Osteoporosis International

, Volume 26, Issue 11, pp 2561–2572 | Cite as

Circulating monocytes: an appropriate model for bone-related study

  • Y. Zhou
  • H.-W. Deng
  • H. ShenEmail author
Review Article



Peripheral blood monocytes (PBMs) are an important source of precursors of osteoclasts, the bone-resorbing cells and the cytokines produced by PBMs that have profound effects on osteoclast differentiation, activation, and apoptosis. So PBMs represent a highly valuable and unique working cell model for bone-related study.

Finding an appropriate working cell model for clinical and (epi-)genomic studies of human skeletal disorders is a challenge. Peripheral blood monocytes (PBMs) can give rise to osteoclasts, the bone-resorbing cells. Particularly, PBMs provide the sole source of osteoclast precursors for adult peripheral skeleton where the bone marrow is normally hematopoietically inactive. PBMs can secrete potent pro- and anti-inflammatory cytokines, which are important for osteoclast differentiation, activation, and apoptosis. Reduced production of PBM cytokines represents a major mechanism for the inhibitory effects of sex hormones on osteoclastogenesis and bone resorption. Abnormalities in PBMs have been linked to various skeletal disorders/traits, strongly supporting for the biological relevance of PBMs with bone metabolism and disorders. Here, we briefly review the origin and further differentiation of PBMs. In particular, we discuss the close relationship between PBMs and osteoclasts, and highlight the utility of PBMs in study the pathophysiological mechanisms underlying various skeletal disorders.


Osteoclast Peripheral blood monocytes Skeletal disorders 



The investigators of this work were partially supported by grants from the NIH (R01AG026564, R01AR050496, and R01AR057049) and the Edward G. Schlieder Endowment as well as the Drs. W. C. Tsai and P. T. Kung Professorship in Biostatistics from Tulane University.

Conflicts of interest



  1. 1.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964. doi: 10.1038/nri1733 PubMedCrossRefGoogle Scholar
  2. 2.
    Liu YZ, Dvornyk V, Lu Y, Shen H, Lappe JM, Recker RR, Deng HW (2005) A novel pathophysiological mechanism for osteoporosis suggested by an in vivo gene expression study of circulating monocytes. J Biol Chem 280(32):29011–29016PubMedCrossRefGoogle Scholar
  3. 3.
    Hirayama T, Danks L, Sabokbar A, Athanasou NA (2002) Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology 41(11):1232–1239PubMedCrossRefGoogle Scholar
  4. 4.
    Laso FJ, Vaquero JM, Almeida J, Marcos M, Orfao A (2007) Production of inflammatory cytokines by peripheral blood monocytes in chronic alcoholism: relationship with ethanol intake and liver disease. Cytometry B Clin Cytom 72(5):408–415. doi: 10.1002/cyto.b.20169 PubMedCrossRefGoogle Scholar
  5. 5.
    Longhi MS, Mitry RR, Samyn M, Scalori A, Hussain MJ, Quaglia A, Mieli-Vergani G, Ma Y, Vergani D (2009) Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells. Hepatology 50(1):130–142. doi: 10.1002/hep.22914 PubMedCrossRefGoogle Scholar
  6. 6.
    Dorffel Y, Latsch C, Stuhlmuller B, Schreiber S, Scholze S, Burmester GR, Scholze J (1999) Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension 34(1):113–117PubMedCrossRefGoogle Scholar
  7. 7.
    Strauss-Ayali D, Conrad SM, Mosser DM (2007) Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol 82(2):244–252. doi: 10.1189/jlb.0307191 PubMedCrossRefGoogle Scholar
  8. 8.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969. doi: 10.1038/nri2448 PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Varol C, Yona S, Jung S (2009) Origins and tissue-context-dependent fates of blood monocytes. Immunol Cell Biol 87(1):30–38. doi: 10.1038/icb.2008.90 PubMedCrossRefGoogle Scholar
  10. 10.
    Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311(5757):83–87. doi: 10.1126/science.1117729 PubMedCrossRefGoogle Scholar
  11. 11.
    Iwasaki H, Akashi K (2007) Myeloid lineage commitment from the hematopoietic stem cell. Immunity 26(6):726–740. doi: 10.1016/j.immuni.2007.06.004 PubMedCrossRefGoogle Scholar
  12. 12.
    Chow A, Brown BD, Merad M (2011) Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11(11):788–798. doi: 10.1038/nri3087 PubMedCrossRefGoogle Scholar
  13. 13.
    Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, Scherberich J, Schmitz J, Shortman K, Sozzani S, Strobl H, Zembala M, Austyn JM, Lutz MB (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116(16):e74–e80. doi: 10.1182/blood-2010-02-258558 PubMedCrossRefGoogle Scholar
  14. 14.
    Ziegler-Heitbrock L, Hofer TP (2013) Toward a refined definition of monocyte subsets. Front Immunol 4:23. doi: 10.3389/fimmu.2013.00023 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. doi: 10.1146/annurev.immunol.021908.132557 PubMedCrossRefGoogle Scholar
  16. 16.
    Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC (2012) The three human monocyte subsets: implications for health and disease. Immunol Res 53(1–3):41–57. doi: 10.1007/s12026-012-8297-3 PubMedCrossRefGoogle Scholar
  17. 17.
    Zawada AM, Rogacev KS, Rotter B, Winter P, Marell RR, Fliser D, Heine GH (2011) SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 118(12):e50–e61. doi: 10.1182/blood-2011-01-326827 PubMedCrossRefGoogle Scholar
  18. 18.
    Weber C, Belge KU, von Hundelshausen P, Draude G, Steppich B, Mack M, Frankenberger M, Weber KS, Ziegler-Heitbrock HW (2000) Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 67(5):699–704PubMedGoogle Scholar
  19. 19.
    Ancuta P, Rao R, Moses A, Mehle A, Shaw SK, Luscinskas FW, Gabuzda D (2003) Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. J Experiment Med 197(12):1701–1707. doi: 10.1084/jem.20022156 CrossRefGoogle Scholar
  20. 20.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82PubMedCrossRefGoogle Scholar
  21. 21.
    Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B, Espevik T, Ziegler-Heitbrock L (2002) The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 168(7):3536–3542PubMedCrossRefGoogle Scholar
  22. 22.
    Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC (2011) Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 118(5):e16–e31. doi: 10.1182/blood-2010-12-326355 PubMedCrossRefGoogle Scholar
  23. 23.
    Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, Jais JP, D’Cruz D, Casanova JL, Trouillet C, Geissmann F (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33(3):375–386. doi: 10.1016/j.immuni.2010.08.012 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Frankenberger M, Sternsdorf T, Pechumer H, Pforte A, Ziegler-Heitbrock HW (1996) Differential cytokine expression in human blood monocyte subpopulations: a polymerase chain reaction analysis. Blood 87(1):373–377PubMedGoogle Scholar
  25. 25.
    Moniuszko M, Bodzenta-Lukaszyk A, Kowal K, Lenczewska D, Dabrowska M (2009) Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients. Clin Immunol 130(3):338–346. doi: 10.1016/j.clim.2008.09.011 PubMedCrossRefGoogle Scholar
  26. 26.
    Kim WK, Sun Y, Do H, Autissier P, Halpern EF, Piatak M Jr, Lifson JD, Burdo TH, McGrath MS, Williams K (2010) Monocyte heterogeneity underlying phenotypic changes in monocytes according to SIV disease stage. J Leukoc Biol 87(4):557–567. doi: 10.1189/jlb.0209082 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Skrzeczynska-Moncznik J, Bzowska M, Loseke S, Grage-Griebenow E, Zembala M, Pryjma J (2008) Peripheral blood CD14high CD16+ monocytes are main producers of IL-10. Scand J Immunol 67(2):152–159. doi: 10.1111/j.1365-3083.2007.02051.x PubMedCrossRefGoogle Scholar
  28. 28.
    Faure S, Meyer L, Costagliola D, Vaneensberghe C, Genin E, Autran B, Delfraissy JF, McDermott DH, Murphy PM, Debre P, Theodorou I, Combadiere C (2000) Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1. Science 287(5461):2274–2277PubMedCrossRefGoogle Scholar
  29. 29.
    Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48(2):405–415PubMedCrossRefGoogle Scholar
  30. 30.
    de Groot CJ, Huppes W, Sminia T, Kraal G, Dijkstra CD (1992) Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non-radioactive in situ hybridization and immunoperoxidase techniques. Glia 6(4):301–309. doi: 10.1002/glia.440060408 PubMedCrossRefGoogle Scholar
  31. 31.
    Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944. doi: 10.1146/annurev.immunol.23.021704.115816 PubMedCrossRefGoogle Scholar
  32. 32.
    Kraal G (1992) Cells in the marginal zone of the spleen. Int Rev Cytol 132:31–74PubMedCrossRefGoogle Scholar
  33. 33.
    van Furth R, Diesselhoff-den Dulk MM (1984) Dual origin of mouse spleen macrophages. J Experiment Med 160(5):1273–1283CrossRefGoogle Scholar
  34. 34.
    van Rooijen N (1992) Liposome-mediated elimination of macrophages. Res Immunol 143(2):215–219PubMedCrossRefGoogle Scholar
  35. 35.
    Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Engleman EG (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3(12):1135–1141. doi: 10.1038/ni852 PubMedCrossRefGoogle Scholar
  36. 36.
    Kanitakis J, Petruzzo P, Dubernard JM (2004) Turnover of epidermal Langerhans’ cells. N Engl J Med 351(25):2661–2662. doi: 10.1056/NEJM200412163512523 PubMedCrossRefGoogle Scholar
  37. 37.
    Matute-Bello G, Lee JS, Frevert CW, Liles WC, Sutlief S, Ballman K, Wong V, Selk A, Martin TR (2004) Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J Immunol Methods 292(1–2):25–34. doi: 10.1016/j.jim.2004.05.010 PubMedCrossRefGoogle Scholar
  38. 38.
    Thomas ED, Ramberg RE, Sale GE, Sparkes RS, Golde DW (1976) Direct evidence for a bone marrow origin of the alveolar macrophage in man. Science 192(4243):1016–1018PubMedCrossRefGoogle Scholar
  39. 39.
    Naito M, Hasegawa G, Takahashi K (1997) Development, differentiation, and maturation of Kupffer cells. Microsc Res Tech 39(4):350–364. doi: 10.1002/(SICI)1097-0029(19971115)39:4<350::AID-JEMT5>3.0.CO;2-L PubMedCrossRefGoogle Scholar
  40. 40.
    Landsman L, Varol C, Jung S (2007) Distinct differentiation potential of blood monocyte subsets in the lung. J Immunol 178(4):2000–2007PubMedCrossRefGoogle Scholar
  41. 41.
    Seta N, Kuwana M (2010) Derivation of multipotent progenitors from human circulating CD14+ monocytes. Exp Hematol 38(7):557–563. doi: 10.1016/j.exphem.2010.03.015 PubMedCrossRefGoogle Scholar
  42. 42.
    Kuwana M, Okazaki Y, Kodama H, Izumi K, Yasuoka H, Ogawa Y, Kawakami Y, Ikeda Y (2003) Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J Leukoc Biol 74(5):833–845. doi: 10.1189/jlb.0403170 PubMedCrossRefGoogle Scholar
  43. 43.
    Kodama H, Inoue T, Watanabe R, Yasuoka H, Kawakami Y, Ogawa S, Ikeda Y, Mikoshiba K, Kuwana M (2005) Cardiomyogenic potential of mesenchymal progenitors derived from human circulating CD14+ monocytes. Stem Cells Dev 14(6):676–686. doi: 10.1089/scd.2005.14.676 PubMedCrossRefGoogle Scholar
  44. 44.
    Kodama H, Inoue T, Watanabe R, Yasutomi D, Kawakami Y, Ogawa S, Mikoshiba K, Ikeda Y, Kuwana M (2006) Neurogenic potential of progenitors derived from human circulating CD14+ monocytes. Immunol Cell Biol 84(2):209–217. doi: 10.1111/j.1440-1711.2006.01424.x PubMedCrossRefGoogle Scholar
  45. 45.
    Kuwana M, Okazaki Y, Kodama H, Satoh T, Kawakami Y, Ikeda Y (2006) Endothelial differentiation potential of human monocyte-derived multipotential cells. Stem Cells 24(12):2733–2743. doi: 10.1634/stemcells.2006-0026 PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao Y, Glesne D, Huberman E (2003) A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A 100(5):2426–2431. doi: 10.1073/pnas.0536882100 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Athanasou NA (1996) Cellular biology of bone-resorbing cells. J Bone Joint Surg Am 78(7):1096–1112PubMedGoogle Scholar
  48. 48.
    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342. doi: 10.1038/nature01658 PubMedCrossRefGoogle Scholar
  49. 49.
