The Pysiology of Bone Turnover

  • R. Pacifici


Bone is remodeled by a sequence of cellular events which occur in discrete locations known as bone remodeling units. This process begins with the activation of mature osteoclasts adhering to the bone surfaces usually covered by lining osteoblasts and with an expansion of the osteoclastic pool. Through the interaction of preexisting and newly formed osteoclasts with osteoblasts, resorption is initiated in discrete areas. This phase, which lasts 2–4 weeks, leads to the formation of focal areas of bone resorption which reach a depth of about 30 μm [1]. Toward the end of the resorption phase mononuclear cells, an important source of cytokines, are typically found at the bottom of the resorption cavity [1]. The transition from resorption to formation is called reversal. This phase is characterized by the accumulation of osteoblast precursors and of a thin layer of inorganic matrix, known as cement line, at the bottom of the resorption pit. The cement line is rich in osteopontin, a RGD-rich protein which may be involved in signaling the cessation of osteoclastic activity. This is followed by the replacement of the removed bone by osteoblasts which accumulate at the base of the resorption lacunae and subsequently fill in the resorption cavity with newly formed bone.


Bone Loss Bone Resorption Stromal Cell Bone Turnover Osteoclast Formation 
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  1. 1.
    Rodan GA (1996) Coupling of bone resorption and formation during bone remodeling. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic, San Diego, pp 289–299Google Scholar
  2. 2.
    Chambers TJ (1980) The cellular basis for bone resorption. Clin Orthop Relat Res 151: 283–293PubMedGoogle Scholar
  3. 3.
    Roodman GD (1996) Advances in bone biology: the osteoclast. Endocr Rev 17: 308–332PubMedGoogle Scholar
  4. 4.
    Suda T, Udagawa N, Nakamura I, Miyaura C, Takahashi N (1995) Modulation of osteoclast differentiation by local factors. Bone 17: S87 - S91Google Scholar
  5. 5.
    Gowen M, Wood DD, Ihrie EJ, McGuire MKB, Russell RGG (1983) An interleukin-i-like factor stimulates bone resorption in vitro. Nature 306: 378–380PubMedGoogle Scholar
  6. 6.
    Lorenzo JA, Sousa SL, Alander C, Raisz LG, Dinarello CA (1987) Comparison of the bone-resorbing activity in the supernatants from phytohemaglutinin-stimulated human peripheral blood mononuclear cells with that of cytokines through the use of an antiserum to interleukin 1. Endocrinology 121: 1164–1170PubMedGoogle Scholar
  7. 7.
    Gowen M, Wood DD, Russell RGG (1985) Stimulation of the proliferation of human bone cells in vitro by human monocyte products with interleukin-1 activity. J Clin Invest 75: 1223–1229PubMedGoogle Scholar
  8. 8.
    Canalis E (1986) Interleukin-1 has independent effects on deoxyribonucleic acid and collagen synthesis in cultures of rat calvariae. Endocrinology 118: 74–81PubMedGoogle Scholar
  9. 9.
    Stashenko P, Dewhirst FE, Rooney ML, Desjardins LA, Heeley JD (1987) Interleukin-i(3 is a potent inhibitor of bone formation in vitro. J Bone Miner Res 2: 559–565PubMedGoogle Scholar
  10. 10.
    Girasole G, Jilka RL, Passeri G, Boswell S, Boder G, Williams DC, Manolagas SC (1992) 17β-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 89: 883–891PubMedGoogle Scholar
  11. 11.
    Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257: 88–91PubMedGoogle Scholar
  12. 12.
    Passeri G, Girasole G, Jilka RL, Manolagas SC (1993) Increased interleukin6 production by murine bone marrow and bone cells after estrogen withdrawal. Endocrinology 133: 822–828PubMedGoogle Scholar
  13. 13.
    Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR (1986) Stimulation of bone resorption and inhibition of bone formation in vitro by human tumor necrosis factor. Nature 319: 516–518PubMedGoogle Scholar
  14. 14.
