.0105-2896.2005.00330.x     Document Type: Review

References (160)

1. Graebe A, Schuck EL, Lensing P, Putcha L, Derendorf H. Physiological, pharmacokinetic, and pharmacodynamic changes in space. J Clin Pharmacol 2004;44:837-853.
2. Vernikos J. Human physiology in space. Bioessays 1996;18:1029-1037.
3. Collet P, et al. Effects of 1- and 6-month spaceflight on bone mass and biochemistry in two humans. Bone 1997;20:547-551.
4. Zittermann A, et al. Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test. Eur J Clin Invest 2000;30:1036-1043.
5. Blanc S, et al. Energy and water metabolism, body composition, and hormonal changes induced by 42 days of enforced inactivity and simulated weightlessness. J Clin Endocrinol Metab 1998;83:4289-4297.
6. Davis BA, et al. Collagenase and tissue plasminogen activator production in developing rat calvariae: normal progression despite fetal exposure to microgravity. Calcif Tissue Int 1998;63:416-422.
7. Cavolina JM, Evans GL, Harris SA, Zhang M, Westerlind KC, Turner RT. The effects of orbital spaceflight on bone histomorphometry and messenger ribonucleic acid levels for bone matrix proteins and skeletal signaling peptides in ovariectomized growing rats. Endocrinology 1997;138:1567-1576.
8. Van Loon JJ, et al. Decreased mineralization and increased calcium release in isolated fetal mouse long bones under near weightlessness. J Bone Miner Res 1995;10:550-557.
9. Chapes SK, Simske SJ, Sonnenfeld G, Miller ES, Zimmerman RJ. Effects of spaceflight and PEG-IL-2 on rat physiological and immunological responses. J Appl Physiol 1999;86:2065-2076.
10. Kimzey SL, Ritzmann SE, Mengel CE, Fischer CL. Skylab experiment results: hematology studies. Acta Astronaut 1975;2:141-154.
11. Lamb LE. The influence of manned space flight on cardiovascular function. Cardiology 1966;48:118-133.
12. Cogoli A, et al. Human lymphocyte activation is depressed at low-g and enhanced at high-g. Physiologist 1979;22:S29-S30.
13. Mack PB, LaChance PA, Vose GP, Vogt FB. Bone demineralization of foot and hand of gemini-titan IV, V and VII astronauts during orbital flight. Am J Roentgenol Radium Ther Nucl Med 1967;100:503-511.
14. Berry CA. Summary of medical experience in the Apollo 7 through 11 manned spaceflights. Aerosp Med 1970;41:500-519.
15. Buderer MC, Rummel JA, Michel EL, Mauldin DG, Sawin CF. Exercise cardiac output following Skylab missions: the second manned Skylab mission. Aviat Space Environ Med 1976;47:365-372.
16. Winter DL. Weightlessness and gravitational physiology. Fed Proc 1977;36:1667-1671.
17. Antonutto G, di Prampero PE. Cardiovascular deconditioning in microgravity: some possible countermeasures. Eur J Appl Physiol 2003;90:283-291.
18. Dietlein LF. Spaceflight and the telltale heart. Am J Surg 1983;145:703-706.
19. Leach CS, Rambaut PC, Di Ferrante N. Amino aciduria in weightlessness. Acta Astronaut 1979;6:1323-1333.
20. Rambaut PC, Johnston RS. Prolonged weightlessness and calcium loss in man. Acta Astronaut 1979;6:1113-1122.
21. Herbison GJ, Talbot JM. Muscle atrophy during space flight: research needs and opportunities. Physiologist 1985;28:520-527.
22. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-342.
23. McCarthy ID. Fluid shifts due to microgravity and their effects on bone: a review of current knowledge. Ann Biomed Eng 2005;33:95-103.
24. Smith SM, et al. Collagen cross-link excretion during space flight and bed rest. J Clin Endocrinol Metab 1998;83:3584-3591.
