Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Jun 1;183(6):2581–2591. doi: 10.1084/jem.183.6.2581

The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures

PMCID: PMC2192607  PMID: 8676079

Abstract

Interleukin (IL)-11 is a multifunctional cytokine whose role in osteoclast development has not been fully elucidated. We examined IL-11 production by primary osteoblasts and the effects of rat monoclonal anti-mouse glycoprotein 130 (gp130) antibody on osteoclast formation, using a coculture of mouse osteoblasts and bone marrow cells. IL-1, TNF alpha, PGE2, parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) similarly induced production of IL-11 by osteoblasts, but IL-6, IL-4, and TGF beta did not. Primary osteoblasts constitutively expressed mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Osteotropic factors did not modulate IL-11R alpha mRNA at 24 h, but steady-state gp130 mRNA expression in osteoblasts was upregulated by 1 alpha,25(OH)2D3, PTH, or IL-1. In cocultures, the formation of multinucleated osteoclast-like cells (OCLs) in response to IL-11, or IL-6 together with its soluble IL-6 receptor was dose- dependently inhibited by rat monoclonal anti-mouse gp130 antibody. Furthermore, adding anti-gp130 antibody abolished OCL formation induced by IL-1, and partially inhibited OCL formation induced by PGE2, PTH, or 1 alpha,25(OH)2D3. During osteoclast formation in marrow cultures, a sequential relationship existed between the expression of calcitonin receptor mRNA and IL-11R alpha mRNA. Osteoblasts as well as OCLs expressed transcripts for IL-11R alpha, as indicated by RT-PCR analysis and in situ hybridization. These results suggest a central role of gp130-coupled cytokines, especially IL-11, in osteoclast development. Since osteoblasts and mature osteoclasts expressed IL-11R alpha mRNA, both bone-forming and bone-resorbing cells are potential targets of IL- 11.

Full Text

The Full Text of this article is available as a PDF (2.0 MB).

