Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jun 1989; 83(6): 1930–1935.
PMCID: PMC303914

Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.

Abstract

Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative potencies as they inhibit bone resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human marrow cultures, and that this may be related to their ability to inhibit bone resorption in vivo.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Altman RD, Johnston CC, Khairi MR, Wellman H, Serafini AN, Sankey RR. Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans). N Engl J Med. 1973 Dec 27;289(26):1379–1384. [PubMed]
  • Russell RG, Smith R, Preston C, Walton RJ, Woods CG. Diphosphonates in Paget's disease. Lancet. 1974 May 11;1(7863):894–898. [PubMed]
  • Canfield R, Rosner W, Skinner J, McWhorter J, Resnick L, Feldman F, Kammerman S, Ryan K, Kunigonis M, Bohne W. Diphosphonate therapy of paget's disease of bone. J Clin Endocrinol Metab. 1977 Jan;44(1):96–106. [PubMed]
  • Khairi MR, Altman RD, DeRosa GP, Zimmermann J, Schenk RK, Johnston CC. Sodium etidronate in the treatment of Paget's disease of bone. A study of long-term results. Ann Intern Med. 1977 Dec;87(6):656–663. [PubMed]
  • Frijlink WB, Bijvoet OL, te Velde J, Heynen G. Treatment of Paget's disease with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (A.P.D.). Lancet. 1979 Apr 14;1(8120):799–803. [PubMed]
  • Douglas DL, Duckworth T, Russell RG, Kanis JA, Preston CJ, Preston FE, Prenton MA, Woodhead JS. Effect of dichloromethylene diphosphonate in Paget's disease of bone and in hypercalcaemia due to primary hyperparathyroidism or malignant disease. Lancet. 1980 May 17;1(8177):1043–1047. [PubMed]
  • Sleeboom HP, Bijvoet OL, van Oosterom AT, Gleed JH, O'Riordan JL. Comparison of intravenous (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate and volume repletion in tumour-induced hypercalcaemia. Lancet. 1983 Jul 30;2(8344):239–243. [PubMed]
  • Percival RC, Paterson AD, Yates AJ, Beard DJ, Douglas DL, Neal FE, Russell RG, Kanis JA. Treatment of malignant hypercalcaemia with clodronate. Br J Cancer. 1985 May;51(5):665–669. [PMC free article] [PubMed]
  • Ralston SH, Gardner MD, Dryburgh FJ, Jenkins AS, Cowan RA, Boyle IT. Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet. 1985 Oct 26;2(8461):907–910. [PubMed]
  • Ohya K, Yamada S, Felix R, Fleisch H. Effect of bisphosphonates on prostaglandin synthesis by rat bone cells and mouse calvaria in culture. Clin Sci (Lond) 1985 Oct;69(4):403–411. [PubMed]
  • Fast DK, Felix R, Dowse C, Neuman WF, Fleisch H. The effects of diphosphonates on the growth and glycolysis of connective-tissue cells in culture. Biochem J. 1978 Apr 15;172(1):97–107. [PMC free article] [PubMed]
  • Stevenson PH, Stevenson JR. Cytotoxic and migration inhibitory effects of bisphosphonates on macrophages. Calcif Tissue Int. 1986 Apr;38(4):227–233. [PubMed]
  • Reitsma PH, Teitelbaum SL, Bijvoet OL, Kahn AJ. Differential action of the bisphosphonates (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) and disodium dichloromethylidene bisphosphonate (Cl2MDP) on rat macrophage-mediated bone resorption in vitro. J Clin Invest. 1982 Nov;70(5):927–933. [PMC free article] [PubMed]
  • Boonekamp PM, van der Wee-Pals LJ, van Wijk-van Lennep MM, Thesing CW, Bijvoet OL. Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner. 1986 Feb;1(1):27–39. [PubMed]
  • FISCHMAN DA, HAY ED. Origin of osteoclasts from mononuclear leucocytes in regenerating newt limbs. Anat Rec. 1962 Aug;143:329–337. [PubMed]
