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NADPH oxidases in bone homeostasis and osteoporosis

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Abstract

Bone formation and degradation are perfectly coordinated. In case of an imbalance of these processes diseases occur associated with exaggerated formation of new bone or bone loss as in osteoporosis. Most studies investigating osteoporosis either focus on osteoblast or osteoclast function and differentiation. Both processes have been suggested to be affected by reactive oxygen species (ROS). Besides a potentially harmful role of ROS, these small molecules are important second messengers. The family of NADPH oxidases produces ROS in a controlled and targeted manner, to specifically regulate signal transduction. This review will highlight the role of reactive oxygen species in bone cell differentiation and bone-loss associated disease with a special focus on osteoporosis and NADPH oxidases as specialized sources of ROS.

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Abbreviations

Steap:

Six-transmembrane epithelial antigen of prostate

IL:

Interleukin

TNF:

Tumour necrosis factor

IFN:

Interferon

TGF:

Transforming growth factor

NAC:

N-acetyl-cysteine

RANK:

Receptor activator of nuclear factor (NF)-κB–receptor

RANKL:

Receptor activator of NF-κB ligand

OPG:

Osteoprotegerin

BMP-2:

Bone morphogenic protein 2

References

  1. Altindag O, Erel O, Soran N et al (2008) Total oxidative/anti-oxidative status and relation to bone mineral density in osteoporosis. Rheumatol Int 28(4):317–321. doi:10.1007/s00296-007-0452-0

    CAS  PubMed  Google Scholar 

  2. Sendur OF, Turan Y, Tastaban E et al (2009) Antioxidant status in patients with osteoporosis: a controlled study. Joint Bone Spine 76(5):514–518. doi:10.1016/j.jbspin.2009.02.005

    CAS  PubMed  Google Scholar 

  3. LeBoff MS, Narweker R, LaCroix A et al (2009) Homocysteine levels and risk of hip fracture in postmenopausal women. J Clin Endocrinol Metabol 94(4):1207–1213. doi:10.1210/jc.2008-1777

    CAS  Google Scholar 

  4. Schröder K (2014) NADPH oxidases in redox regulation of cell adhesion and migration. Antioxid Redox Signal 20(13):2043–2058. doi:10.1089/ars.2013.5633

    PubMed  Google Scholar 

  5. Schröder K, Kohnen A, Aicher A et al (2009) NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells. Circ Res 105(6):537–544. doi:10.1161/CIRCRESAHA.109.205138

    PubMed  Google Scholar 

  6. Adachi T, Togashi H, Suzuki A et al (2005) NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 41(6):1272–1281. doi:10.1002/hep.20719

    CAS  PubMed  Google Scholar 

  7. Lee C, Lin C, Lee I et al (2011) Activation and induction of cytosolic phospholipase A2 by TNF-α mediated through Nox2, MAPKs, NF-κB, and p300 in human tracheal smooth muscle cells. J Cell Physiol 226(8):2103–2114. doi:10.1002/jcp.22537

    CAS  PubMed  Google Scholar 

  8. Wilkinson-Berka JL, Rana I, Armani R et al (2013) Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy. Clin Sci 124(10):597–615. doi:10.1042/CS20120212

    CAS  PubMed  Google Scholar 

  9. Miyano K, Sumimoto H (2007) Role of the small GTPase Rac in p22phox-dependent NADPH oxidases. Biochimie 89(9):1133–1144. doi:10.1016/j.biochi.2007.05.003

    CAS  PubMed  Google Scholar 

  10. Banfi B, Clark RA, Steger K et al (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem 278(6):3510–3513. doi:10.1074/jbc.C200613200

    CAS  PubMed  Google Scholar 

  11. Ueno N, Takeya R, Miyano K et al (2005) The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators. J Biol Chem 280(24):23328–23339. doi:10.1074/jbc.M414548200

    CAS  PubMed  Google Scholar 

  12. Helmcke I, Heumüller S, Tikkanen R et al (2009) Identification of structural elements in Nox1 and Nox4 controlling localization and activity. Antioxid Redox Signal 11(6):1279–1287. doi:10.1089/ARS.2008.2383

    CAS  PubMed  Google Scholar 

  13. Al Ghouleh I, Frazziano G, Rodriguez AI et al (2013) Aquaporin 1, Nox1, and Ask1 mediate oxidant-induced smooth muscle cell hypertrophy. Cardiovasc Res 97(1):134–142. doi:10.1093/cvr/cvs295

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Katsuyama M, Matsuno K, Yabe-Nishimura C (2012) Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. J Clin Biochem Nutr 50(1):9–22. doi:10.3164/jcbn.11-06SR

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Bedard K, Krause K (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313. doi:10.1152/physrev.00044.2005

    CAS  PubMed  Google Scholar 

  16. Bedard K, Jaquet V, Krause K (2012) NOX5: from basic biology to signaling and disease. Free Radic Biol Med 52(4):725–734. doi:10.1016/j.freeradbiomed.2011.11.023

    CAS  PubMed  Google Scholar 

  17. Lyle AN, Deshpande NN, Taniyama Y et al (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105(3):249–259. doi:10.1161/CIRCRESAHA.109.193722

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Sturrock A, Cahill B, Norman K et al (2006) Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290(4):L661–L673. doi:10.1152/ajplung.00269.2005

    CAS  PubMed  Google Scholar 

  19. Clempus RE, Sorescu D, Dikalova AE et al (2007) Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol 27(1):42–48. doi:10.1161/01.ATV.0000251500.94478.18

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Goettsch C, Babelova A, Trummer O et al (2013) NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. J Clin Invest 123(11):4731–4738. doi:10.1172/JCI67603

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Hecker L, Vittal R, Jones T et al (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15(9):1077–1081. doi:10.1038/nm.2005

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Li J, Stouffs M, Serrander L et al (2006) The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell 17(9):3978–3988. doi:10.1091/mbc.E05-06-0532

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Takac I, Schröder K, Zhang L et al (2011) The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 286(15):13304–13313. doi:10.1074/jbc.M110.192138

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Paffenholz R, Bergstrom RA, Pasutto F et al (2004) Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev 18(5):486–491. doi:10.1101/gad.1172504

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Kao C, Tai L, Chiou S et al (2010) Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. Stem Cells Dev 19(2):247–258. doi:10.1089/scd.2009.0186

    CAS  PubMed  Google Scholar 

  26. Manolagas SC, Parfitt AM (2010) What old means to bone. Trends Endocrinol Metab 21(6):369–374. doi:10.1016/j.tem.2010.01.010

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Lane D, Matte I, Laplante C et al (2013) Osteoprotegerin (OPG) activates integrin, focal adhesion kinase (FAK), and Akt signaling in ovarian cancer cells to attenuate TRAIL-induced apoptosis. J Ovarian Res 6(1):82. doi:10.1186/1757-2215-6-82

    PubMed Central  PubMed  Google Scholar 

  28. Boyce BF (2013) Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res 92(10):860–867. doi:10.1177/0022034513500306

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Huang JC, Sakata T, Pfleger LL et al (2004) PTH Differentially Regulates Expression of RANKL and OPG. J Bone Miner Res 19(2):235–244. doi:10.1359/JBMR.0301226

    CAS  PubMed  Google Scholar 

  30. Hjortnaes J, Butcher J, Figueiredo J et al (2010) Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J 31(16):1975–1984. doi:10.1093/eurheartj/ehq237

    CAS  PubMed Central  PubMed  Google Scholar 

  31. McCarthy I (2006) The physiology of bone blood flow: a review. J Bone Joint Surg Am 88((suppl_2)):4. doi:10.2106/JBJS.F.00890

    PubMed  Google Scholar 

  32. Zaidi M (2007) Skeletal remodeling in health and disease. Nat Med 13(7):791–801. doi:10.1038/nm1593

    CAS  PubMed  Google Scholar 

  33. Pinzone JJ, Hall BM, Thudi NK et al (2009) The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113(3):517–525. doi:10.1182/blood-2008-03-145169

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Jian J, Pelle E, Huang X (2009) Iron and menopause: does increased iron affect the health of postmenopausal women? Antioxid Redox Signal 11(12):2939–2943. doi:10.1089/ARS.2009.2576

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Zarjou A, Jeney V, Arosio P et al (2010) Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J Bone Miner Res 25(1):164–172. doi:10.1359/jbmr.091002

    CAS  PubMed  Google Scholar 

  36. Yang X, Chen-Barrett Y, Arosio P et al (1998) Reaction paths of iron oxidation and hydrolysis in horse spleen and recombinant human ferritins. Biochemistry 37(27):9743–9750. doi:10.1021/bi973128a

    CAS  PubMed  Google Scholar 

  37. Tsay J, Yang Z, Ross FP et al (2010) Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 116(14):2582–2589. doi:10.1182/blood-2009-12-260083

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Jia P, Xu YJ, Zhang ZL et al (2012) Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J Orthop Res 30(11):1843–1852. doi:10.1002/jor.22133

    CAS  PubMed  Google Scholar 

  39. Nojiri H, Saita Y, Morikawa D et al (2011) Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res 26(11):2682–2694. doi:10.1002/jbmr.489

    CAS  PubMed  Google Scholar 

  40. Monnier VM, Glomb M, Elgawish A et al (1996) The mechanism of collagen cross-linking in diabetes: a puzzle nearing resolution. Diabetes 45(Suppl 3):S67–S72

    CAS  PubMed  Google Scholar 

  41. Morikawa D, Nojiri H, Saita Y et al (2013) Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. J Bone Miner Res 28(11):2368–2380. doi:10.1002/jbmr.1981

    CAS  PubMed  Google Scholar 

  42. Dernbach E, Urbich C, Brandes RP et al (2004) Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. Blood 104(12):3591–3597. doi:10.1182/blood-2003-12-4103

    CAS  PubMed  Google Scholar 

  43. Fatokun AA, Stone TW, Smith RA (2008) Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species. Eur J Pharmacol 587(1–3):35–41. doi:10.1016/j.ejphar.2008.03.024

    CAS  PubMed  Google Scholar 

  44. Cai W, Zhang M, Yu Y et al (2013) Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast. Mol Cell Biochem 373(1–2):1–9. doi:10.1007/s11010-012-1450-4

    CAS  PubMed  Google Scholar 

  45. Choi EM (2011) Luteolin protects osteoblastic MC3T3-E1 cells from antimycin A-induced cytotoxicity through the improved mitochondrial function and activation of PI3K/Akt/CREB. Toxicol In Vitro 25(8):1671–1679. doi:10.1016/j.tiv.2011.07.004

    CAS  PubMed  Google Scholar 

  46. Choi EM, Lee YS (2012) Protective effect of apocynin on antimycin A-induced cell damage in osteoblastic MC3T3-E1 cells. J Appl Toxicol 32(9):714–721. doi:10.1002/jat.1689

    CAS  PubMed  Google Scholar 

  47. Choi EM, Lee YS (2011) Involvement of PI3K/Akt/CREB and redox changes in mitochondrial defect of osteoblastic MC3T3-E1 cells. Toxicol In Vitro 25(5):1085–1088. doi:10.1016/j.tiv.2011.03.022

    CAS  PubMed  Google Scholar 

  48. Mandal CC, Ganapathy S, Gorin Y et al (2011) Reactive oxygen species derived from Nox4 mediate BMP2 gene transcription and osteoblast differentiation. Biochem J 433(2):393–402. doi:10.1042/BJ20100357

    CAS  PubMed  Google Scholar 

  49. Schröder K, Wandzioch K, Helmcke I et al (2009) Nox4 acts as a switch between differentiation and proliferation in preadipocytes. Arterioscler Thromb Vasc Biol 29(2):239–245. doi:10.1161/ATVBAHA.108.174219

    PubMed  Google Scholar 

  50. van Driel M, van Leeuwen Johannes P T M (2014) Vitamin D endocrine system and osteoblasts. Bonekey Rep 3:493. doi:10.1038/bonekey.2013.227

    PubMed  Google Scholar 

  51. Somjen D, Katzburg S, Grafi-Cohen M et al (2011) Vitamin D metabolites and analogs induce lipoxygenase mRNA expression and activity as well as reactive oxygen species (ROS) production in human bone cell line. J Steroid Biochem Mol Biol 123(1–2):85–89. doi:10.1016/j.jsbmb.2010.11.010

    CAS  PubMed  Google Scholar 

  52. Boyan BD, Bonewald LF, Sylvia VL et al (2002) Evidence for distinct membrane receptors for 1 alpha,25-(OH)(2)D(3) and 24R,25-(OH)(2)D(3) in osteoblasts. Steroids 67(3–4):235–246

    CAS  PubMed  Google Scholar 

  53. Atkins GJ, Kostakis P, Pan B et al (2003) RANKL expression is related to the differentiation state of human osteoblasts. J Bone Miner Res 18(6):1088–1098. doi:10.1359/jbmr.2003.18.6.1088