Selected References

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

  1. Akatsu T., Takahashi N., Udagawa N., Imamura K., Yamaguchi A., Sato K., Nagata N., Suda T. Role of prostaglandins in interleukin-1-induced bone resorption in mice in vitro. J Bone Miner Res. 1991 Feb;6(2):183–189. doi: 10.1002/jbmr.5650060212. [DOI] [PubMed] [Google Scholar]
  2. Akatsu T., Tamura T., Takahashi N., Udagawa N., Tanaka S., Sasaki T., Yamaguchi A., Nagata N., Suda T. Preparation and characterization of a mouse osteoclast-like multinucleated cell population. J Bone Miner Res. 1992 Nov;7(11):1297–1306. doi: 10.1002/jbmr.5650071109. [DOI] [PubMed] [Google Scholar]
  3. Arend W. P., Dayer J. M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):151–160. doi: 10.1002/art.1780380202. [DOI] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Elias J. A., Tang W., Horowitz M. C. Cytokine and hormonal stimulation of human osteosarcoma interleukin-11 production. Endocrinology. 1995 Feb;136(2):489–498. doi: 10.1210/endo.136.2.7835281. [DOI] [PubMed] [Google Scholar]
  6. Elias J. A., Zheng T., Whiting N. L., Trow T. K., Merrill W. W., Zitnik R., Ray P., Alderman E. M. IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. J Immunol. 1994 Mar 1;152(5):2421–2429. [PubMed] [Google Scholar]
  7. Girasole G., Passeri G., Jilka R. L., Manolagas S. C. Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest. 1994 Apr;93(4):1516–1524. doi: 10.1172/JCI117130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hilton D. J., Hilton A. A., Raicevic A., Rakar S., Harrison-Smith M., Gough N. M., Begley C. G., Metcalf D., Nicola N. A., Willson T. A. Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction. EMBO J. 1994 Oct 17;13(20):4765–4775. doi: 10.1002/j.1460-2075.1994.tb06802.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ikeda E., Kusaka M., Hakeda Y., Yokota K., Kumegawa M., Yamamoto S. Effect of interleukin 1 beta on osteoblastic clone MC3T3-E1 cells. Calcif Tissue Int. 1988 Sep;43(3):162–166. doi: 10.1007/BF02571314. [DOI] [PubMed] [Google Scholar]
  10. Ikegame M., Rakopoulos M., Zhou H., Houssami S., Martin T. J., Moseley J. M., Findlay D. M. Calcitonin receptor isoforms in mouse and rat osteoclasts. J Bone Miner Res. 1995 Jan;10(1):59–65. doi: 10.1002/jbmr.5650100110. [DOI] [PubMed] [Google Scholar]
  11. Jimi E., Shuto T., Koga T. Macrophage colony-stimulating factor and interleukin-1 alpha maintain the survival of osteoclast-like cells. Endocrinology. 1995 Feb;136(2):808–811. doi: 10.1210/endo.136.2.7835314. [DOI] [PubMed] [Google Scholar]
  12. Kishimoto T., Akira S., Narazaki M., Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995 Aug 15;86(4):1243–1254. [PubMed] [Google Scholar]
  13. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  14. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  15. Maier R., Ganu V., Lotz M. Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases. J Biol Chem. 1993 Oct 15;268(29):21527–21532. [PubMed] [Google Scholar]
  16. Neuhaus H., Bettenhausen B., Bilinski P., Simon-Chazottes D., Guénet J. L., Gossler A. Etl2, a novel putative type-I cytokine receptor expressed during mouse embryogenesis at high levels in skin and cells with skeletogenic potential. Dev Biol. 1994 Dec;166(2):531–542. doi: 10.1006/dbio.1994.1335. [DOI] [PubMed] [Google Scholar]
  17. Ohsaki Y., Takahashi S., Scarcez T., Demulder A., Nishihara T., Williams R., Roodman G. D. Evidence for an autocrine/paracrine role for interleukin-6 in bone resorption by giant cells from giant cell tumors of bone. Endocrinology. 1992 Nov;131(5):2229–2234. doi: 10.1210/endo.131.5.1425421. [DOI] [PubMed] [Google Scholar]
  18. Palacios R., Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. doi: 10.1016/s0092-8674(85)80053-2. [DOI] [PubMed] [Google Scholar]
  19. Paul S. R., Bennett F., Calvetti J. A., Kelleher K., Wood C. R., O'Hara R. M., Jr, Leary A. C., Sibley B., Clark S. C., Williams D. A. Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7512–7516. doi: 10.1073/pnas.87.19.7512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rodan S. B., Rodan G. A., Simmons H. A., Walenga R. W., Feinstein M. B., Raisz L. G. Bone resorptive factor produced by osteosarcoma cells with osteoblastic features is PGE2. Biochem Biophys Res Commun. 1981 Oct 30;102(4):1358–1365. doi: 10.1016/s0006-291x(81)80161-1. [DOI] [PubMed] [Google Scholar]
