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. 1986 Oct;78(4):894–898. doi: 10.1172/JCI112677

Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures.

N Takahashi, B R MacDonald, J Hon, M E Winkler, R Derynck, G R Mundy, G D Roodman
PMCID: PMC423711  PMID: 3489738

Abstract

Transforming growth factor-alpha (TGF-alpha) is synthesized by a variety of tumor cell lines and stimulates osteoclastic bone resorption in vitro. The mechanism by which TGF-alpha increases osteoclast activity is unknown. We used a human marrow culture system that forms osteoclast-like multinucleated cells (MNCs) to determine the effects of recombinant human TGF-alpha on MNC formation. Addition of 0.01 ng/ml TGF-alpha for the 1st week followed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for the subsequent 2 wk significantly increased MNCs. Treatment of these cultures with TGF-alpha without later addition of 1,25(OH)2D3 did not increase MNC formation. Autoradiographic studies revealed that TGF-alpha stimulated proliferation of precursors for MNCs, and 1,25(OH)2D3 increased their rate of fusion into MNCs. Addition of murine epidermal growth factor (EGF) (0.1 ng/ml) followed by 1,25(OH)2D3 also significantly stimulated MNC formation. These data suggest that TGF-alpha and EGF may stimulate bone resorption by increasing the proliferation of osteoclast precursors, which leads to increased numbers of osteoclasts.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  2. Ibbotson K. J., D'Souza S. M., Ng K. W., Osborne C. K., Niall M., Martin T. J., Mundy G. R. Tumor-derived growth factor increases bone resorption in a tumor associated with humoral hypercalcemia of malignancy. Science. 1983 Sep 23;221(4617):1292–1294. doi: 10.1126/science.6577602. [DOI] [PubMed] [Google Scholar]
  3. Ibbotson K. J., D'Souza S. M., Smith D. D., Carpenter G., Mundy G. R. EGF receptor antiserum inhibits bone resorbing activity produced by a rat Leydig cell tumor associated with the humoral hypercalcemia of malignancy. Endocrinology. 1985 Jan;116(1):469–471. doi: 10.1210/endo-116-1-469. [DOI] [PubMed] [Google Scholar]
  4. Ibbotson K. J., Harrod J., Gowen M., D'Souza S., Smith D. D., Winkler M. E., Derynck R., Mundy G. R. Human recombinant transforming growth factor alpha stimulates bone resorption and inhibits formation in vitro. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2228–2232. doi: 10.1073/pnas.83.7.2228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ibbotson K. J., Roodman G. D., McManus L. M., Mundy G. R. Identification and characterization of osteoclast-like cells and their progenitors in cultures of feline marrow mononuclear cells. J Cell Biol. 1984 Aug;99(2):471–480. doi: 10.1083/jcb.99.2.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ibbotson K. J., Twardzik D. R., D'Souza S. M., Hargreaves W. R., Todaro G. J., Mundy G. R. Stimulation of bone resorption in vitro by synthetic transforming growth factor-alpha. Science. 1985 May 24;228(4702):1007–1009. doi: 10.1126/science.3859011. [DOI] [PubMed] [Google Scholar]
  7. Lee D. C., Rose T. M., Webb N. R., Todaro G. J. Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha. Nature. 1985 Feb 7;313(6002):489–491. doi: 10.1038/313489a0. [DOI] [PubMed] [Google Scholar]
  8. MacDonald B. R., Mundy G. R., Clark S., Wang E. A., Kuehl T. J., Stanley E. R., Roodman G. D. 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. doi: 10.1002/jbmr.5650010210. [DOI] [PubMed] [Google Scholar]
  9. Marquardt H., Hunkapiller M. W., Hood L. E., Twardzik D. R., De Larco J. E., Stephenson J. R., Todaro G. J. Transforming growth factors produced by retrovirus-transformed rodent fibroblasts and human melanoma cells: amino acid sequence homology with epidermal growth factor. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4684–4688. doi: 10.1073/pnas.80.15.4684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Massagué J. Epidermal growth factor-like transforming growth factor. I. Isolation, chemical characterization, and potentiation by other transforming factors from feline sarcoma virus-transformed rat cells. J Biol Chem. 1983 Nov 25;258(22):13606–13613. [PubMed] [Google Scholar]