    Thomson BM, Mundy GR, Chambers TJ (1987) Tumor necrosis factor a and ß induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 138: 775–779PubMedGoogle Scholar
  15. 15.
    Takahashi N, Udagawa N, Akatsu T, Tanaka H, Shionome M, Suda T (1991) Role of colony-stimulating factors in osteoclast development. J Bone Miner Res 6: 977–985PubMedGoogle Scholar
  16. 16.
    Tanaka S, Takahashi N, Udagawa N, Tamura T, Akatsu T, Stanley ER, Kurokawa T, Suda T (1993) Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91: 257–263PubMedGoogle Scholar
  17. 17.
    Schneider GB, Relfson M (1989) Pluripotent hemopoietic stem cells give rise to osteoclasts in vitro: effect of rGM-CSF. Bone Miner 5: 129–138PubMedGoogle Scholar
  18. 18.
    Kurihara N, Suda T, Miura Y, Nakauchi H, Kodama H, Hiura K, Hakeda Y, Kumegawa M (1989) Generation of osteoclasts from isolated hematopoietic progenitor cells. Blood 74: 1295–1302PubMedGoogle Scholar
  19. 19.
    Nguyen L, Dewhirst FE, Hauschka PV, Stashenko P (1991) Interleukin-113 stimulates bone resorption and inhibits bone formation in vivo. Lymphokine Cytokine Res 10: 15–21PubMedGoogle Scholar
  20. 20.
    Boyce BF, Aufdemorte TB, Garrett IR, Yates AJP, Mundy GR (1989) Effects of interleukin-1 on bone turnover in normal mice. Endocrinology 125: 1142–1150PubMedGoogle Scholar
  21. 21.
    Sabatini, M, Boyce B,Aufdemorte T, Bonewald L, Mundy GR (1988) Infusions of recombinant human interleukin 1 alpha and beta cause hypercalcemia in normal mice. Proc Natl Acad Sci USA 85: 5235–5239Google Scholar
  22. 22.
    Johnson RA, Boyce BF, Mundy GR, Roodman GD (1989) Tumors producing human tumor necrosis factor induce hypercalcemia and osteoclastic bone resorption in nude mice. Endocrinology 124: 1424–1427PubMedGoogle Scholar
  23. 23.
    Hughes DE, Jilka RL, Manolagas S, Dallas SL, Bonewald LF, Mundy GR, Boyce BF (1995) Sex steroids promote osteoclast apoptosis in vitro and in vivo. J Bone Miner Res 10: 48 (abstract)Google Scholar
  24. 24.
    Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD (1989) Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclast-like cells in vitro. J Bone Miner Res 4: 113–118PubMedGoogle Scholar
  25. 25.
    Suda T, Takahashi N, Martin TJ (1992) Modulation of osteoclast differentiation. Endocr Rev 13: 66–80PubMedGoogle Scholar
  26. 26.
    Srivastava S, McHugh K, Kimble R, Ross FP, Pacifici R (1995) Estrogen down regulates the expression of M-CSF mRNA in bone marrow stromal cells by stimulating the production of the transcription factor EGR-1. J Bone Miner Res 10 [Suppl 1]: S18Google Scholar
  27. 27.
    Carter DB, Deibel MR Jr, Dunn C J, Tomich C-S C, Laborde AL, Slightom JL, Berger AE, Bienkowski MJ, Sun FF, McEwan RN, Harris PKW, Yem AW, Waszak GA, Chosay JG, Sieu LC, Hardee MM, Zurcher-Neely HA, Reardon IM, Heinrikson RL, Truesdell SE, Shelly JA, Eessalu TE, Taylor BM, Tracey DE (1990) Purification, cloning, expression and biological characterization of an interleukin-i receptor antagonist protein. Nature 344: 633–638PubMedGoogle Scholar
  28. 28.
    Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC (1990) Interleukin-1 receptor antagonist activity of a human interleukin-i inhibitor. Nature 343: 336–340PubMedGoogle Scholar
  29. 29.