  21. Saito M., Yoshida K., Hibi M., Taga T., Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992 Jun 15;148(12):4066–4071. [PubMed] [Google Scholar]
  22. Saito T., Yasukawa K., Suzuki H., Futatsugi K., Fukunaga T., Yokomizo C., Koishihara Y., Fukui H., Ohsugi Y., Yawata H. Preparation of soluble murine IL-6 receptor and anti-murine IL-6 receptor antibodies. J Immunol. 1991 Jul 1;147(1):168–173. [PubMed] [Google Scholar]
  23. Shinar D. M., Rodan G. A. Biphasic effects of transforming growth factor-beta on the production of osteoclast-like cells in mouse bone marrow cultures: the role of prostaglandins in the generation of these cells. Endocrinology. 1990 Jun;126(6):3153–3158. doi: 10.1210/endo-126-6-3153. [DOI] [PubMed] [Google Scholar]
  24. Suda T., Takahashi N., Martin T. J. Modulation of osteoclast differentiation. Endocr Rev. 1992 Feb;13(1):66–80. doi: 10.1210/edrv-13-1-66. [DOI] [PubMed] [Google Scholar]
  25. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  26. Takahashi N., Akatsu T., Udagawa N., Sasaki T., Yamaguchi A., Moseley J. M., Martin T. J., Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988 Nov;123(5):2600–2602. doi: 10.1210/endo-123-5-2600. [DOI] [PubMed] [Google Scholar]
  27. Takahashi N., Yamana H., Yoshiki S., Roodman G. D., Mundy G. R., Jones S. J., Boyde A., Suda T. Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology. 1988 Apr;122(4):1373–1382. doi: 10.1210/endo-122-4-1373. [DOI] [PubMed] [Google Scholar]
  28. Tamura T., Udagawa N., Takahashi N., Miyaura C., Tanaka S., Yamada Y., Koishihara Y., Ohsugi Y., Kumaki K., Taga T. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11924–11928. doi: 10.1073/pnas.90.24.11924. [DOI] [PMC free article] [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. Tso J. Y., Sun X. H., Kao T. H., Reece K. S., Wu R. Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res. 1985 Apr 11;13(7):2485–2502. doi: 10.1093/nar/13.7.2485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Udagawa N., Takahashi N., Akatsu T., Sasaki T., Yamaguchi A., Kodama H., Martin T. J., Suda T. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology. 1989 Oct;125(4):1805–1813. doi: 10.1210/endo-125-4-1805. [DOI] [PubMed] [Google Scholar]
  32. Udagawa N., Takahashi N., Akatsu T., Tanaka H., Sasaki T., Nishihara T., Koga T., Martin T. J., Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7260–7264. doi: 10.1073/pnas.87.18.7260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Udagawa N., Takahashi N., Katagiri T., Tamura T., Wada S., Findlay D. M., Martin T. J., Hirota H., Taga T., Kishimoto T. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med. 1995 Nov 1;182(5):1461–1468. doi: 10.1084/jem.182.5.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yang L., Yang Y. C. Regulation of interleukin (IL)-11 gene expression in IL-1 induced primate bone marrow stromal cells. J Biol Chem. 1994 Dec 30;269(52):32732–32739. [PubMed] [Google Scholar]
  35. Yin T., Miyazawa K., Yang Y. C. Characterization of interleukin-11 receptor and protein tyrosine phosphorylation induced by interleukin-11 in mouse 3T3-L1 cells. J Biol Chem. 1992 Apr 25;267(12):8347–8351. [PubMed] [Google Scholar]
  36. Yin T., Taga T., Tsang M. L., Yasukawa K., Kishimoto T., Yang Y. C. Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol. 1993 Sep 1;151(5):2555–2561. [PubMed] [Google Scholar]
  37. Yin T., Yasukawa K., Taga T., Kishimoto T., Yang Y. C. Identification of a 130-kilodalton tyrosine-phosphorylated protein induced by interleukin-11 as JAK2 tyrosine kinase, which associates with gp130 signal transducer. Exp Hematol. 1994 May;22(5):467–472. [PubMed] [Google Scholar]
  38. Yoshida K., Taga T., Saito M., Suematsu S., Kumanogoh A., Tanaka T., Fujiwara H., Hirata M., Yamagami T., Nakahata T. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):407–411. doi: 10.1073/pnas.93.1.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zhou H., Choong P., McCarthy R., Chou S. T., Martin T. J., Ng K. W. In situ hybridization to show sequential expression of osteoblast gene markers during bone formation in vivo. J Bone Miner Res. 1994 Sep;9(9):1489–1499. doi: 10.1002/jbmr.5650090922. [DOI] [PubMed] [Google Scholar]
  40. Zhou H., Hammonds R. G., Jr, Findlay D. M., Fuller P. J., Martin T. J., Ng K. W. Retinoic acid modulation of mRNA levels in malignant, nontransformed, and immortalized osteoblasts. J Bone Miner Res. 1991 Jul;6(7):767–777. doi: 10.1002/jbmr.5650060715. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES