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Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride

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Micromolar concentrations of aluminum sulfate consistently stimulated [3H]thymidine incorporation into DNA and increased cellular alkaline phosphatase activity (an osteoblastic differentiation marker) in osteoblast-line cells of chicken and human. The stimulations were highly reproducible, and were biphasic and dose-dependent with the maximal stimulatory dose varied from experiment to experiment. The mitogenic doses of aluminum ion also stimulated collagen synthesis in cultured human osteosarcoma TE-85 cells, suggesting that aluminum ion might stimulate bone formation in vitro. The effects of mitogenic doses of aluminum ion on basal osteocalcin secretion by normal human osteoblasts could not be determined since there was little, if any, basal secretion of osteocalcin by these cells. 1,25 Dihydroxyvitamin D3 significantly stimulated the secretion of osteocalcin and the specific activity of cellular alkaline phosphatase in the human osteoblasts. Although mitogenic concentrations of aluminum ion potentiated the 1,25 dihydroxyvitamin D3-dependent stimulation of osteocalcin secretion, they significantly inhibited the hormone-mediated activation of cellular alkaline phosphatase activity. Mitogenic concentrations of aluminum ion did not stimulate cAMP production in human osteosarcoma TE85 cells, indicating that the mechanism of aluminum ion does not involve cAMP. The mitogenic activity of aluminum ion is different from that of fluoride because (a) unlike fluoride, its mitogenic activity was unaffected by culture medium changes; (b) unlike fluoride, its mitogenic activity was nonspecific for bone cells; and (c) aluminum ion interacted with fluoride on the stimulation of the proliferation of osteoblastic-line cells, and did not share the same rate-limiting step(s) as that of fluoride. PTH interacted with and potentiated the bone cell mitogenic activity of aluminum ion, and thereby is consistent with the possibility that the in vivo osteogenic actions of aluminum ion might depend on PTH. In summary, low concentrations of aluminum ion could act directly on osteoblasts to stimulate their proliferation and differentiation by a mechanism that is different from fluoride.

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  1. 1.

    Ward MK, Feest TG, Ellis HA, Parkinson IS, Kerr DNS: Osteomalacic dialysis osteodystrophy: evidence for a water-borne etiological agent, probably aluminum. Lancet 1: 841–845, 1978

  2. 2.

    Boyce BF, Fell GS, Elder HY, Junor BJ, Elliot HL, Beastall G, Fogelman I, Boyle IT: Hypercalcaemic osteomalacia due to aluminum toxicity. Lancet 2: 1009–1013, 1982

  3. 3.

    Platts MM, Goode GC, Hislop LS: Composition of the domestic water supply and the incidence of fractures and encephalopathy in patients on home dialysis. Br Med J 2: 657–660, 1977

  4. 4.

    Blumenthal NC, Posner AS: In vitro model of aluminum-induced osteomalacia: inhibition of hydroxyapatite formation and growth. Calcif Tissue Int 36: 439–441, 1984

  5. 5.

    Maloney NA, Ott SM, Alfrey AC, Miller NL, Coburn JW, Sherrard DJ: Histological quantitation of aluminum in iliac bone from patients with renal failure. J Lab Clin Med 99: 206–216, 1982

  6. 6.

    Hodsman AB, Sherrard DJ, Alfrey AC, Ott S, Brickman AS, Miller NL, Maloney NA, Coburn JW: Bone aluminum and histomorphometric features of renal osteodystropy. J Clin Endocrinol Metab 54: 539–546, 1982

  7. 7.

    Dunstan CR, Evans RA, Hills E, Wong SVP, Alfrey AC: Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure. Calcif Tissue Int 36: 133–138, 1984

  8. 8.

    Galceran T, Finch J, Bergfeld M, Coburn J, Martin K, Teitelbaum S, Slatopolsky E: Biological effects of aluminum on normal dogs: studies on the isolated perfused bone. Endocrinology 121: 406–413, 1987

  9. 9.

    Quarles LD, Gitelman HJ, Drezner MK: Induction of the de novo bone formation in the beagle. A novel effect of aluminum. J Clin Invest 81: 1056–1066, 1988

  10. 10.

    Quarles LD, Murphy G, Vogler JB, Drezner MK: Aluminum-induce neo-osteogenesis: a generalized process affecting trabecular network in the axial skeleton. J Bone Min Res 5: 625–635, 1990

  11. 11.