    Arend WP (1991) Interleukin 1 receptor antagonist: a new member of the interleukin 1 family. J Clin Invest 88: 1445–1451PubMedGoogle Scholar
  30. 30.
    Dinarello CA (1991) Interleukin-1 and interleukin-i antagonism. Blood 77: 1627–1652PubMedGoogle Scholar
  31. 31.
    Seckinger P, Klein-Nulend J, Alander C, Thompson RC, Dayer J-M, Raisz LG (1990) Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol 145: 4181–4184PubMedGoogle Scholar
  32. 32.
    Thompson RC, Dripps DJ, Eisenberg SP (1991) IL-ira: properties and uses of an interleukin-i receptor antagonist. Agents Actions [Suppl] 35: 41–49Google Scholar
  33. 33.
    Symons JA, Young PR, Duff GW (1995) Soluble type iI interleukin 1 (il-i) receptor binds and blocks processing of il-i-beta precursor and loses affinity for it-1 receptor antagonist. Proc Natl Acad Sci USA 92: 1714–1718PubMedGoogle Scholar
  34. 34.
    Burger D, Chicheportiche R, Giri JG, Dayer JM (1995) The inhibitory activity of human interleukin-i receptor anatgonist is enhanced by type II interleukin-I soluble receptor and hindered by type I interleukin-i soluble receptor. J Clin Invest 96: 38–41PubMedGoogle Scholar
  35. 35.
    Hansen MB, Svenson M, Bendtzen K (1990) Human anti-interleukin 1a antibodies. Immunol Lett 30: 133–140Google Scholar
  36. 36.
    Simon JA, Eastgate JA, Duff GW (1990) A soluble binding protein specific for interleukin 1ß is produced by activated mononuclear cells. Cytokine 2: 190–198Google Scholar
  37. 37.
    Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV (1991) Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci 88: 5134–5138PubMedGoogle Scholar
  38. 38.
    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 I release. Proc Natl Acad Sci USA 86: 2398–2402PubMedGoogle Scholar
  39. 39.
    Pioli G, Basini G, Pedrazzoni M, Musetti G, Ulietti V, Bresciani D, Villa P, Bac-ci A, Hughes D, Russell G, Passeri M (1992) Spontaneous release of interleukin-1 and interleukin-6 by peripheral blood monocytes after ovariectomy. Clin Sci 83: 503–507PubMedGoogle Scholar
  40. 40.
    Ralston SH, Russell RGG, Gowen M (1990) Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women. J Bone Miner Res 5: 983–988PubMedGoogle Scholar
  41. 41.
    Fiore CE, Falcidia E, Foti R, Motta M, Tamburino C (1993) Differences in the time course of the effects of oophorectomy in women on parameters of bone metabolism and interleukin-1 levels in the circulation. Bone Miner 20: 79–85PubMedGoogle Scholar
  42. 42.
    Matsuda T, Matsui K, Shimakoshi Y, Aida Y, Hukuda S (1991) 1-Hydroxyethilidene-1, 1-bisphosphonate decreases the postovariectomy-enhanced interleukin-1 production by peritoneal macrophages in adult rats. Calcif Tissue Int 49: 403–406PubMedGoogle Scholar
  43. 43.
    Kaneki M, Nakamura T, Masuyama A, Chen JT, Seimiya Y, Shiraki M, Ouchi Y, Orimo H (1991) The effect of menopause on IL-1 and IL-6 release from peripheral blood monocytes. J Bone Miner Res 6: 76 (abstract)Google Scholar
  44. 44.
    Zarrabeitia MT, Riancho JA, Amado JA, Napal J, Gonzales-Macias J (1991) Cytokine production by blood cells in postmenopausal osteoporosis. Bone Miner 14: 161–167PubMedGoogle Scholar
  45. 45.
    Hustmyer FG, Walker E, Yu XP, Girasole G, Sakagami Y, Peacock M, Manolagas SC (1993) Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis. J Bone Miner Res 8: 51–59PubMedGoogle Scholar
  46. 46.