25. Caillot-Augusseau A, Lafage-Proust MH, Soler C, Pernod J, Dubois F, Alexandre C. Bone formation and resorption biological markers in cosmonauts during and after a 180-day space flight (Euromir 95). Clin Chem 1998;44:578-585.
26. LeBlanc A, et al. Bone mineral and lean tissue loss after long duration space flight. J Musculoskelet Neuronal Interact 2000;1:157-160.
27. Vico L, et al. Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet 2000;355:1607-1611.
28. Lang T, LeBlanc A, Evans H, Lu Y, Genant H, Yu A. Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight. J Bone Miner Res 2004;19:1006-1012.
29. Morey ER, Baylink DJ. Inhibition of bone formation during space flight. Science 1978;201:1138-1141.
30. Cann CE, Adachi RR. Bone resorption and mineral excretion in rats during spaceflight. Am J Physiol 1983;244:R327-R331.
31. Turner RT, Evans GL, Wakley GK. Spaceflight results in depressed cancellous bone formation in rat humeri. Aviat Space Environ Med 1995;66:770-774.
32. Wronski TJ, Morey-Holton ER, Doty SB, Maese AC, Walsh CC. Histomorphometric analysis of rat skeleton following spaceflight. Am J Physiol 1987;252:R252-R255.
33. Wronski TJ, Morey ER. Recovery of the rat skeleton from the adverse effects of simulated weightlessness. Metab Bone Dis Relat Res 1983;4:347-352.
34. Evans GL, Morey-Holton E, Turner RT. Spaceflight has compartment- and gene-specific effects on mRNA levels for bone matrix proteins in rat femur. J Appl Physiol 1998;84:2132-2137.
35. Vico L, Bourrin S, Genty C, Palle S, Alexandre C. Histomorphometric analyses of cancellous bone from COSMOS 2044 rats. J Appl Physiol 1993;75:2203-2208.
36. Lafage-Proust MH, Collet P, Dubost JM, Laroche N, Alexandre C, Vico L. Space-related bone mineral redistribution and lack of bone mass recovery after reambulation in young rats. Am J Physiol 1998;274:R324-R334.
37. Zerath E, et al. Spaceflight inhibits bone formation independent of corticosteroid status in growing rats. J Bone Miner Res 2000;15:1310-1320.
38. Zerath E, Grynpas M, Holy X, Viso M, Patterson-Buckendahl P, Marie PJ. Spaceflight affects bone formation in rhesus monkeys: a histological and cell culture study. J Appl Physiol 2002;93:1047-1056.
39. Zerath E, et al. Effects of spaceflight and recovery on rat humeri and vertebrae: histological and cell culture studies. J Appl Physiol 1996;81:164-171.
40. Sonnenfeld G, Shearer WT. Immune function during space flight. Nutrition 2002;18:899-903.
41. Cogoli A, Tschopp A. Lymphocyte reactivity during spaceflight. Immunol Today 1985;6:1-4.
42. Cogoli A, Valluchi-Morf M, Mueller M, Briegleb W. Effect of hypogravity on human lymphocyte activation. Aviat Space Environ Med 1980;51:29-34.
43. Konstantinova IV, Rykova M, Meshkov D, Peres C, Husson D, Schmitt DA. Natural killer cells after ALTAIR mission. Acta Astronaut 1995;36:713-718.
44. Taylor GR, Janney RP. In vivo testing confirms a blunting of the human cell-mediated immune mechanism during space flight. J Leukoc Biol 1992;51:129-132.
45. Gmunder FK, Konstantinova I, Cogoli A, Lesnyak A, Bogomolov W, Grachov AW. Cellular immunity in cosmonauts during long duration spaceflight on board the orbital MIR station. Aviat Space Environ Med 1994;65:419-423.
46. Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL. Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 2004;72:174-179.
47. Stowe RP, Mehta SK, Ferrando AA, Feeback DL, Pierson DL. Immune responses and latent herpesvirus reactivation in spaceflight. Aviat Space Environ Med 2001;72:884-891.