    Quarles LD, Gitelman HJ, Drezner MK: Aluminum-induced de novo bone formation in the Beagle. A parathyroid hormone-dependent event. J Clin Invest 83: 1644–1650, 1989

  12. 12.

    Jones TR, Antonetti DL, Reid TW: Aluminum ions stimulate mitosis in murine cells in tissue culture. J Cell Biochem 30: 31–39, 1986

  13. 13.

    Smith JB: Aluminum ions stimulate DNA synthesis in quiescent cultures of swiss 3T3 cells. J Cell Physiol 118: 298–304, 1984

  14. 14.

    Puzas JE, Drivdahl RH, Howard GA, Baylink DJ: Endogenous inhibitor of bone cell proliferation. Proc Soc Exp Biol Med 166: 113–122, 1981

  15. 15.

    Wergedal JE, Baylink DJ: Characterization of cells isolated and cultured from human bone. Proc Soc Expl Biol Med 176: 27–31, 1984

  16. 16.

    Wergedal JE, Mohan S, Lundy M, Baylink DJ: Skeletal growth factor and other growth factors known to be present in bone matrix stimulate proliferation and protein synthesis in human bone cells. J Bone Min Res 5: 179–186, 1990

  17. 17.

    Rhim JS, Cho HY, Huebner RJ: Non-producer human cells induced by murine sarcoma virus. Int J Cancer 15: 23–29, 1975

  18. 18.

    Gospodarowicz D, Bialecki H, Greenburg G: Purification of the fibroblast growth factor activity from bovine brain. J Biol Chem 253: 3736–3741, 1978

  19. 19.

    Lau KHW, Lee MY, Linkhart TA, Mohan S, Vermeiden J, Liu CC, Baylink DJ: A mouse tumor-derived osteolytic factor stimulates bone resorption by a mechanism involving local prostaglandins production in bone. Biochim Biophys Acta 840: 56–68, 1985

  20. 20.

    Farley JR, Fitzsimmons R, Talyor AK, Jorch UM, Lau KHW: Direct effects of ethanol on bone resorption and formation in vitro. Arch Biochem Biophys 238: 305–314, 1985

  21. 21.

    Farley JR, Jorch UM: Differential effects of phospholipids on skeletal alkaline phosphatase activity in extracts, in situ and in circulation. Arch Biochem Biophys 221: 477–488, 1983

  22. 22.

    Thomas PS, Farquhar MN: Specific measurement of DNA in nuclei and nucleic acids using diaminobenzoic acid. Anal Biochem 89: 35–44, 1978

  23. 23.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275, 1951

  24. 24.

    Beresford JN, Gallagher JA, Russell RGG: 1,25-Dihydroxyvitamin D3 and human bone-derived cells in vitro: effects on alkaline phosphatase, type I collagen and proliferation. Endocrinology 119: 1776–1785, 1986

  25. 25.

    Taylor AK, Linkhart SG, Mohan S, Baylink DJ: Development of a new radioimmunoassay for human osteocalcin: Evidence for a midmolecule epitope. Metabolism 37: 872–877, 1988

  26. 26.

    Lau KHW, Tanimoto H, Baylink DJ: Vandate stimulates bone cell proliferation and bone collagen synthesis in vitro. Endocrinology 123: 2858–2867, 1988

  27. 27.

    Price PA, Baukol SA: 1,25-dihydroxyvitamin D3 increases synthesis of the vitamin K-dependent bone protein by osteosarcoma cells. J Biol Chem 255: 11660–11663, 1980

  28. 28.

    Martin RB: Ternary hydroxide complexes in neutral solutions of Al+3 and F. Biochem Biophys Res Commun 155: 1194–1200, 1988

  29. 29.

    Farley JR, Wergedal JE, Baylink DJ: Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone forming cells. Science 222: 330–332, 1983

  30. 30.

    Wergedal JE, Lau KHW, Baylink DJ: Fluoride and bovine bone extract influence cell proliferation and phosphatase activities in human bone cell cultures. Clin Orthopaed Rel Res 233: 274–282, 1988

  31. 31.

    Farley JR, Tarbaux N, Hall S, Baylink DJ: Evidence that fluoride-stimulated 3[H]-thymidine incorporation in embryonic chick calvarial cell cultures is dependent on the presence of a bone cell mitogen, sensitive to changes in the phosphate concentration, and modulated by systemic skeletal effectors. Metabolism 37: 988–995, 1988

  32. 32.

    Lau KHW, Farley JR, Freeman TK, Baylink DJ: A proposed mechanism of the mitogenic action of fluoride on bone cells: inhibition of the activity of an osteoblastic acid phosphatase. Metabolism 38: 858–868, 1989

  33. 33.

    Marc S, Leiber D, Harbon S: Fluoroaluminates mimic muscarinic- and oxytocin-receptor-mediated generation of inositol phosphates and contraction in the intact guinea-pig myometrium. Role for a pertussis/cholera-toxin-insensitive G protein. Biochem J 255: 705–713, 1988

  34. 34.

    Woods NM, Dixon CJ, Cuthbertson KSR, Cobbold PH: Fluoroaluminate mimics agonist application in single rat hepatocytes. Biochem J 265: 613–615, 1990

  35. 35.

    Malluche HH, Sherman D, Meyer W, Ritz E, Norman AW, Massry SG: Effects of long-term infusion of physiologic doses of 1–34 PTH on bone. Am J Physiol 242: 17197–17201, 1982

  36. 36.

    Howard GA, Bottemiller BL, Turner RT, Rader JI, Baylink DJ: Parathyroid hormone stimulates bone formation and resorption in organ culture: Evidence for a coupling mechanism. Proc Natl Acad Sci USA 78: 3204–3208, 1981

  37. 37.

    Wong GL: Skeletal effects of parathyroid hormone. In: Bone and Mineral Research. Peck WA (ed.) 4th ed. Elsevier Sci Publishing Co. Inc., New York. 1986, pp 103–129

  38. 38.

    Farley JR, Baylink DJ: Skeletal alkaline phosphatase activity as a bone formation index in vitro. Metabolism 35: 563–571, 1986

  39. 39.

    Price PA, Parthemore JG, Deftos LJ: New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease. J Clin Invest 66: 878–838, 1980

  40. 40.

    Garcia-Carrasco M, Gruson M, de Vernejoul MC, Denne MA, Miravet L: Osteocalcin and bone morphometric parameters in adults without bone disease. Calcif Tissue Int 42: 13–17, 1988

  41. 41.

    Pun KK, Ho PWM, Lau P: Effects of aluminum on the parathyroid hormone receptors of bone. Kidney Int 37: 72–78, 1990

  42. 42.

    Litosch I: Regulatory GTP-binding proteins: emerging concepts on their role in cell function. Life Sci 41: 251–258, 1987

  43. 43.

    Evans DB, Russell RGG, Brown BL, Dobson PRM: Agents affecting adenylate cyclase activity modulate the stimulatory action of 1,25-dihydroxyvitamin D3 on the production of osteocalcin by human bone cells. Biochem Biophys Res Commun 164: 1076–1085, 1989

  44. 44.

    Boyer JL, Waldo GL, Evans T, Northup JK, Downes CP, Harden TK: Modification of AIF4 - and receptor-stimulated phospholipase C activity by G-protein ßτ subunits. J Biol Chem 264: 13917–13922, 1989

  45. 45.

    Paris S, Chambard J-C, Pouyssegur J: Tyrosine kinase-activating growth factor potentiate thrombin- and AlF 4-induced phosphoinositide breakdown in hamster fibroblasts. Evidence for positive cross-talk between the two mitogenic signaling pathways. J Biol Chem 263: 12893–12900, 1988

  46. 46.

    Lieberherr M, Grosse B, Cournot-Witmer G, Thil CL, Balsan S: In vitro effects of aluminum on bone phosphatases: a possible interaction with bPTH and vitamin D3 metabolites. Calcif Tissue Int 34: 280–284, 1982

  47. 47.

    Quarles LD, Castillo SA, Drezner MK: Aluminum-induced replication of osteoblast precursors: A potential mechanism underlying neo-osteogenesis. J Bone Min Res 4 (Suppl 1): abs 54, 1989

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Correspondence to K. -H. William Lau.

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William Lau, K.-., Yoo, A. & Wang, S.P. Aluminum stimulates the proliferation and differentiation of osteoblasts in vitro by a mechanism that is different from fluoride. Mol Cell Biochem 105, 93–105 (1991).

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Key words

  • aluminum
  • osteoblasts
  • fluoride
  • bone formation
  • proliferation
  • differentiation