    Udagawa N, Takahashi N, Katagiri T, Tamura T, Wada S, Findlay DM, Martin TJ, Hirota H, Tada T, Kishimoto T, Suda T (1995) Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med 182: 1461–1468PubMedGoogle Scholar
  47. 47.
    Kurihara N, Civin C, Roodman GD (1991) Osteotropic factor responsiveness of highly purified populations of early and late precursors for human multi-nucleated cells expressing the osteoclast phenotype. J Bone Miner Res 6: 257–261PubMedGoogle Scholar
  48. 48.
    Roodman GD (1992) Interleukin-6: an osteotropic factor? J Bone Miner Res 7: 475–478PubMedGoogle Scholar
  49. 49.
    Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, OhsugiY, Kumaki K, Taga T, Kishimoto T, Suda T (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin-6. Proc Natl Acad Sci USA 90: 11924–11928Google Scholar
  50. 50.
    Lowik CWGM, van der Pluijm G, Bloys H, Hoekman K, Bijvoet OL, Aarden LA, Papapoulos SE (1989) Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate IL-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis. Biochem Biophys Res Commun 162: 1546–1552PubMedGoogle Scholar
  51. 51.
    Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R (1994) Interleukin1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 94: 2397–2406PubMedGoogle Scholar
  52. 52.
    Kania DM, Binkley N, Checovich M, Havighurst T, Schilling M, Ershler WB (1995) Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J Am Geriatr Soc 43: 236–239PubMedGoogle Scholar
  53. 53.
    Woodroofe C, Muller W, Ruther U (1992) Long-term consequences of interleukin-6 overexpression in transgenic mice. DNA Cell Biol 11: 587–592PubMedGoogle Scholar
  54. 54.
    Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano T, Kishimoto T (1989) IgGi plasmacytosis in interleukin-6 transgenic mice. Proc Natl Acad Sci USA 86: 7547–7551PubMedGoogle Scholar
  55. 55.
    Felix R, Cecchini MG, Fleish H (1990) Macrophage colony-stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology 127: 2592–2597PubMedGoogle Scholar
  56. 56.
    Yoshida HS, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Schultz LD (1990) The murine mutation osteopetrosis is in the coding region of macrophage colony stimulating factor gene. Nature 345: 442–444PubMedGoogle Scholar
  57. 57.
    Macdonald BR, Mundy GR, Clark S, Wang EA, Kuehl TJ, Stanley ER, Rood-man GD (1986) Effects of human recombinant CSF-GM and highly purified CSF-i on the formation of multi-nucleated cells with osteoclast characteristics in long-term bone marrow cultures. J Bone Miner Res 1: 227–232PubMedGoogle Scholar
  58. 58.
    Lorenzo JA, Souss SL, Fonseca JM, Hock JM, Medlock ES (1987) Colony-stimulating factors regulate the development of mu1tinucleated osteoclasts from recently replicated cells in vitro. J Clin Invest 160: 164–160Google Scholar
  59. 59.
    Kurihara N, Chenu C, Miller M, Civin C, Roodman GD (1990) Identification of committed mononuclear precursors for osteoclast-like cells formed in long term human marrow cultures. Endocrinology 126: 2733–2741PubMedGoogle Scholar
  60. 60.
    Matayoshi A, Brown C, DiPersio J, Haugh J, Abu-Amer Y, Liapis H, Kuestner R, Pacifici R (1996) Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells. Proc Natl Acad Sci USA 93: 10785–10790PubMedGoogle Scholar
  61. 61.
    Fibbe WE, Van Damme J, Billiau A, Goselink HM, Vogt PJ, Van Eeden PR, Altroch BW, Falkenburg JHF (1988) Intereleukin-1 induces human marrow stromal cells in long term cultures to produce G-CSF and M-CSF. Blood 71: 431–435Google Scholar
  62. 62.