    CAS  PubMed  Google Scholar 

  54. Tilyard MW, Spears GF, Thomson J et al (1992) Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 326(6):357–362. doi:10.1056/NEJM199202063260601

    CAS  PubMed  Google Scholar 

  55. Eisman JA, Bouillon R (2014) Vitamin D: direct effects of vitamin D metabolites on bone: lessons from genetically modified mice. Bonekey Rep 3:499. doi:10.1038/bonekey.2013.233

    PubMed  Google Scholar 

  56. Yin H, Shi Z, Yu Y et al (2012) Protection against osteoporosis by statins is linked to a reduction of oxidative stress and restoration of nitric oxide formation in aged and ovariectomized rats. Eur J Pharmacol 674(2–3):200–206. doi:10.1016/j.ejphar.2011.11.024

    CAS  PubMed  Google Scholar 

  57. Huang W, Shang W, Li D et al (2012) Simvastatin protects osteoblast against H2O2-induced oxidative damage via inhibiting the upregulation of Nox4. Mol Cell Biochem 360(1–2):71–77. doi:10.1007/s11010-011-1045-5

    CAS  PubMed  Google Scholar 

  58. Walsh MC, Choi Y (2003) Biology of the TRANCE axis. Cytokine Growth Factor Rev 14(3–4):251–263

    CAS  PubMed  Google Scholar 

  59. Lomaga MA, Yeh WC, Sarosi I et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13(8):1015–1024

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Kadono Y, Okada F, Perchonock C et al (2005) Strength of TRAF6 signalling determines osteoclastogenesis. EMBO Rep 6(2):171–176. doi:10.1038/sj.embor.7400345

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Chandel NS, Schumacker PT, Arch RH (2001) Reactive oxygen species are downstream products of TRAF-mediated signal transduction. J Biol Chem 276(46):42728–42736. doi:10.1074/jbc.M103074200

    CAS  PubMed  Google Scholar 

  62. Zhou J, Ye S, Fujiwara T et al (2013) Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation. J Biol Chem 288(42):30064–30074. doi:10.1074/jbc.M113.478750

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Srinivasan S, Koenigstein A, Joseph J et al (2010) Role of mitochondrial reactive oxygen species in osteoclast differentiation. Ann N Y Acad Sci 1192:245–252. doi:10.1111/j.1749-6632.2009.05377.x

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Lee NK, Choi YG, Baik JY et al (2005) A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106(3):852–859. doi:10.1182/blood-2004-09-3662

    CAS  PubMed  Google Scholar 

  65. Sasaki H, Yamamoto H, Tominaga K et al (2009) NADPH oxidase-derived reactive oxygen species are essential for differentiation of a mouse macrophage cell line (RAW264.7) into osteoclasts. J Med Invest 56(1–2):33–41

    PubMed  Google Scholar 

  66. Sasaki H, Yamamoto H, Tominaga K et al (2009) Receptor activator of nuclear factor-kappaB ligand-induced mouse osteoclast differentiation is associated with switching between NADPH oxidase homologues. Free Radic Biol Med 47(2):189–199. doi:10.1016/j.freeradbiomed.2009.04.025

    CAS  PubMed  Google Scholar 

  67. Nakanishi A, Hie M, Iitsuka N et al (2013) A crucial role for reactive oxygen species in macrophage colony-stimulating factor-induced RANK expression in osteoclastic differentiation. Int J Mol Med 31(4):874–880. doi:10.3892/ijmm.2013.1258

    CAS  PubMed  Google Scholar 

  68. Daiber A (2010) Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 1797(6–7):897–906. doi:10.1016/j.bbabio.2010.01.032

    CAS  PubMed  Google Scholar 

  69. Yang S, Madyastha P, Bingel S et al (2001) A new superoxide-generating oxidase in murine osteoclasts. J Biol Chem 276(8):5452–5458. doi:10.1074/jbc.M001004200

    CAS  PubMed  Google Scholar 

  70. Yang S, Zhang Y, Ries W et al (2004) Expression of Nox4 in osteoclasts. J Cell Biochem 92(2):238–248. doi:10.1002/jcb.20048

    CAS  PubMed  Google Scholar 

  71. Schröder K, Zhang M, Benkhoff S et al (2012) Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 110(9):1217–1225. doi:10.1161/CIRCRESAHA.112.267054