  11. Massagué J. Epidermal growth factor-like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J Biol Chem. 1983 Nov 25;258(22):13614–13620. [PubMed] [Google Scholar]
  12. Mundy G. R., Ibbotson K. J., D'Souza S. M., Simpson E. L., Jacobs J. W., Martin T. J. The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med. 1984 Jun 28;310(26):1718–1727. doi: 10.1056/NEJM198406283102607. [DOI] [PubMed] [Google Scholar]
  13. Mundy G. R., Ibbotson K. J., D'Souza S. M. Tumor products and the hypercalcemia of malignancy. J Clin Invest. 1985 Aug;76(2):391–394. doi: 10.1172/JCI111984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Raisz L. G., Simmons H. A., Sandberg A. L., Canalis E. Direct stimulation of bone resorption by epidermal growth factor. Endocrinology. 1980 Jul;107(1):270–273. doi: 10.1210/endo-107-1-270. [DOI] [PubMed] [Google Scholar]
  15. Richman C. M., Chess L., Yankee R. A. Purification and characterization of granulocytic progenitor cells (CFU-C) from human peripheral blood using immunologic surface markers. Blood. 1978 Jan;51(1):1–8. [PubMed] [Google Scholar]
  16. Roberts A. B., Frolik C. A., Anzano M. A., Sporn M. B. Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc. 1983 Jun;42(9):2621–2626. [PubMed] [Google Scholar]
  17. Roodman G. D., Hutton J. J., Bollum F. J. DNA polymerase, thymidine kinase and DNA synthesis in erythropoietic mouse spleen cells separated on bovine serum albumin gradients. Biochim Biophys Acta. 1976 Apr 2;425(4):478–491. doi: 10.1016/0005-2787(76)90012-5. [DOI] [PubMed] [Google Scholar]
  18. Roodman G. D., Ibbotson K. J., MacDonald B. R., Kuehl T. J., Mundy G. R. 1,25-Dihydroxyvitamin D3 causes formation of multinucleated cells with several osteoclast characteristics in cultures of primate marrow. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8213–8217. doi: 10.1073/pnas.82.23.8213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Smith J. M., Sporn M. B., Roberts A. B., Derynck R., Winkler M. E., Gregory H. Human transforming growth factor-alpha causes precocious eyelid opening in newborn mice. Nature. 1985 Jun 6;315(6019):515–516. doi: 10.1038/315515a0. [DOI] [PubMed] [Google Scholar]
  20. Stern P. H., Krieger N. S., Nissenson R. A., Williams R. D., Winkler M. E., Derynck R., Strewler G. J. Human transforming growth factor-alpha stimulates bone resorption in vitro. J Clin Invest. 1985 Nov;76(5):2016–2019. doi: 10.1172/JCI112202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Stewart A. F., Horst R., Deftos L. J., Cadman E. C., Lang R., Broadus A. E. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980 Dec 11;303(24):1377–1383. doi: 10.1056/NEJM198012113032401. [DOI] [PubMed] [Google Scholar]
  22. Tam J. P. Physiological effects of transforming growth factor in the newborn mouse. Science. 1985 Aug 16;229(4714):673–675. doi: 10.1126/science.3860952. [DOI] [PubMed] [Google Scholar]
  23. Tashjian A. H., Jr, Levine L. Epidermal growth factor stimulates prostaglandin production and bone resorption in cultured mouse calvaria. Biochem Biophys Res Commun. 1978 Dec 14;85(3):966–975. doi: 10.1016/0006-291x(78)90638-1. [DOI] [PubMed] [Google Scholar]
  24. Tashjian A. H., Jr, Voelkel E. F., Lazzaro M., Singer F. R., Roberts A. B., Derynck R., Winkler M. E., Levine L. Alpha and beta human transforming growth factors stimulate prostaglandin production and bone resorption in cultured mouse calvaria. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4535–4538. doi: 10.1073/pnas.82.13.4535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Twardzik D. R. Differential expression of transforming growth factor-alpha during prenatal development of the mouse. Cancer Res. 1985 Nov;45(11 Pt 1):5413–5416. [PubMed] [Google Scholar]
  26. de Larco J. E., Todaro G. J. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4001–4005. doi: 10.1073/pnas.75.8.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]

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