    Rifas L, Kenney JS, Marcelli M, Pacifici R, Dawson LL, Cheng S, Avioli LV (1995) Production of interleukin-6 in human osteoblasts and human bone marrow stromal cells: evidence that induction by interleukin-i and tumor necrosis factor-a is not regulated by ovarian steroids. Endocrinology 136: 4056–4067 (abstract)PubMedGoogle Scholar
  63. 63.
    Pacifici R, Carano A, Santoro SA, Rifas L, Jeffrey JJ, Malone JD, McCracken R, Avioli LV (1991) Bone matrix constituents stimulate interleukin-i release from human blood mononuclear cells. J Clin Invest 87: 221–228PubMedGoogle Scholar
  64. 64.
    Hemler ME (1988) Adhesive protein receptors on hematopoietic cells. Immunol Today 9: 109–113PubMedGoogle Scholar
  65. 65.
    Pacifici R, Basilico C, Roman J, Zutter MM, Santoro SA, McCracken R (1992) Collagen-induced release of interleukin 1 from human blood mononuclear cells Potentiation by fibronectin binding to the alpha 5 beta 1 integrin. J Clin Invest 89: 61–67PubMedGoogle Scholar
  66. 66.
    Pacifici R, Roman J, Kimble R, Civitelli R, Brownfield CM, Bizzarri C (1994) Ligand binding to monocyte a5131 integrin activates the a2(31 receptor via the a5 subunit cytoplasmatic domain and protein kinase C. J.Immuno1 153: 2222–2233Google Scholar
  67. 67.
    Hynes RO (1986) Fibronectins. Sci Am 254: 42–51Google Scholar
  68. 68.
    Oldberg A, Franzen A, Heinegard D (1986) Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell binding sequence. Proc Natl Acad Sci USA 83: 8819–8823PubMedGoogle Scholar
  69. 69.
    Lian JB, Dunn K, Key LL Jr (1986) In vitro degradation of bone particles by human monocytes is decreased with the depletion of the vitamin K-dependent bone protein from the matrix. Endocrinology 118: 1636–1642PubMedGoogle Scholar
  70. 70.
    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 USA 84: 4616–4620PubMedGoogle Scholar
  71. 71.
    Pacifici R, Brown C, Rifas L, Avioli LV (1990) TNFa and GM-CSF secretion from human blood monocytes: effect of menopause and estrogen replacement. J Bone Miner Res 5: 145 (abstract)Google Scholar
  72. 72.
    Schulof RS, Nayor PH, Sztein MB, Goldstein AL (1987) Thymic physiology and biochemistry. Adv Clin Chem 26: 203–292PubMedGoogle Scholar
  73. 73.
    Paavonen T, Andersson LC, Adlercreutz H (1981) Sex hormone regulation of in vitro immune response. Estradiol enhances human B cell maturation via inhibition of suppressor T cells in pokeweed mitogen-stimulated cultures. J Exp Med 154: 1935–1945PubMedGoogle Scholar
  74. 74.
    Polla BS, Healy AM, Byrne M, Krane SM (1987) 1,25-Dihydroxyvitamin D3 induces collagen binding to the human monocyte line U937. J Clin Invest 80: 962–969PubMedGoogle Scholar
  75. 75.
    Dinarello CL, Ikejima T, Warner SJC, Orencole SF, Lonneman G, Cannon JG, Libby P (1987) Interleukin-1 induces interleukin-i. I. Induction of circulating interleukin-i in rabbits in vivo and in human mononuclear cells in vitro. J Immunol 139: 1902–1908PubMedGoogle Scholar
  76. 76.
    Oursler MJ, Cortese C, Keeting P, Anderson MA, Bonde SK, Riggs BL, Spelsberg TC (1991) Modulation of transforming growth factor-beta production in normal human osteoblast-like cells by 17 beta-estradiol and parathyroid hormone. Endocrinology 129: 3313–3320PubMedGoogle Scholar
  77. 77.
    Turner RT, Riggs BL, Spelsberg TC (1994) Skeletal effects of estrogen. Endocr Rev 15: 275–300PubMedGoogle Scholar
  78. 78.