    Xing L, Schwarz EM, Boyce BF (2005) Osteoclast precursors, RANKL/RANK, and immunology. Immunol Rev 208:19–29. doi: 10.1111/j.0105-2896.2005.00336.x PubMedCrossRefGoogle Scholar
  50. 50.
    Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T (1990) Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A 87(18):7260–7264PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Custer RPAF (1932) Studies of the structure and function of bone marrow: variations in cellularity in various bones with advancing years of life and their relative response to stimuli. J Lab Clin Med 17:960–962Google Scholar
  52. 52.
    Zambonin Zallone A, Teti A, Primavera MV (1984) Monocytes from circulating blood fuse in vitro with purified osteoclasts in primary culture. J Cell Sci 66:335–342PubMedGoogle Scholar
  53. 53.
    Horton MA, Spragg JH, Bodary SC, Helfrich MH (1994) Recognition of cryptic sites in human and mouse laminins by rat osteoclasts is mediated by beta 3 and beta 1 integrins. Bone 15(6):639–646PubMedCrossRefGoogle Scholar
  54. 54.
    Parfitt AM (1994) Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 55(3):273–286. doi: 10.1002/jcb.240550303 PubMedCrossRefGoogle Scholar
  55. 55.
    Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN (2009) Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature 458(7237):524–528. doi: 10.1038/nature07713 PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN (2010) Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J Exp Med 207(13):2793–2798. doi: 10.1084/jem.20101474 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Yu X, Huang Y, Collin-Osdoby P, Osdoby P (2003) Stromal cell-derived factor-1 (SDF-1) recruits osteoclast precursors by inducing chemotaxis, matrix metalloproteinase-9 (MMP-9) activity, and collagen transmigration. J Bone Min Res : Off J Am Soc Bone Min Res 18(8):1404–1418. doi: 10.1359/jbmr.2003.18.8.1404 CrossRefGoogle Scholar
  58. 58.
    Kikuta J, Kawamura S, Okiji F, Shirazaki M, Sakai S, Saito H, Ishii M (2013) Sphingosine-1-phosphate-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D. Proc Natl Acad Sci U S A 110(17):7009–7013. doi: 10.1073/pnas.1218799110 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Komano Y, Nanki T, Hayashida K, Taniguchi K, Miyasaka N (2006) Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts. Arthritis Res Therapy 8(5):R152. doi: 10.1186/ar2046 CrossRefGoogle Scholar
  60. 60.
    Chiu YG, Shao T, Feng C, Mensah KA, Thullen M, Schwarz EM, Ritchlin CT (2010) CD16 (FcRgammaIII) as a potential marker of osteoclast precursors in psoriatic arthritis. Arthritis Res Therapy 12(1):R14. doi: 10.1186/ar2915 CrossRefGoogle Scholar
  61. 61.
    Lari R, Kitchener PD, Hamilton JA (2009) The proliferative human monocyte subpopulation contains osteoclast precursors. Arthritis Res Therapy 11(1):R23. doi: 10.1186/ar2616 CrossRefGoogle Scholar
  62. 62.
    Jacome-Galarza CE, Lee SK, Lorenzo JA, Aguila HL (2013) Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 28(5):1203–1213. doi: 10.1002/jbmr.1822 PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Atkins GJ, Bouralexis S, Haynes DR, Graves SE, Geary SM, Evdokiou A, Zannettino AC, Hay S, Findlay DM (2001) Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone. Bone 28(4):370–377PubMedCrossRefGoogle Scholar
  64. 64.
    Udagawa N, Takahashi N, Yasuda H, Mizuno A, Itoh K, Ueno Y, Shinki T, Gillespie MT, Martin TJ, Higashio K, Suda T (2000) Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141(9):3478–3484. doi: 10.1210/endo.141.9.7634 PubMedGoogle Scholar
  65. 65.
    Atkins GJ, Kostakis P, Vincent C, Farrugia AN, Houchins JP, Findlay DM, Evdokiou A, Zannettino AC (2006) RANK expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. J Bone Miner Res 21(9):1339–1349. doi: 10.1359/jbmr.060604 PubMedCrossRefGoogle Scholar
  66. 66.
    Kim N, Kadono Y, Takami M, Lee J, Lee SH, Okada F, Kim JH, Kobayashi T, Odgren PR, Nakano H, Yeh WC, Lee SK, Lorenzo JA, Choi Y (2005) Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Experiment Med 202(5):589–595. doi: 10.1084/jem.20050978 CrossRefGoogle Scholar
  67. 67.
