Journal of Cell Science, Vol 107, Issue 11 3055-3064, Copyright © 1994 by Company of Biologists

JOURNAL ARTICLES

The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts

PA Hill, G Murphy, AJ Docherty, RM Hembry, TA Millican, JJ Reynolds and MC Meikle
Cell and Molecular Biology Department, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.

We have compared the effects of a general matrix metalloproteinase (MMP) inhibitor (CT435) with those of a concentration-dependent specific gelatinase inhibitor (CT543; Ki < 20 nM) on bone resorption in vitro. The test systems consisted of measuring: (i) the release of 45Ca2+ from prelabelled mouse calvarial explants; (ii) the release of 45Ca2+ from prelabelled osteoid-free calvarial explants co-cultured with purified chicken osteoclasts; and (iii) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. Both CT435 and CT543 dose-dependently inhibited the release of 45Ca2+ from neonatal calvarial bones stimulated by either parathyroid hormone or 1,25-dihydroxyvitamin D3. Moreover, CT543 produced a 40% inhibition at a concentration (10(-8) M) selective for the inhibition of human gelatinases A and B. CT435 (10(-5) M) and CT543 (10(-5) M) partially inhibited the release of 45Ca2+ from osteoid-free calvarial explants by chicken osteoclasts with a maximum of approximately 25% for unstimulated cultures, and approximately 36% for cultures stimulated by interleukin-1 alpha (IL-1 alpha; 10(-10) M). Neither inhibitor prevented lacunar resorption on ivory by unstimulated rat osteoclasts, but the compounds produced a partial reduction in both the number and total surface area of lacunae in IL-1 alpha-stimulated cultures, with maximal action at 10(-5) M. Neither of the inhibitors affected protein or DNA synthesis, nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme beta-glucuronidase. Immunocytochemistry demonstrated that isolated rabbit osteoclasts constitutively expressed gelatinase A and synthesized gelatinase B, collagenase and stromelysin, as well as the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) following IL-1 alpha stimulation. These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption. They further suggest that MMPs produced by osteoclasts are released into the sub-osteoclastic resorption zone where they participate in bone collagen degradation.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				G. Kayaoglu and D. Orstavik VIRULENCE FACTORS OF ENTEROCOCCUS FAECALIS: RELATIONSHIP TO ENDODONTIC DISEASE Critical Reviews in Oral Biology & Medicine, September 1, 2004; 15(5): 308 - 320. [Abstract] [Full Text] [PDF]

				P. Spessotto, F. M. Rossi, M. Degan, R. Di Francia, R. Perris, A. Colombatti, and V. Gattei Hyaluronan-CD44 interaction hampers migration of osteoclast-like cells by down-regulating MMP-9 J. Cell Biol., September 16, 2002; 158(6): 1133 - 1144. [Abstract] [Full Text] [PDF]

				B. Winding, R. NicAmhlaoibh, H. Misander, P. Hoegh-Andersen, T. L. Andersen, C. Holst-Hansen, A.-M. Heegaard, N. T. Foged, N. Brunner, and J.-M. Delaisse Synthetic Matrix Metalloproteinase Inhibitors Inhibit Growth of Established Breast Cancer Osteolytic Lesions and Prolong Survival in Mice Clin. Cancer Res., June 1, 2002; 8(6): 1932 - 1939. [Abstract] [Full Text] [PDF]

				J. A. Nemeth, R. Yousif, M. Herzog, M. Che, J. Upadhyay, B. Shekarriz, S. Bhagat, C. Mullins, R. Fridman, and M. L. Cher Matrix Metalloproteinase Activity, Bone Matrix Turnover, and Tumor Cell Proliferation in Prostate Cancer Bone Metastasis J Natl Cancer Inst, January 2, 2002; 94(1): 17 - 25. [Abstract] [Full Text] [PDF]

				J. G. Conway, R. C. Andrews, B. Beaudet, D. M. Bickett, V. Boncek, T. A. Brodie, R. L. Clark, R. C. Crumrine, M. A. Leenitzer, D. L. McDougald, et al. Inhibition of Tumor Necrosis Factor-alpha (TNF-alpha ) Production and Arthritis in the Rat by GW3333, a Dual Inhibitor of TNF-alpha -Converting Enzyme and Matrix Metalloproteinases J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 900 - 908. [Abstract] [Full Text]

				M. T. Engsig, Q.-J. Chen, T. H. Vu, A.-C. Pedersen, B. Therkidsen, L. R. Lund, K. Henriksen, T. Lenhard, N. T. Foged, Z. Werb, et al. Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones J. Cell Biol., November 13, 2000; 151(4): 879 - 890. [Abstract] [Full Text] [PDF]

				P. A. Hill, A. Tumber, S. Papaioannou, and M. C. Meikle The Cellular Actions of Interleukin-11 on Bone Resorption in Vitro Endocrinology, April 1, 1998; 139(4): 1564 - 1572. [Abstract] [Full Text] [PDF]

				K. Kusano, C. Miyaura, M. Inada, T. Tamura, A. Ito, H. Nagase, K. Kamoi, and T. Suda Regulation of Matrix Metalloproteinases (MMP-2, -3, -9, and -13) by Interleukin-1 and Interleukin-6 in Mouse Calvaria: Association of MMP Induction with Bone Resorption Endocrinology, March 1, 1998; 139(3): 1338 - 1345. [Abstract] [Full Text] [PDF]

				L. S. Holliday, H. G. Welgus, C. J. Fliszar, G. M. Veith, J. J. Jeffrey, and S. L. Gluck Initiation of Osteoclast Bone Resorption by Interstitial Collagenase J. Biol. Chem., August 29, 1997; 272(35): 22053 - 22058. [Abstract] [Full Text] [PDF]

				T Sato, M del Carmen Ovejero, P Hou, A. Heegaard, M Kumegawa, N. Foged, and J. Delaisse Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts J. Cell Sci., January 3, 1997; 110(5): 589 - 596. [Abstract] [PDF]

				L Blavier and J. Delaisse Matrix metalloproteinases are obligatory for the migration of preosteoclasts to the developing marrow cavity of primitive long bones J. Cell Sci., January 12, 1995; 108(12): 3649 - 3659. [Abstract] [PDF]

				H. Vaananen and M Horton The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure J. Cell Sci., January 8, 1995; 108(8): 2729 - 2732. [PDF]