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. 1988 Aug;82(2):680–685. doi: 10.1172/JCI113647

Transforming growth factor beta inhibits bone resorption in fetal rat long bone cultures.

J Pfeilschifter 1, S M Seyedin 1, G R Mundy 1
PMCID: PMC303563  PMID: 3165385

Abstract

TGF-beta 1 is a polypeptide that is abundant in bone matrix, is produced by bone cells, and modulates proliferation and differentiated functions of osteoblastic cells in vitro. TGF-beta 2 is a closely related polypeptide that was originally isolated from bone matrix. TGF-beta 1 has been shown previously to stimulate prostaglandin production in cultures of neonatal mouse calvariae, which causes these bones to resorb. We found similar effects with TGF-beta 2. In comparison, TGF-beta 1 and TGF-beta 2 failed to stimulate bone resorption in fetal rat long bone cultures during a 3-d incubation period in concentrations up to 50-100 times greater than those capable of inducing bone resorption in calvariae. Incubation with TGF-beta 1 for a further 3 d decreased bone resorption up to 30%. Moreover, bone resorption induced by the bone-resorbing agents IL 1 and 1,25-dihydroxyvitamin D3 was partially or completely inhibited by TGF-beta 1 and TGF-beta 2 during the second half of the 6-d incubation period. Inhibition of DNA synthesis with hydroxyurea inhibited bone resorption in long bones in a similar pattern to that seen with TGF-beta 1. The inhibitory effects of TGF-beta 1 and TGF-beta 2 on bone resorption in long bone cultures may therefore be due to inhibition of osteoclast precursor proliferation.