    Ross FP, Teitelbaum SL (2005) alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 208:88–105. doi: 10.1111/j.0105-2896.2005.00331.x PubMedCrossRefGoogle Scholar
  68. 68.
    Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Experiment Med 190(12):1741–1754CrossRefGoogle Scholar
  69. 69.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN, Lee SY, Choi Y (1997) TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272(40):25190–25194PubMedCrossRefGoogle Scholar
  70. 70.
    Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER (2002) Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99(1):111–120PubMedCrossRefGoogle Scholar
  71. 71.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442–444. doi: 10.1038/345442a0 PubMedCrossRefGoogle Scholar
  72. 72.
    Weir EC, Lowik CW, Paliwal I, Insogna KL (1996) Colony stimulating factor-1 plays a role in osteoclast formation and function in bone resorption induced by parathyroid hormone and parathyroid hormone-related protein. J Bone Miner Res 11(10):1474–1481. doi: 10.1002/jbmr.5650111014 PubMedCrossRefGoogle Scholar
  73. 73.
    Weir EC, Horowitz MC, Baron R, Centrella M, Kacinski BM, Insogna KL (1993) Macrophage colony-stimulating factor release and receptor expression in bone cells. J Bone Miner Res 8(12):1507–1518. doi: 10.1002/jbmr.5650081214 PubMedCrossRefGoogle Scholar
  74. 74.
    Rambaldi A, Young DC, Griffin JD (1987) Expression of the M-CSF (CSF-1) gene by human monocytes. Blood 69(5):1409–1413PubMedGoogle Scholar
  75. 75.
    Lader CS, Flanagan AM (1998) Prostaglandin E2, interleukin 1alpha, and tumor necrosis factor-alpha increase human osteoclast formation and bone resorption in vitro. Endocrinology 139(7):3157–3164. doi: 10.1210/endo.139.7.6085 PubMedGoogle Scholar
  76. 76.
    Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ (2002) TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143(3):1108–1118. doi: 10.1210/endo.143.3.8701 PubMedGoogle Scholar
  77. 77.
    Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25(3):255–259PubMedCrossRefGoogle Scholar
  78. 78.
    Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Experiment Med 191(2):275–286CrossRefGoogle Scholar
  79. 79.
    Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000) Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275(7):4858–4864PubMedCrossRefGoogle Scholar
  80. 80.
    Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115(2):282–290. doi: 10.1172/JCI23394 PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Kindle L, Rothe L, Kriss M, Osdoby P, Collin-Osdoby P (2006) Human microvascular endothelial cell activation by IL-1 and TNF-alpha stimulates the adhesion and transendothelial migration of circulating human CD14+ monocytes that develop with RANKL into functional osteoclasts. J Bone Miner Res 21(2):193–206. doi: 10.1359/JBMR.051027 PubMedCrossRefGoogle Scholar
  82. 82.
    Uy HL, Dallas M, Calland JW, Boyce BF, Mundy GR, Roodman GD (1995) Use of an in vivo model to determine the effects of interleukin-1 on cells at different stages in the osteoclast lineage. J Bone Miner Res 10(2):295–301. doi: 10.1002/jbmr.5650100217 PubMedCrossRefGoogle Scholar
  83. 83.
    Jimi E, Nakamura I, Duong LT, Ikebe T, Takahashi N, Rodan GA, Suda T (1999) Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp Cell Res 247(1):84–93. doi: 10.1006/excr.1998.4320 PubMedCrossRefGoogle Scholar
  84. 84.
    Jimi E, Shuto T, Koga T (1995) Macrophage colony-stimulating factor and interleukin-1 alpha maintain the survival of osteoclast-like cells. Endocrinology 136(2):808–811. doi: 10.1210/endo.136.2.7835314 PubMedGoogle Scholar
  85. 85.
    Horowitz MC, Lorenzo J (1996) Local regulators of bone: IL-1, TNF, and lymphotoxin, interferon gamma, IL-8, IL-10, IL-4, the LIF/IL-6 family and additional cytokines. In: Bilezikian LR J, Rodan G (eds) Principals of bone biology. Academic, San DiegoGoogle Scholar
  86. 86.
    Mormann M, Thederan M, Nackchbandi I, Giese T, Wagner C, Hansch GM (2008) Lipopolysaccharides (LPS) induce the differentiation of human monocytes to osteoclasts in a tumour necrosis factor (TNF) alpha-dependent manner: a link between infection and pathological bone resorption. Mol Immunol 45(12):3330–3337. doi: 10.1016/j.molimm.2008.04.022 PubMedCrossRefGoogle Scholar
  87. 87.
    Seta N, Okazaki Y, Kuwana M (2008) Human circulating monocytes can express receptor activator of nuclear factor-kappaB ligand and differentiate into functional osteoclasts without exogenous stimulation. Immunol Cell Biol 86(5):453–459. doi: 10.1038/icb.2008.4 PubMedCrossRefGoogle Scholar
  88. 88.
    Pacifici R, Carano A, Santoro SA, Rifas L, Jeffrey JJ, Malone JD, McCracken R, Avioli LV (1991) Bone matrix constituents stimulate interleukin-1 release from human blood mononuclear cells. J Clin Invest 87(1):221–228. doi: 10.1172/JCI114975 PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Pacifici R, Rifas L, Teitelbaum S, Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV, Peck WA (1987) Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci U S A 84(13):4616–4620PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Pacifici R, Rifas L, McCracken R, Vered I, McMurtry C, Avioli LV, Peck WA (1989) Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release. Proc Natl Acad Sci U S A 86(7):2398–2402PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Manolagas SC, Kousteni S, Jilka RL (2002) Sex steroids and bone. Recent Prog Horm Res 57:385–409PubMedCrossRefGoogle Scholar
  92. 92.
    Syed F, Khosla S (2005) Mechanisms of sex steroid effects on bone. Biochem Biophys Res Commun 328(3):688–696. doi: 10.1016/j.bbrc.2004.11.097 PubMedCrossRefGoogle Scholar
  93. 93.
    Frenkel B, Hong A, Baniwal SK, Coetzee GA, Ohlsson C, Khalid O, Gabet Y (2010) Regulation of adult bone turnover by sex steroids. J Cell Physiol 224(2):305–310. doi: 10.1002/jcp.22159 PubMedCrossRefGoogle Scholar
  94. 94.
    Schurman L, Sedlinsky C, Mangano A, Sen L, Leiderman S, Fernandez G, Theas S, Damilano S, Gurfinkel M, Seilicovich A (2001) Estrogenic status influences nitric oxide-regulated TNF-alpha release from human peripheral blood monocytes. Experiment Clin Endocrinol Diabetes : Off J, German Soc Endocrinol [and] German Diabetes Assoc 109(6):340–344. doi: 10.1055/s-2001-17401 CrossRefGoogle Scholar
  95. 95.
    Morishita M, Miyagi M, Iwamoto Y (1999) Effects of sex hormones on production of interleukin-1 by human peripheral monocytes. J Periodontol 70(7):757–760. doi: 10.1902/jop.1999.70.7.757 PubMedCrossRefGoogle Scholar
  96. 96.
    Lea CK, Sarma U, Flanagan AM (1999) Macrophage colony stimulating-factor transcripts are differentially regulated in rat bone-marrow by gender hormones. Endocrinology 140(1):273–279. doi: 10.1210/endo.140.1.6451 PubMedGoogle Scholar
  97. 97.
    Zhao R (2012) Immune regulation of osteoclast function in postmenopausal osteoporosis: a critical interdisciplinary perspective. Int J Med Sci 9(9):825–832. doi: 10.7150/ijms.5180 PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 130(5):811–823. doi: 10.1016/j.cell.2007.07.025 PubMedCrossRefGoogle Scholar
  99. 99.
    Michael H, Harkonen PL, Vaananen HK, Hentunen TA (2005) Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res 20(12):2224–2232. doi: 10.1359/JBMR.050803 PubMedCrossRefGoogle Scholar
  100. 100.
    Jevon M, Hirayama T, Brown MA, Wass JA, Sabokbar A, Ostelere S, Athenasou NA (2003) Osteoclast formation from circulating precursors in osteoporosis. Scand J Rheumatol 32(2):95–100PubMedCrossRefGoogle Scholar
  101. 101.
    Reddy SV, Menaa C, Singer FR, Demulder A, Roodman GD (1999) Cell biology of Paget’s disease. J Bone Miner Res 14(Suppl 2):3–8PubMedCrossRefGoogle Scholar
  102. 102.