    PubMed  Google Scholar 

  72. van Phan T, Sul O, Ke K et al (2013) Carbon monoxide protects against ovariectomy-induced bone loss by inhibiting osteoclastogenesis. Biochem Pharmacol 85(8):1145–1152. doi:10.1016/j.bcp.2013.01.014

    PubMed  Google Scholar 

  73. Hyeon S, Lee H, Yang Y et al (2013) Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radic Biol Med 65:789–799. doi:10.1016/j.freeradbiomed.2013.08.005

    CAS  PubMed  Google Scholar 

  74. Gurney EP, Nachtigall MJ, Nachtigall LE et al (2014) The Women’s Health Initiative trial and related studies: 10 years later: a clinician’s view. J Steroid Biochem Mol Biol 142C:4–11. doi:10.1016/j.jsbmb.2013.10.009

    Google Scholar 

  75. Almeida M, Han L, Martin-Millan M et al (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282(37):27285–27297. doi:10.1074/jbc.M702810200

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Muthusami S, Ramachandran I, Muthusamy B et al (2005) Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. Clin Chim Acta 360(1–2):81–86. doi:10.1016/j.cccn.2005.04.014

    CAS  PubMed  Google Scholar 

  77. Lean JM, Jagger CJ, Kirstein B et al (2005) Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. Endocrinology 146(2):728–735. doi:10.1210/en.2004-1021

    CAS  PubMed  Google Scholar 

  78. Jagger CJ, Lean JM, Davies JT et al (2005) Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology 146(1):113–118. doi:10.1210/en.2004-1058

    CAS  PubMed  Google Scholar 

  79. Gower BA, Casazza K (2013) Divergent effects of obesity on bone health. J Clin Densitom 16(4):450–454. doi:10.1016/j.jocd.2013.08.010

    PubMed  Google Scholar 

  80. Parhami F, Garfinkel A, Demer LL (2000) Role of lipids in osteoporosis. Arterioscler Thromb Vasc Biol 20(11):2346–2348. doi:10.1161/01.ATV.20.11.2346

    CAS  PubMed  Google Scholar 

  81. Iqbal J, Sun L, Cao J et al (2013) Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci 110(27):11115–11120. doi:10.1073/pnas.1220919110

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Mikosch P (2014) Alcohol and bone. Wien Med Wochenschr 164(1–2):15–24. doi:10.1007/s10354-013-0258-5

    PubMed  Google Scholar 

  83. Saville PD (1965) Changes in bone mass with age and alcoholism. J Bone Joint Surg Am 47:492–499

    CAS  PubMed  Google Scholar 

  84. Chen J, Haley RL, Hidestrand M et al (2006) Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaB ligand in osteoblasts. J Pharmacol Exp Ther 319(3):1182–1190. doi:10.1124/jpet.106.109454

    CAS  PubMed  Google Scholar 

  85. Chen J, Lazarenko OP, Shankar K et al (2011) Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats. J Pharmacol Exp Ther 336(3):734–742. doi:10.1124/jpet.110.175091

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Sumi D, Hayashi T, Matsui-Hirai H et al (2003) 17beta-estradiol inhibits NADPH oxidase activity through the regulation of p47phox mRNA and protein expression in THP-1 cells. Biochim Biophys Acta 1640(2–3):113–118

    CAS  PubMed  Google Scholar 

  87. Mercer KE, Sims CR, Yang CS et al (2014) Loss of functional NADPH oxidase 2 protects against alcohol-induced bone resorption in female p47phox−/− mice. Alcohol Clin Exp Res 38(3):672–682. doi:10.1111/acer.12305

    CAS  PubMed  Google Scholar 

  88. Chen J, Shankar K, Nagarajan S et al (2008) Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-kappaB ligand signaling cascade. J Pharmacol Exp Ther 324(1):50–59. doi:10.1124/jpet.107.130351

    CAS  PubMed  Google Scholar 

  89. Wosje KS, Kalkwarf HJ (2007) Bone density in relation to alcohol intake among men and women in the United States. Osteoporos Int 18(3):391–400. doi:10.1007/s00198-006-0249-0

    CAS  PubMed  Google Scholar 

  90. Oršolić N, Goluža E, Đikić D et al (2013) Role of flavonoids on oxidative stress and mineral contents in the retinoic acid-induced bone loss model of rat. Eur J Nutr. doi:10.1007/s00394-013-0622-7

    PubMed  Google Scholar 

  91. Kotake S, Udagawa N, Takahashi N et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103(9):1345–1352. doi:10.1172/JCI5703