    Pacifici R, Vannice JL, Rifas L, Kimble RB (1993) Monocytic secretion of interleukin-1 receptor antagonist in normal and osteoporotic women: effect of menopause and estrogen/progesterone therapy. J Clin Endocrinol Metab 77: 1135–1141PubMedGoogle Scholar
  79. 79.
    Tan P, Shore A, Leary P, Keystone EC (1984) Interleukin abnormalities in recently active rheumatoid arthritis. J Rheumato 111:593–596Google Scholar
  80. 80.
    Fakih H, Baggett B, Holtz G, Tsang K-Y, Lee JC, Williamson HO (1987) Interleukin 1: a possible role in the infertility associated with endometriosis. Fertil Steril 47: 213–217PubMedGoogle Scholar
  81. 81.
    Pacifici R, Rothstein M, Rifas L, Lau KH, Baylink DJ, Avioli LV, Hruska K (1990) Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria. J Clin Endocrinol Metab 71: 138–145PubMedGoogle Scholar
  82. 82.
    Sambrook PN, Reeve J (1988) Bone disease in rheumatoid arthritis. Clin Sci 74: 225–230PubMedGoogle Scholar
  83. 83.
    Comite F, Delman M, Hutchinson-Williams K, DeCherney AH, Jensen P (1989) Reduced bone mass in reproductive-aged women with endometriosis. J Clin Endocrinol Metab 69: 837–842PubMedGoogle Scholar
  84. 84.
    Pacifici R (1997) Idiopathic hypercalciuria and osteoporosis. Distinct clinical manifestations of increased cytokine-induced bone resorption? J Clin Endocrinol Metab 82: 29–31PubMedGoogle Scholar
  85. 85.
    Ralston SH (1994) Analysis of gene expression in human bone biopsies by polymerase chain reaction: evidence for enhanced cytokine expression in postmenopausal osteoporosis. J Bone Miner Res 9: 883–890PubMedGoogle Scholar
  86. 86.
    Cohen-Solal ME, Graulet AM, Denne MA, Gueris J, Baylink D, de Vernejoul MC (1993) Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: Involvement of cytokines. J Clin Endocrinol Metab 77: 1648–1653PubMedGoogle Scholar
  87. 87.
    Pottratz ST, Bellido T, Mocharia H, Crabb D, Manolagas S (1994) 143-Estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest 93: 944–950PubMedGoogle Scholar
  88. 88.
    Ray A, Prefontaine KE, Ray P (1994) Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem 269: 12940–12946PubMedGoogle Scholar
  89. 89.
    Stein B, Yang MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa-B and C/EBP beta. Mol Cell Biol 15: 4971–4979PubMedGoogle Scholar
  90. 90.
    Rickard D, Russell G, Gowen M (1992) Oestradiol inhibits the release of tumour necrosis factor but not interleukin 6 from adult human osteoblasts in vitro. Osteoporosis Int 2: 94–102Google Scholar
  91. 91.
    Chaudhary LR, Spelsberg TC, Riggs BL (1992) Production of various cytokines by normal human osteoblast-like cells in response to interleukin-1ß and tumor necrosis factor-a: lack of regulation by i713-estradiol. Endocrinology 130: 2528–2534PubMedGoogle Scholar
  92. 92.
    Girasole G, Pedrazzoni M, Giuliani N, Passeri G, Passeri M (1995) Increased serum soluble interleukin-6 receptor levels are induced by ovariectomy, prevented by estrogen replacement and reversed by alendronate administration. J Bone Miner Res 10: A86Google Scholar
  93. 93.
    McKane R, Khosla S, Peterson J, Egan K, Riggs BL (1993) Effect of age and menopause on serum interleukin-1ß and intereleukin-6- levels in women. J Bone Miner Res 8: 162AGoogle Scholar
  94. 94.