    Neale SD, Smith R, Wass JA, Athanasou NA (2000) Osteoclast differentiation from circulating mononuclear precursors in Paget’s disease is hypersensitive to 1,25-dihydroxyvitamin D(3) and RANKL. Bone 27(3):409–416PubMedCrossRefGoogle Scholar
  103. 103.
    Mabilleau G, Petrova NL, Edmonds ME, Sabokbar A (2008) Increased osteoclastic activity in acute Charcot’s osteoarthropathy: the role of receptor activator of nuclear factor-kappaB ligand. Diabetologia 51(6):1035–1040. doi: 10.1007/s00125-008-0992-1 PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Baumhauer JF, O’Keefe RJ, Schon LC, Pinzur MS (2006) Cytokine-induced osteoclastic bone resorption in Charcot arthropathy: an immunohistochemical study. Foot Ankle Int / Am Orthopaedic Foot Ankle Soc Swiss Foot Ankle Soc 27(10):797–800Google Scholar
  105. 105.
    Deng FY, Lei SF, Zhang Y, Zhang YL, Zheng YP, Zhang LS, Pan R, Wang L, Tian Q, Shen H, Zhao M, Lundberg YW, Liu YZ, Papasian CJ, Deng HW (2011) Peripheral blood monocyte-expressed ANXA2 gene is involved in pathogenesis of osteoporosis in humans. Molecular & cellular proteomics : MCP 10 (11):M111 011700. doi: 10.1074/mcp.M111.011700
  106. 106.
    Deng FY, Zhu W, Zeng Y, Zhang JG, Yu N, Liu YZ, Liu YJ, Tian Q, Deng HW (2014) Is GSN significant for hip BMD in female Caucasians? Bone 63:69–75. doi: 10.1016/j.bone.2014.02.015 PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Chen XD, Xiao P, Lei SF, Liu YZ, Guo YF, Deng FY, Tan LJ, Zhu XZ, Chen FR, Recker RR, Deng HW (2010) Gene expression profiling in monocytes and SNP association suggest the importance of the STAT1 gene for osteoporosis in both Chinese and Caucasians. J Bone Miner Res 25(2):339–355. doi: 10.1359/jbmr.090724 PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Farber CR (2010) Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data. J Bone Miner Res 25(11):2359–2367. doi: 10.1002/jbmr.138 PubMedCrossRefGoogle Scholar
  109. 109.
    Farber CR (2013) Systems-level analysis of genome-wide association data. G3 3(1):119–129. doi: 10.1534/g3.112.004788 PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Lei SF, Wu S, Li LM, Deng FY, Xiao SM, Jiang C, Chen Y, Jiang H, Yang F, Tan LJ, Sun X, Zhu XZ, Liu MY, Liu YZ, Chen XD, Deng HW (2009) An in vivo genome wide gene expression study of circulating monocytes suggested GBP1, STAT1 and CXCL10 as novel risk genes for the differentiation of peak bone mass. Bone 44(5):1010–1014. doi: 10.1016/j.bone.2008.05.016 PubMedCrossRefGoogle Scholar
  111. 111.
    He H, Zhang L, Li J, Wang YP, Zhang JG, Shen J, Guo YF, Deng HW (2014) Integrative analysis of GWASs, human protein interaction, and gene expression identified gene modules associated with BMDs. J Clin Endocrinol Metab 99(11):E2392–E2399. doi: 10.1210/jc.2014-2563 PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Otero K, Turnbull IR, Poliani PL, Vermi W, Cerutti E, Aoshi T, Tassi I, Takai T, Stanley SL, Miller M, Shaw AS, Colonna M (2009) Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat Immunol 10(7):734–743. doi: 10.1038/ni.1744 PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Novack DV, Faccio R (2011) Osteoclast motility: putting the brakes on bone resorption. Ageing Res Rev 10(1):54–61. doi: 10.1016/j.arr.2009.09.005 PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Fuller K, Owens JM, Jagger CJ, Wilson A, Moss R, Chambers TJ (1993) Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Experiment Med 178(5):1733–1744CrossRefGoogle Scholar
  115. 115.
    Fuller K, Wong B, Fox S, Choi Y, Chambers TJ (1998) TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Experiment Med 188(5):997–1001CrossRefGoogle Scholar
  116. 116.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176PubMedCrossRefGoogle Scholar
  117. 117.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95(7):3597–3602PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Lee YM, Fujikado N, Manaka H, Yasuda H, Iwakura Y (2010) IL-1 plays an important role in the bone metabolism under physiological conditions. Int Immunol 22(10):805–816. doi: 10.1093/intimm/dxq431 PubMedCrossRefGoogle Scholar
  119. 119.
    Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S (2008) Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem 283(17):11535–11540. doi: 10.1074/jbc.M607999200 PubMedCrossRefGoogle Scholar
  120. 120.
    Duplomb L, Baud’huin M, Charrier C, Berreur M, Trichet V, Blanchard F, Heymann D (2008) Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology 149(7):3688–3697. doi: 10.1210/en.2007-1719 PubMedCrossRefGoogle Scholar
  121. 121.
    Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T, Martin TJ, Gillespie MT (2001) Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res 16(10):1787–1794. doi: 10.1359/jbmr.2001.16.10.1787 PubMedCrossRefGoogle Scholar
  122. 122.
    Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ (2000) A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci 113(Pt 13):2445–2453PubMedGoogle Scholar
  123. 123.
    Ji JD, Park-Min KH, Shen Z, Fajardo RJ, Goldring SR, McHugh KP, Ivashkiv LB (2009) Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors. J Immunol 183(11):7223–7233. doi: 10.4049/jimmunol.0900072 PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Kohara H, Kitaura H, Fujimura Y, Yoshimatsu M, Morita Y, Eguchi T, Masuyama R, Yoshida N (2011) IFN-gamma directly inhibits TNF-alpha-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions. Immunol Lett 137(1–2):53–61. doi: 10.1016/j.imlet.2011.02.017 PubMedCrossRefGoogle Scholar
  125. 125.
    Cao Z, Moore BT, Wang Y, Peng XH, Lappe JM, Recker RR, Xiao P (2014) MiR-422a as a potential cellular microRNA biomarker for postmenopausal osteoporosis. PLoS One 9(5):e97098. doi: 10.1371/journal.pone.0097098 PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Nose M, Yamazaki H, Hagino H, Morio Y, Hayashi S, Teshima R (2009) Comparison of osteoclast precursors in peripheral blood mononuclear cells from rheumatoid arthritis and osteoporosis patients. J Bone Miner Metab 27(1):57–65. doi: 10.1007/s00774-008-0011-0 PubMedCrossRefGoogle Scholar
  127. 127.
    Kim SJ, Chen Z, Chamberlain ND, Essani AB, Volin MV, Amin MA, Volkov S, Gravallese EM, Arami S, Swedler W, Lane NE, Mehta A, Sweiss N, Shahrara S (2014) Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J Immunol 193(8):3902–3913. doi: 10.4049/jimmunol.1302998 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Shibuya H, Nakasa T, Adachi N, Nagata Y, Ishikawa M, Deie M, Suzuki O, Ochi M (2013) Overexpression of microRNA-223 in rheumatoid arthritis synovium controls osteoclast differentiation. Modern Rheumatol / Jap Rheumat Assoc 23(4):674–685. doi: 10.1007/s10165-012-0710-1 CrossRefGoogle Scholar
  129. 129.
    Kwok SK, Cho ML, Park MK, Oh HJ, Park JS, Her YM, Lee SY, Youn J, Ju JH, Park KS, Kim SI, Kim HY, Park SH (2012) Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum 64(3):740–751. doi: 10.1002/art.33390 PubMedCrossRefGoogle Scholar
  130. 130.
    Soderstrom K, Stein E, Colmenero P, Purath U, Muller-Ladner U, de Matos CT, Tarner IH, Robinson WH, Engleman EG (2010) Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A 107(29):13028–13033. doi: 10.1073/pnas.1000546107 PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Nagy ZB, Gergely P, Donath J, Borgulya G, Csanad M, Poor G (2008) Gene expression profiling in Paget’s disease of bone: upregulation of interferon signaling pathways in pagetic monocytes and lymphocytes. J Bone Miner Res 23(2):253–259. doi: 10.1359/jbmr.071021 PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2015

Authors and Affiliations

  1. 1.Center for Bioinformatics and Genomics, Department of Biostatistics and BioinformaticsTulane UniversityNew OrleansUSA
  2. 2.Cell and Molecular Biology DepartmentTulane UniversityNew OrleansUSA
  3. 3.Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical MedicineTulane UniversityNew OrleansUSA

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