Abstract
Estrogens are important regulators of bone cell function. Osteoblast-derived membrane type 1 matrix metalloproteinses (MT1-MMP) have recently been implied to play an important role in the process of bone resorption by proteolytically activating latent matrix metal-loproteinase-2 (proMMP-2) at the cell surface and degrading tumor necrosis factor-α (TNF-α). In the present study, we observed the effects of 17β-estradiol (E2) on MT1-MMP production and subsequent activation of latent matrix proMMP-2, and also proMMP-2 secretion in cultures of human osteoblastic MG-63 cells. Western immunoblot analysis showed that treatment with increasing doses of E2 in MG-63 cells caused a dose-dependent increase in expression of MT1-MMP protein. Confocal immunohistochemistry analysis also confirmed that E2 induced MT1-MMP synthesis in MG-63 cells. We found unexpectedly that although MT1-MMP synthesis was up-regulated by E2 in cultures of MG-63 cells, activation of proMMP-2 was unchanged, which can be attributed partly to the undetectable tissue inhibitor of metalloproteinase-2 (TIMP-2) protein in MG-63 cells by Western immunoblotting. ProMMP-2 production was also not influenced by E2. In conclusion, E2 induces MT1-MMP protein expression in MG-63 cells while it is not followed by proMMP-2 activation, E2 may suppress bone resorption by accentuated degradation of TNF-α which mediated through increasingly MT1-MMP production in osteoblastic cells.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Turner R.T, Riggs B.L., Spelsberg T.C. Skeletal effects of estrogen. Endocr. Rev. 1994, 16: 275–300.
Rifas L., Fausto A., Scott M.J., Avioli L.V., Welgus H.G. Expression of metalloproteinase and tissue inhibitor of metalloptroteinase in human osteoblast-like cells: metalloproteinase biosythesis. Endocrinology 1994, 134: 213–221.
Meikle M.C., Bord S., Hembry R.M., Compston J., Croucher P.I., Reynold J.J. Human osteoblast in culture synthesize collagenase and other matrix metalloproteinases in response to osteotropic hormones and cytokines. J. Cell. Sci. 1992, 103: 1093–1099.
Westermarck J., Kahari V. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999, 13: 781–792.
Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 1994, 370: 61–65.
Aimes R.T., Quigley J.P. Matrix metalloproteinase-2 is an interstitial collagenase. J. Biol. Chem. 1995, 270: 5872–5876.
D’Ortho M.P., Will H., Atkinson S., Butler G., Messent A., Gavrilovic J., Smith B., Timpl R., Zardi L., Murphy G. Membrane-type matrix metalloproteinase 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur. J. Biochem. 1997, 250: 751–757.
Sato T., del Carmen Ovejero M., Hou P., Heegaard A.M., Kumegawa M., N.T., Delaisse J.M. Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts. J. Cell. Sci. 1997, 110: 589–596.
Zuker S., Drews M., Conner C., Foda H.D., DeClerck Y.A., Langley K.E., Bahou W.F., Docherty A.J.P., Cao J. Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase (MT1-MMP). J. Biol. Chem. 1998, 273: 1216–1222.
Wang Z., Juttermann R., Soloway P.D. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J. Biol. Chem. 2000, 275: 26411–26415.
Ko Y.C., Langley K.E., Mendiaz E.A., Parker V.P., Taylor S.M., DeClerck Y.A. The C-terminal domain of tissue inhibitor of metal-loproteinases-2 is required for cell binding but not for antimetalloproteinase activity. Biochem. Biophys. Res. Commun. 1997, 236: 100–105.
Emmert-Buck M.R., Emonard H.P., Corcoran M.L., Foidart J.M., Stetler-Stevenson W.G. Cell surface binding of TIMP-2 and pro-MMP-2/TIMP-2 complex. FEBS Lett. 1995, 364: 28–32.
Gearing A.J.H., Beckett P., Christodoulou M., Churchill M., Clements J., Davidson A.H., Drummond A.H., Galloeay W.A., R., Gordon J.L., T.M., Mangan M., Miller K., Nayee P., Owen S., Patel S., Thomas W., Wells G., Wood L.M., Woolley K. Processing of tumor necrosis factor-a precursor by metalloproteinases. Nature 1994, 370: 555–557.
McGeehan G.M., Becherer J.D., Jr R.C.B., Boyer C.M., Champion B., Connolly K.M., Conway J.G., Furdon P., Karp S., Kidao S., McElroy A.B., Nichols J., Pryzwansky K.M., Schoenen F., Sekut L., Truesdale A., Verghese M., Warner J., Ways J.P. Regulation of tumor necrosis factor-α processing by a metalloproteinase inhibitor. Nature 1994, 370: 558–561.
Manolagas S.C., Jilka R.L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 1995, 332: 305–311.
Qu Q., Harkonen P.L., Monkkonen J., Vaananen H.K. Conditioned medium of estrogen-treated osteoblasts inhibits osteoclast maturation and function in vitro. Bone 1999, 25: 211–215.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liao, E.Y., Luo, Xh., Deng, X.G. et al. Effects of 17β-estradiol on the expression of membrane type 1 matrix metalloproteinase (MT1-MMP) and MMP-2 in human osteoblastic MG-63 cell cultures. J Endocrinol Invest 24, 876–881 (2001). https://doi.org/10.1007/BF03343945
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03343945