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Huang H, Kim HJ, Chang E et al (2009) IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling. Cell Death Differ 16(10):1332–1343. doi:10.1038/cdd.2009.74

    CAS  PubMed  Google Scholar 

  93. Hultqvist M, Olofsson P, Holmberg J et al (2004) Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci 101(34):12646–12651. doi:10.1073/pnas.0403831101

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Gelderman KA, Hultqvist M, Pizzolla A et al (2007) Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J Clin Invest 117(10):3020–3028. doi:10.1172/JCI31935

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Engdahl C, Lindholm C, Stubelius A et al (2013) Periarticular bone loss in antigen-induced arthritis. Arthritis Rheum 65(11):2857–2865. doi:10.1002/art.38114

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Cedergren J, Forslund T, Sundqvist T et al (2007) Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients. J Rheumatol 34(11):2162–2170

    CAS  PubMed  Google Scholar 

  97. Ralston SH (1997) The michael mason prize essay 1997, Nitric oxide and bone: what a gas! Br J Rheumatol 36(8):831–838

    CAS  PubMed  Google Scholar 

  98. Korkmaz Y, Baumann MA, Schroder H et al (2004) Localization of the NO-cGMP signaling pathway molecules, NOS III-phosphorylation sites, ERK1/2, and Akt/PKB in osteoclasts. J Periodontol 75(8):1119–1125. doi:10.1902/jop.2004.75.8.1119

    CAS  PubMed  Google Scholar 

  99. Armour KE, Ralston SH (1998) Estrogen upregulates endothelial constitutive nitric oxide synthase expression in human osteoblast-like cells. Endocrinology 139(2):799–802. doi:10.1210/endo.139.2.5910

    CAS  PubMed  Google Scholar 

  100. Zaman G, Pitsillides AA, Rawlinson SC et al (1999) Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res 14(7):1123–1131. doi:10.1359/jbmr.1999.14.7.1123

    CAS  PubMed  Google Scholar 

  101. Aguirre J, Buttery L, O’Shaughnessy M et al (2001) Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation, reduced bone volume, and defects in osteoblast maturation and activity. Am J Pathol 158(1):247–257. doi:10.1016/S0002-9440(10)63963-6

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Felson DT, Zhang Y, Hannan MT et al (1993) Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res 8(5):567–573. doi:10.1002/jbmr.5650080507

    CAS  PubMed  Google Scholar 

  103. Thomas T, Burguera B (2002) Is leptin the link between fat and bone mass? J Bone Miner Res 17(9):1563–1569. doi:10.1359/jbmr.2002.17.9.1563

    CAS  PubMed  Google Scholar 

  104. Turner RT, Kalra SP, Wong CP et al (2013) Peripheral leptin regulates bone formation. J Bone Miner Res 28(1):22–34. doi:10.1002/jbmr.1734

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Benkhoff S, Loot AE, Pierson I et al (2012) Leptin potentiates endothelium-dependent relaxation by inducing endothelial expression of neuronal NO synthase. Arterioscler Thromb Vasc Biol 32(7):1605–1612. doi:10.1161/ATVBAHA.112.251140

    CAS  PubMed  Google Scholar 

  106. Percival MD, Ouellet M, Campagnolo C et al (1999) Inhibition of cathepsin K by nitric oxide donors: evidence for the formation of mixed disulfides and a sulfenic acid. Biochemistry 38(41):13574–13583

    CAS  PubMed  Google Scholar 

  107. Jamal SA, Reid LS, Hamilton CJ (2013) The effects of organic nitrates on osteoporosis: a systematic review. Osteoporos Int 24(3):763–770. doi:10.1007/s00198-012-2262-9

    CAS  PubMed  Google Scholar 

  108. Kaur H, Halliwell B (1994) Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients. FEBS Lett 350(1):9–12

    CAS  PubMed  Google Scholar 

  109. Van’t Hof RJ, Ralston SH (2001) Nitric oxide and bone. Immunology 103(3):255–261

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The author thanks Ralf P. Brandes for critical reading the manuscript and making helpful suggestions. This work was supported by the Deutsche Forschungsgemeinschaft (SFB815/TP1).

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  1. Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Universität Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Katrin Schröder

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Schröder, K. NADPH oxidases in bone homeostasis and osteoporosis. Cell. Mol. Life Sci. 72, 25–38 (2015). https://doi.org/10.1007/s00018-014-1712-2

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