    Khosla S, Peterson JM, Egan K, Jones JD, Riggs LB (1994) Circulating cytokine levels in osteoporotic and normal women. J Clin Endocrinol Metab 79: 707–711PubMedGoogle Scholar
  95. 95.
    Kimble RB, Matayoshi AB, Vannice JL, Kung VT, Williams C, Pacifici R (1995) Simultaneous block of interleukin-i and tumor necrosis factor is required to completely prevent bone loss in the early post-ovariectomy period. Endocrinology 136: 3054–3061PubMedGoogle Scholar
  96. 96.
    Kimble RB, Vannice JL, Bloedow DC, Thompson RC, Hopfer W, Kung V, Brownfield C, Pacifici R (1994) Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest 93: 1959–1967PubMedGoogle Scholar
  97. 97.
    Kimble RB, Matayoshi AB,Vannice JL, Pacifici R (1994) Long-term treatment with IL-1 receptor antagonist (IL-ira) blocks bone loss in ovariectomized rats. J Bone Miner Res 9: (in press) (abstract)Google Scholar
  98. 98.
    Kimble RB, Bain SD, Pacifici R (1997) The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12: 935–941PubMedGoogle Scholar
  99. 99.
    Ammann P, Garcia I, Rizzoli R, Meyer JM, Vassali P, Bonjour JP (1995) Trans-genic mice expressing high levels of soluble tumor necrosis factor receptor]. fusion protein are protected from bone loss caused by estrogen deficiency. J Bone Miner Res 10 [Suppl 1]: 1 (abstract)Google Scholar
  100. 100.
    Wronski TJ, Dann LM, Qi H, Yen CF (1993) Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats. Calcif Tissue Int 53: 210–216PubMedGoogle Scholar
  101. 101.
    Kimble RB, Vannice JL, Brownfield C, Pacifici R (1994) Persistent bone-sparing effect of interleukin-i receptor antagonist: a hypothesis on the role of IL-1 in ovariectomy induced bone loss. Calcif Tissue Int 55: 260–265PubMedGoogle Scholar
  102. 102.
    Routtenberg A (1995) Knockout mouse fault lines (letter). Nature 374: 314–315PubMedGoogle Scholar
  103. 103.
    Pacifici R (1992) Is there a causal role of IL-1 in postmenopausal bone loss? Calcif Tissue Int 50: 295–299PubMedGoogle Scholar
  104. 104.
    Bellido T, Girasole G, Passeri G, Yu X P, Mocharla A, Jilka RL, Notides A, Manolagas SC (1993) Demonstration of estrogen and vitamin D receptors in bone marrow-derived stromal cells: up-regulation of the estrogen receptor by 1,25-dihydroxyvitamin-D3. Endocrinology 133: 553–562PubMedGoogle Scholar
  105. 105.
    Oursler MJ, Osdoby P, Pyfferoen J, Riggs BL, Spelsberg TC (1991) Avian osteoclasts as estrogen target cells. Proc Natl Acad Sci USA 88: 6613–6617PubMedGoogle Scholar
  106. 106.
    Oursler MJ, Pederson L, Pyfferoen J, Osdoby P, Fitzpatrick L, Spelsberg TC (1993) Estrogen modulation of avian osteoclast lysosomal gene expression. Endocrinology 132: 1373–1380PubMedGoogle Scholar
  107. 107.
    Horowitz M (1993) Cytokines and estrogen in bone: anti-osteoporotic effects. Science 260: 626–627PubMedGoogle Scholar
  108. 108.
    Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R (1996) Estrogen deficiency increases the ability of stromal cells to support osteoclastogenesis via an IL-i and TNF mediated stimulation of M-CSF production. J Biol Chem 271: 28890–28897PubMedGoogle Scholar
  109. 109.
    Bellido T, Girasole G, Passeri G, Jilka RL, Manolagas SC (1994) gp130 mRNA is increased by PTH and cytokines and decreased by sex steroids in stromal/osteoblastic cells. J Bone Miner Res 9:12 (abstract)Google Scholar

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  • R. Pacifici

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