48. Cogoli A. Signal transduction in T lymphocytes in microgravity. Gravit Space Biol Bull 1997;10:5-16.
49. Cogoli A. Space flight and the immune system. Vaccine 1993;11:496-503.
50. Kimzey SL, Johnson PC, Ritzman SE, Mengel CE. Hematology and immunology studies: the second manned Skylab mission. Aviat Space Environ Med 1976;47:383-390.
51. Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM. Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res 1990;5:843-850.
52. Scheld K, et al. Nitrogen metabolism and bone metabolism markers in healthy adults during 16 weeks of bed rest. Clin Chem 2001;47:1688-1695.
53. Uebelhart D, et al. Modifications of bone and connective tissue after orthostatic bedrest. Osteoporos Int 2000;11:59-67.
54. Arnaud SB, Sherrard DJ, Maloney N, Whalen RT, Fung P. Effects of 1-week head-down tilt bed rest on bone formation and the calcium endocrine system. Aviat Space Environ Med 1992;63:14-20.
55. Zerwekh JE, Ruml LA, Gottschalk F, Pak CY. The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects. J Bone Miner Res 1998;13:1594-1601.
56. Baecker N, et al. Bone resorption is induced on the second day of bed rest: results of a controlled crossover trial. J Appl Physiol 2003;95:977-982.
57. Inoue M, Tanaka H, Moriwake T, Oka M, Sekiguchi C, Seino Y. Altered biochemical markers of bone turnover in humans during 120 days of bed rest. Bone 2000;26:281-286.
58. Lueken SA, Arnaud SB, Taylor AK, Baylink DJ. Changes in markers of bone formation and resorption in a bed rest model of weightlessness. J Bone Miner Res 1993;8:1433-1438.
59. Kim H, Iwasaki K, Miyake T, Shiozawa T, Nozaki S, Yajima K. Changes in bone turnover markers during 14-day 6 degrees head-down bed rest. J Bone Miner Metab 2003;21:311-315.
60. Morey-Holton ER, Globus RK. Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight. Bone 1998;22:83S-88S.
61. Bloomfield SA, Allen MR, Hogan HA, Delp MD. Site- and compartment-specific changes in bone with hindlimb unloading in mature adult rats. Bone 2002;31:149-157.
62. Matsumoto T, Nakayama K, Kodama Y, Fuse H, Nakamura T, Fukumoto S. Effect of mechanical unloading and reloading on periosteal bone formation and gene expression in tail-suspended rapidly growing rats. Bone 1998;22:89S-93S.
63. Hefferan TE, Evans GL, Lotinun S, Zhang M, Morey-Holton E, Turner RT. Effect of gender on bone turnover in adult rats during simulated weightlessness. J Appl Physiol 2003;95:1775-1780.
64. Dehority W, et al. Bone and hormonal changes induced by skeletal unloading in the mature male rat. Am J Physiol 1999;276:E62-E69.
65. Patterson-Buckendahl P, Globus RK, Bikle DD, Cann CE, Morey-Holton E. Effects of simulated weightlessness on rat osteocalcin and bone calcium. Am J Physiol 1989;257:R1103-R1109.
66. Barou O, Palle S, Vico L, Alexandre C, Lafage-Proust MH. Hindlimb unloading in rat decreases preosteoblast proliferation assessed in vivo with BrdU incorporation. Am J Physiol 1998;274:E108-E114.
67. Grano M, et al. Rat hindlimb unloading by tail suspension reduces osteoblast differentiation, induces IL-6 secretion, and increases bone resorption in ex vivo cultures. Calcif Tissue Int 2002;70:176-185.
68. Kostenuik PJ, Halloran BP, Morey-Holton ER, Bikle DD. Skeletal unloading inhibits the in vitro proliferation and differentiation of rat osteoprogenitor cells. Am J Physiol 1997;273:E1133-E1139.
69. Gardner JR, Hess CP, Webb AG, Tsika RW, Dawson MJ, Gulani V. Magnetic resonance microscopy of morphological alterations in mouse trabecular bone structure under conditions of simulated microgravity. Magn Reson Med 2001;45:1122-1125.
70. Goodwin TJ, Prewett TL, Wolf DA, Spaulding GF. Reduced shear stress: a major component in the ability of mammalian tissues to form three-dimensional assemblies in simulated microgravity. J Cell Biochem 1993;51:301-311.
71. Hammond TG, Hammond JM. Optimized suspension culture: the rotating-wall vessel. Am J Physiol Renal Physiol 2001;281:F12-F25.
72. Sarkar D, Nagaya T, Koga K, Kambe F, Nomura Y, Seo H. Rotation in clinostat results in apoptosis of osteoblastic ROS 17/ 2.8 cells. J Gravit Physiol 2000;7:P71-P72.
73. Pardo SJ, et al. Simulated microgravity using the random positioning machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts. Am J Physiol Cell Physiol 2005;288:C1211-C1221.
74. Wronski TJ, Morey-Holton E, Jee WS. Skeletal alterations in rats during space flight. Adv Space Res 1981;1:135-140.
75. Wronski TJ, Morey-Holton ER. Skeletal response to simulated weightlessness: a comparison of suspension techniques. Aviat Space Environ Med 1987;58:63-68.
76. Vico L, Chappard D, Palle S, Bakulin AV, Novikov VE, Alexandre C. Trabecular bone remodeling after seven days of weightlessness exposure (BIOCOSMOS 1667). Am J Physiol 1988;255:R243-R247.
77. Westerlind KC, Turner RT. The skeletal effects of spaceflight in growing rats: tissue-specific alterations in mRNA levels for TGF-beta. J Bone Miner Res 1995;10:843-848.
78. Rodionova NV, Shevel IM, Oganov VS, Novikov VE, Kabitskaya OE. Bone ultrastructural changes in Bion 11 rhesus monkeys. J Gravit Physiol 2000;7:S157-S161.
79. Garetto LP, Gonsalves MR, Morey ER, Durnova G, Roberts WE. Preosteoblast production 55 hours after a 12.5-day spaceflight on Cosmos 1887. FASEB J 1990;4:24-28.
80. Hughes-Fulford M, Lewis ML. Effects of microgravity on osteoblast growth activation. Exp Cell Res 1996;224:103-109.
81. Carmeliet G, Nys G, Bouillon R. Microgravity reduces the differentiation of human osteoblastic MG-63 cells. J Bone Miner Res 1997;12:786-794.
82. Carmeliet G, Nys G, Stockmans I, Bouillon R. Gene expression related to the differentiation of osteoblastic cells is altered by microgravity. Bone 1998;22:139S-143S.
83. Landis WJ, Hodgens KJ, Block D, Toma CD, Gerstenfeld LC. Spaceflight effects on cultured embryonic chick bone cells. J Bone Miner Res 2000;15:1099-1112.
84. Stowe RP, et al. Leukocyte subsets and neutrophil function after short-term spaceflight. J Leukoc Biol 1999;65:179-186.
85. Bakos A, Varkonyi A, Minarovits J, Batkai L. Effect of simulated microgravity on human lymphocytes. J Gravit Physiol 2001;8:P69-P70.
86. Narayanan R, Smith CL, Weigel NL. Vector-averaged gravity-induced changes in cell signaling and vitamin D receptor activity in MG-63 cells are reversed by a 1,25-(OH)2D3 analog, EB1089. Bone 2002;31:381-388.
87. Ontiveros C, McCabe LR. Simulated microgravity suppresses osteoblast phenotype, Runx2 levels and AP-1 transactivation. J Cell Biochem 2003;88:427-437.
88. Sudo H, Kodama HA, Amagai Y, Yamamoto S, Kasai S. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol 1983;96:191-198.
89. Zayzafoon M, Gathings WE, McDonald JM. Modeled microgravity inhibits osteogenic differentiation of human mesenchymal stem cells and increases adipogenesis. Endocrinology 2004;145:2421-2432.
90. Meyers VE, Zayzafoon M, Gonda SR, Gathings WE, McDonald JM. Modeled microgravity disrupts collagen I/integrin signaling during osteoblastic differentiation of human mesenchymal stem cells. J Cell Biochem 2004;93:697-707.
91. Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147.
92. Bruder SP, Jaiswal N, Ricalton NS, Mosca JD, Kraus KH, Kadiyala S. Mesenchymal stem cells in osteobiology and applied bone regeneration. Clin Orthop 1998: S247-256.
93. Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone 1992;1:81-88.
94. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998;176:57-66.
95. Banerjee C, et al. Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem 1997;66:1-8.
96. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997;89:747-754.
97. Lecka-Czernik B, et al. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2. J Cell Biochem 1999;74:357-371.
98. Nakamura H, Kumei Y, Monta S, Shimokawa H, Ohya K, Shinomiya K. Antagonism between apoptotic (Bax/Bcl-2) and anti-apoptotic (IAP) signals in human osteoblastic cells under vector-averaged gravity condition. Ann N Y Acad Sci 2003;1010:143-147.
99. Owen TA, et al. Progressive development of the rat osteoblast phenotype in vitro: reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol 1990;143:420-430.
100. Siggelkow H, et al. Development of the osteoblast phenotype in primary human osteoblasts in culture: comparison with rat calvarial cells in osteoblast differentiation. J Cell Biochem 1999;75:22-35.
101. Kafantari H, Kounadi E, Fatouros M, Milonakis M, Tzaphlidou M. Structural alterations in rat skin and bone collagen fibrils induced by ovariectomy. Bone 2000;26:349-353.
102. Xiao G, Cui Y, Ducy P, Karsenty G, Franceschi RT. Ascorbic acid-dependent activation of the osteocalcin promoter in MC3T3-E1 preosteoblasts: requirement for collagen matrix synthesis and the presence of an intact OSE2 sequence. Mol Endocrinol 1997;11:1103-1113.
103. Gronthos S, Simmons PJ, Graves SE, Robey PG. Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone 2001;28:174-181.
104. Schneider GB, Zaharias R, Stanford C. Osteoblast integral adhesion and signaling regulate mineralization. J Dent Res 2001;80:1540-1544.
105. Xiao G, Wang D, Benson MD, Karsenty G, Franceschi RT. Role of the alpha2-integrin in osteoblast-specific gene expression and activation of the Osf2 transcription factor. J Biol Chem 1998;273:32988-32994.
106. Gebken J, et al. Hypergravity stimulates collagen synthesis in human osteoblast-like cells: evidence for the involvement of p44/ 42 MAP-kinases (ERK 1/2). J Biochem (Tokyo) 1999;126:676-682.
107. Sakata T, Wang Y, Halloran BP, Elalieh HZ, Cao J, Bikle DD. Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways. J Bone Miner Res 2004;19:436-446.
108. Hughes-Fulford M, Gilbertson V. Osteoblast fibronectin mRNA, protein synthesis, and matrix are unchanged after exposure to microgravity. FASEB J 1999;13 (Suppl.):S121-S127.
109. Klement BJ, Young QM, George BJ, Nokkaew M. Skeletal tissue growth, differentiation and mineralization in the NASA rotating wall vessel. Bone 2004;34:487-498.
110. Rodriguez JP, Gonzalez M, Rios S, Cambiazo V. Cytoskeletal organization of human mesenchymal stem cells (MSC) changes during their osteogenic differentiation. J Cell Biochem 2004;93:721-731.
111. Carlsson SI, Bertilaccio MT, Ballabio E, Maier JA. Endothelial stress by gravitational unloading: effects on cell growth and cytoskeletal organization. Biochim Biophys Acta 2003;1642:173-179.
112. Guignandon A, Akhouayri O, Laroche N, Lafage-Proust MH, Alexandre C, Vico L. Focal contacts organization in osteoblastic cells under microgravity and cyclic deformation conditions. Adv Space Res 2003;32:1561-1567.
113. Schatten H, Lewis ML, Chakrabarti A. Spaceflight and clinorotation cause cytoskeleton and mitochondria changes and increases in apoptosis in cultured cells. Acta Astronaut 2001;49:399-418.
114. Uva BM, et al. Clinorotation-induced weightlessness influences the cytoskeleton of glial cells in culture. Brain Res 2002;934:132-139.
115. Hall A. G proteins and small GTPases: distant relatives keep in touch. Science 1998;280:2074-2075.
116. Kimura K, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996;273:245-248.
117. Maekawa M, et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999;285:895-898.
118. Schoenwaelder SM, Burridge K. Bidirectional signaling between the cytoskeleton and integrins. Curr Opin Cell Biol 1999;11:274-286.
119. Lou Z, Billadeau DD, Savoy DN, Schoon RA, Leibson PJ. A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes. J Immunol 2001;167:5749-5757.
120. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 2004;6:483-495.
121. Sordella R, Jiang W, Chen GC, Curto M, Settleman J. Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis. Cell 2003;113:147-158.
122. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002;110:673-687.
123. Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999;285:1028-1032.
124. Takeuchi Y, Suzawa M, Kikuchi T, Nishida E, Fujita T, Matsumoto T. Differentiation and transforming growth factor-beta receptor down-regulation by collagen-alpha2beta1 integrin interaction is mediated by focal adhesion kinase and its downstream signals in murine osteoblastic cells. J Biol Chem 1997;272:29309-29316.
125. Tsuchida M, Manthei ER, Alam T, Knechtle SJ, Hamawy MM. Regulation of T cell receptor- and CD28-induced tyrosine phosphorylation of the focal adhesion tyrosine kinases Pyk2 and Fak by protein kinase C. A role for protein tyrosine phosphatases. J Biol Chem 2000;275:1344-1350.
126. Clark EA, King WG, Brugge JS, Symons M, Hynes RO. Integrin-mediated signals regulated by members of the rho family of GTPases. J Cell Biol 1998;142:573-586.
127. Boutahar N, Guignandon A, Vico L, Lafage-Proust MH. 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 2004;279:30588-30599.
128. Freitas F, et al. Fluoroaluminate stimulates phosphorylation of p130 Cas and Fak and increases attachment and spreading of preosteoblastic MC3T3-E1 cells. Bone 2002;30:99-108.
129. Jeschke M, Standke GJ, Scaronuscarona M. Fluoroaluminate induces activation and association of Src and Pyk2 tyrosine kinases in osteoblastic MC3T3-E1 cells. J Biol Chem 1998;273:11354-11361.
130. Tamura Y, et al. Focal adhesion kinase activity is required for bone morphogenetic protein - Smad1 signaling and osteoblastic differentiation in murine MC3T3-E1 cells. J Bone Miner Res 2001;16:1772-1779.
131. Perinpanayagam H, Zaharias R, Stanford C, Brand R, Keller J, Schneider G. Early cell adhesion events differ between osteoporotic and non-osteoporotic osteoblasts. J Orthop Res 2001;19:993-1000.
132. Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/ mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 1997;272:13189-13195.
133. Xiao G, et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem 2000;275:4453-4459.
134. Chen HC, Appeddu PA, Isoda H, Guan JL. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem 1996;271:26329-26334.
135. Yamamoto D, Sonoda Y, Hasegawa M, Funakoshi-Tago M, Aizu-Yokota E, Kasahara T. FAK overexpression upregulates cyclin D3 and enhances cell proliferation via the PKC and PI3-kinase-Akt pathways. Cell Signal 2003;15:575-583.
136. Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol 2001;212:83-91.
137. Maroni P, Bendinelli P, Piccoletti R. Early intracellular events induced by in vivo leptin treatment in mouse skeletal muscle. Mol Cell Endocrinol 2003;201:109-121.
138. Backup P, Westerlind K, Harris S, Spelsberg T, Kline B, Turner R. Spaceflight results in reduced mRNA levels for tissue-specific proteins in the musculoskeletal system. Am J Physiol 1994;266:E567-E573.
139. Saito M, Soshi S, Fujii K. Effect of hyper- and microgravity on collagen post-translational controls of MC3T3-E1 osteoblasts. J Bone Miner Res 2003;18:1695-1705.
140. Lai CF, et al. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem 2001;276:14443-14450.
141. Xiao G, Gopalakrishnan R, Jiang D, Reith E, Benson MD, Franceschi RT. Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J Bone Miner Res 2002;17:101-110.
142. Janderova L, McNeil M, Murrell AN, Mynatt RL, Smith SR. Human mesenchymal stem cells as an in vitro model for human adipogenesis. Obes Res 2003;11:65-74.
143. Hughes-Fulford M. The role of signaling pathways in osteoblast gravity perception. J Gravit Physiol 2002;9:P257-P260.
144. Bikle DD, Sakata T, Halloran BP. The impact of skeletal unloading on bone formation. Gravit Space Biol Bull 2003;16:45-54.
145. Muniyappa R, Xu R, Ram JL, Sowers JR. Inhibition of Rho protein stimulates iNOS expression in rat vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2000;278:H1762-H1768.
146. Witteck A, Yao Y, Fechir M, Forstermann U, Kleinert H. Rho protein-mediated changes in the structure of the actin cytoskeleton regulate human inducible NO synthase gene expression. Exp Cell Res 2003;287:106-115.
147. MacPherson H, Noble BS, Ralston SH. Expression and functional role of nitric oxide synthase isoforms in human osteoblast-like cells. Bone 1999;24:179-185.
148. Ralston SH, Todd D, Helfrich M, Benjamin N, Grabowski PS. Human osteoblast-like cells produce nitric oxide and express inducible nitric oxide synthase. Endocrinology 1994;135:330-336.
149. Giordano A, et al. Evidence for a functional nitric oxide synthase system in brown adipocyte nucleus. FEBS Lett 2002;514:135-140.
150. Yan H, et al. Nitric oxide promotes differentiation of rat white preadipocytes in culture. J Lipid Res 2002;43:2123-2129.
151. Engeli S, et al. Regulation of the nitric oxide system in human adipose tissue. J Lipid Res 2004;45:1640-1648.
152. Ma J, Kahwaji CI, Ni Z, Vaziri ND, Purdy RE. Effects of simulated microgravity on arterial nitric oxide synthase and nitrate and nitrite content. J Appl Physiol 2003;94:83-92.
153. Vaziri ND, Ding Y, Sangha DS, Purdy RE. Upregulation of NOS by simulated microgravity, potential cause of orthostatic intolerance. J Appl Physiol 2000;89:338-344.
154. Carlsson SI, Bertilaccio MT, Ascari I, Bradamante S, Maier JA. Modulation of human endothelial cell behaviour in simulated microgravity. J Gravit Physiol 2002;9:P273-P274.
155. Ingram AJ, James L, Cai L, Thai K, Ly H, Scholey JW. NO inhibits stretch-induced MAPK activity by cytoskeletal disruption. J Biol Chem 2000;275:40301-40306.
156. Krepinsky JC, Ingram AJ, Tang D, Wu D, Liu L, Scholey JW. Nitric oxide inhibits stretch-induced MAPK activation in mesangial cells through RhoA inactivation. J Am Soc Nephrol 2003;14:2790-2800.
157. Nyhan D, Kim S, Dunbar S, Li D, Shoukas A, Berkowitz DE. Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide. J Appl Physiol 2002;92:33-40.
158. Sangha DS, Vaziri ND, Ding Y, Purdy RE. Vascular hyporesponsiveness in simulated microgravity: role of nitric oxide-dependent mechanisms. J Appl Physiol 2000;88:507-517.
159. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997;15:323-350.
160. Meyers VE, Zayzafoon M, Douglas JT, McDonald JM. RhoA and cytoskeletal disruption mediate reduced osteoblastogenesis and enhanced odiogenesis of human mesenchymal stem cells in madeled microgravity. J Bone Miner Res 2005;10:1858-1866.