  • Kahn AJ, Simmons DJ. Investigation of cell lineage in bone using a chimaera of chick and quial embryonic tissue. Nature. 1975 Nov 27;258(5533):325–327. [PubMed]
  • Ash P, Loutit JF, Townsend KM. Osteoclasts derived from haematopoietic stem cells. Nature. 1980 Feb 14;283(5748):669–670. [PubMed]
  • MacDonald BR, Takahashi N, McManus LM, Holahan J, Mundy GR, Roodman GD. Formation of multinucleated cells that respond to osteotropic hormones in long term human bone marrow cultures. Endocrinology. 1987 Jun;120(6):2326–2333. [PubMed]
  • Di Persio JF, Brennan JK, Lichtman MA, Speiser BL. Human cell lines that elaborate colon-stimulating activity for the marrow cells of man and other species. Blood. 1978 Mar;51(3):507–519. [PubMed]
  • Das SK, Stanley ER, Guilbert LJ, Forman LW. Human colony-stimulating factor (CSF-1) radioimmunoassay: resolution of three subclasses of human colony-stimulating factors. Blood. 1981 Sep;58(3):630–641. [PubMed]
  • Horton MA, Lewis D, McNulty K, Pringle JA, Chambers TJ. Monoclonal antibodies to osteoclastomas (giant cell bone tumors): definition of osteoclast-specific cellular antigens. Cancer Res. 1985 Nov;45(11 Pt 2):5663–5669. [PubMed]
  • Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. [PubMed]
  • Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. [PubMed]
  • Takahashi N, MacDonald BR, Hon J, Winkler ME, Derynck R, Mundy GR, Roodman GD. Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures. J Clin Invest. 1986 Oct;78(4):894–898. [PMC free article] [PubMed]
  • Takahashi N, Mundy GR, Roodman GD. Recombinant human interferon-gamma inhibits formation of human osteoclast-like cells. J Immunol. 1986 Dec 1;137(11):3544–3549. [PubMed]
  • Chambers TJ, Fuller K, Darby JA, Pringle JA, Horton MA. Monoclonal antibodies against osteoclasts inhibit bone resorption in vitro. Bone Miner. 1986 Apr;1(2):127–135. [PubMed]
  • Fuller K, Chambers TJ. Generation of osteoclasts in cultures of rabbit bone marrow and spleen cells. J Cell Physiol. 1987 Sep;132(3):441–452. [PubMed]
  • Baron R, Neff L, Tran Van P, Nefussi JR, Vignery A. Kinetic and cytochemical identification of osteoclast precursors and their differentiation into multinucleated osteoclasts. Am J Pathol. 1986 Feb;122(2):363–378. [PMC free article] [PubMed]
  • MacDonald BR, Mundy GR, Clark S, Wang EA, Kuehl TJ, Stanley ER, Roodman GD. Effects of human recombinant CSF-GM and highly purified CSF-1 on the formation of multinucleated cells with osteoclast characteristics in long-term bone marrow cultures. J Bone Miner Res. 1986 Apr;1(2):227–233. [PubMed]
  • Cecchini MG, Felix R, Fleisch H, Cooper PH. Effect of bisphosphonates on proliferation and viability of mouse bone marrow-derived macrophages. J Bone Miner Res. 1987 Apr;2(2):135–142. [PubMed]
  • Boonekamp PM, Löwik CW, van der Wee-Pals LJ, van Wijk-van Lennep ML, Bijvoet OL. Enhancement of the inhibitory action of APD on the transformation of osteoclast precursors into resorbing cells after dimethylation of the amino group. Bone Miner. 1987 Feb;2(1):29–42. [PubMed]
  • Minaire P, Berard E, Meunier PJ, Edouard C, Goedert G, Pilonchery G. Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J Clin Invest. 1981 Oct;68(4):1086–1092. [PMC free article] [PubMed]
  • De Vries HR, Bijvoet OL. Results of prolonged treatment of Paget's disease of bone with disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP). Neth J Med. 1974;17(6):281–298. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...