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Selected References

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

  1. Baird A., Durkin T. Inhibition of endothelial cell proliferation by type beta-transforming growth factor: interactions with acidic and basic fibroblast growth factors. Biochem Biophys Res Commun. 1986 Jul 16;138(1):476–482. doi: 10.1016/0006-291x(86)90305-0. [DOI] [PubMed] [Google Scholar]
  2. Centrella M., Massagué J., Canalis E. Human platelet-derived transforming growth factor-beta stimulates parameters of bone growth in fetal rat calvariae. Endocrinology. 1986 Nov;119(5):2306–2312. doi: 10.1210/endo-119-5-2306. [DOI] [PubMed] [Google Scholar]
  3. Centrella M., McCarthy T. L., Canalis E. Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone. J Biol Chem. 1987 Feb 25;262(6):2869–2874. [PubMed] [Google Scholar]
  4. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Ishibashi T., Miller S. L., Burstein S. A. Type beta transforming growth factor is a potent inhibitor of murine megakaryocytopoiesis in vitro. Blood. 1987 Jun;69(6):1737–1741. [PubMed] [Google Scholar]
  7. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lorenzo J. A., Quinton J., Sousa S., Raisz L. G. Effects of DNA and prostaglandin synthesis inhibitors on the stimulation of bone resorption by epidermal growth factor in fetal rat long-bone cultures. J Clin Invest. 1986 Jun;77(6):1897–1902. doi: 10.1172/JCI112517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lorenzo J. A., Raisz L. G., Hock J. M. DNA synthesis is not necessary for osteoclastic responses to parathyroid hormone in cultured fetal rat long bones. J Clin Invest. 1983 Dec;72(6):1924–1929. doi: 10.1172/JCI111156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Marquardt H., Lioubin M. N., Ikeda T. Complete amino acid sequence of human transforming growth factor type beta 2. J Biol Chem. 1987 Sep 5;262(25):12127–12131. [PubMed] [Google Scholar]
  11. Massagué J. The TGF-beta family of growth and differentiation factors. Cell. 1987 May 22;49(4):437–438. doi: 10.1016/0092-8674(87)90443-0. [DOI] [PubMed] [Google Scholar]
  12. Masui T., Wakefield L. M., Lechner J. F., LaVeck M. A., Sporn M. B., Harris C. C. Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2438–2442. doi: 10.1073/pnas.83.8.2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McSheehy P. M., Chambers T. J. Osteoblast-like cells in the presence of parathyroid hormone release soluble factor that stimulates osteoclastic bone resorption. Endocrinology. 1986 Oct;119(4):1654–1659. doi: 10.1210/endo-119-4-1654. [DOI] [PubMed] [Google Scholar]
  14. Pfeilschifter J., D'Souza S. M., Mundy G. R. Effects of transforming growth factor-beta on osteoblastic osteosarcoma cells. Endocrinology. 1987 Jul;121(1):212–218. doi: 10.1210/endo-121-1-212. [DOI] [PubMed] [Google Scholar]
  15. Pfeilschifter J., Mundy G. R. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A. 1987 Apr;84(7):2024–2028. doi: 10.1073/pnas.84.7.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. RAISZ L. G. BONE RESORPTION IN TISSUE CULTURE. FACTORS INFLUENCING THE RESPONSE TO PARATHYROID HORMONE. J Clin Invest. 1965 Jan;44:103–116. doi: 10.1172/JCI105117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Reynolds J. J., Dingle J. T. Time course of action of calcitonin on resorbing mouse bones in vitro. Nature. 1968 Jun 22;218(5147):1178–1179. doi: 10.1038/2181178a0. [DOI] [PubMed] [Google Scholar]
  19. Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Robey P. G., Young M. F., Flanders K. C., Roche N. S., Kondaiah P., Reddi A. H., Termine J. D., Sporn M. B., Roberts A. B. Osteoblasts synthesize and respond to transforming growth factor-type beta (TGF-beta) in vitro. J Cell Biol. 1987 Jul;105(1):457–463. doi: 10.1083/jcb.105.1.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Segarini P. R., Roberts A. B., Rosen D. M., Seyedin S. M. Membrane binding characteristics of two forms of transforming growth factor-beta. J Biol Chem. 1987 Oct 25;262(30):14655–14662. [PubMed] [Google Scholar]
  22. Seyedin S. M., Segarini P. R., Rosen D. M., Thompson A. Y., Bentz H., Graycar J. Cartilage-inducing factor-B is a unique protein structurally and functionally related to transforming growth factor-beta. J Biol Chem. 1987 Feb 15;262(5):1946–1949. [PubMed] [Google Scholar]
  23. Seyedin S. M., Thompson A. Y., Bentz H., Rosen D. M., McPherson J. M., Conti A., Siegel N. R., Galluppi G. R., Piez K. A. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986 May 5;261(13):5693–5695. [PubMed] [Google Scholar]
  24. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  25. Stashenko P., Dewhirst F. E., Peros W. J., Kent R. L., Ago J. M. Synergistic interactions between interleukin 1, tumor necrosis factor, and lymphotoxin in bone resorption. J Immunol. 1987 Mar 1;138(5):1464–1468. [PubMed] [Google Scholar]
  26. Tashjian A. H., Jr, Hohmann E. L., Antoniades H. N., Levine L. Platelet-derived growth factor stimulates bone resorption via a prostaglandin-mediated mechanism. Endocrinology. 1982 Jul;111(1):118–124. doi: 10.1210/endo-111-1-118. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Tashjian A. H., Jr, Voelkel E. F., Lazzaro M., Goad D., Bosma T., Levine L. Tumor necrosis factor-alpha (cachectin) stimulates bone resorption in mouse calvaria via a prostaglandin-mediated mechanism. Endocrinology. 1987 May;120(5):2029–2036. doi: 10.1210/endo-120-5-2029. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Thomson B. M., Saklatvala J., Chambers T. J. Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med. 1986 Jul 1;164(1):104–112. doi: 10.1084/jem.164.1.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tucker R. F., Shipley G. D., Moses H. L., Holley R. W. Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science. 1984 Nov 9;226(4675):705–707. doi: 10.1126/science.6093254. [DOI] [PubMed] [Google Scholar]
  32. Wrann M., Bodmer S., de Martin R., Siepl C., Hofer-Warbinek R., Frei K., Hofer E., Fontana A. T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J. 1987 Jun;6(6):1633–1636. doi: 10.1002/j.1460-2075.1987.tb02411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. YOUNG C. W., HODAS S. HYDROXYUREA: INHIBITORY EFFECT ON DNA METABOLISM. Science. 1964 Nov 27;146(3648):1172–1174. doi: 10.1126/science.146.3648.1172. [DOI] [PubMed] [Google Scholar]

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