Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor

doi:10.1084/jem.182.2.449

This Article

	Full Text (PDF, 1541K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Conway, J. G.
	Articles by Clark, R. L.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Conway, J. G.
	Articles by Clark, R. L.


Social Bookmarking

	What's this?

ARTICLES

Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor

JG Conway, JA Wakefield, RH Brown, BE Marron, L Sekut, SA Stimpson, A McElroy, JA Menius, JJ Jeffreys and RL Clark
Department of Pharmacology, Glaxo Inc., Research Triangle Park, North Carolina 27709, USA.

Considerable evidence has associated the expression of matrix metalloproteinases (MMPs) with the degradation of cartilage and bone in chronic conditions such as arthritis. Direct evaluation of MMPs' role in vivo has awaited the development of MMP inhibitors with appropriate pharmacological properties. We have identified butanediamide, N4- hydroxy-2-(2-methylpropyl)-N1-[2-[[2-(morpholinyl)ethyl]-,[S- (R*,S*)] (GI168) as a potent MMP inhibitor with sufficient solubility and stability to permit evaluation in an experimental model of chronic destructive arthritis (adjuvant-induced arthritis) in rats. In this model, pronounced acute and chronic synovial inflammation, distal tibia and metatarsal marrow hyperplasia associated with osteoclasia, severe bone and cartilage destruction, and ectopic new bone growth are well developed by 3 wk after adjuvant injection. Rats were injected with Freund's adjuvant on day 0. GI168 was was administered systemically from days 8 to 21 by osmotic minipumps implanted subcutaneously. GI168 at 6, 12, and 25 mg/kg per d reduced ankle swelling in a dose-related fashion. Radiological and histological ankle joint evaluation on day 22 revealed a profound dose related inhibition of bone and cartilage destruction in treated rats relative to rats receiving vehicle alone. A significant reduction in edema, pannus formation, periosteal new bone growth and the numbers of adherent marrow osteoclasts was also noted. However, no significant decrease in polymorphonuclear and mononuclear leukocyte infiltration of synovium and marrow hematopoietic cellularity was seen. This unique profile of antiarthritic activity indicates that GI168 is osteo- and chondro-protective, and it supports a direct role for MMP in cartilage and bone damage and pannus formation in adjuvant- induced arthritis.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Jones, D H., Kong, Y-Y, Penninger, J M (2002). Role of RANKL and RANK in bone loss and arthritis. Ann Rheum Dis 61: ii32-39 [Abstract] [Full Text]
Hou, W.-S., Li, Z., Gordon, R. E., Chan, K., Klein, M. J., Levy, R., Keysser, M., Keyszer, G., Bromme, D. (2001). Cathepsin K Is a Critical Protease in Synovial Fibroblast-Mediated Collagen Degradation. Am. J. Pathol. 159: 2167-2177 [Abstract] [Full Text]
Li, X., Bradford, B. U., Wheeler, M. D., Stimpson, S. A., Pink, H. M., Brodie, T. A., Schwab, J. H., Thurman, R. G. (2001). Dietary Glycine Prevents Peptidoglycan Polysaccharide-Induced Reactive Arthritis in the Rat: Role for Glycine-Gated Chloride Channel. Infect. Immun. 69: 5883-5891 [Abstract] [Full Text]
Conway, J. G., Andrews, R. C., Beaudet, B., Bickett, D. M., Boncek, V., Brodie, T. A., Clark, R. L., Crumrine, R. C., Leenitzer, M. A., McDougald, D. L., Han, B., Hedeen, K., Lin, P., Milla, M., Moss, M., Pink, H., Rabinowitz, M. H., Tippin, T., Scates, P. W., Selph, J., Stimpson, S. A., Warner, J., Becherer, J. D. (2001). 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. 298: 900-908 [Abstract] [Full Text]
Medina, O. P., Söderlund, T., Laakkonen, L. J., Tuominen, E. K. J., Koivunen, E., Kinnunen, P. K. J. (2001). Binding of Novel Peptide Inhibitors of Type IV Collagenases to Phospholipid Membranes and Use in Liposome Targeting to Tumor Cells in Vitro. Cancer Res. 61: 3978-3985 [Abstract] [Full Text]
Daniel, C., Duffield, J., Brunner, T., Steinmann-Niggli, K., Lods, N., Marti, H.-P. (2001). Matrix Metalloproteinase Inhibitors Cause Cell Cycle Arrest and Apoptosis in Glomerular Mesangial Cells. J. Pharmacol. Exp. Ther. 297: 57-68 [Abstract] [Full Text]
Lee, P.-P. H., Hwang, J.-J., Murphy, G., Ip, M. M. (2000). Functional Significance of MMP-9 in Tumor Necrosis Factor-Induced Proliferation and Branching Morphogenesis of Mammary Epithelial Cells. Endocrinology 141: 3764-3773 [Abstract] [Full Text]
Stallmach, A, Chan, C C, Ecker, K-W, Feifel, G, Herbst, H, Schuppan, D, Zeitz, M (2000). Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 47: 415-422 [Abstract] [Full Text]
Barille, S., Bataille, R., Rapp, M.-J., Harousseau, J.-L., Amiot, M. (1999). Production of Metalloproteinase-7 (Matrilysin) by Human Myeloma Cells and Its Potential Involvement in Metalloproteinase-2 Activation. J. Immunol. 163: 5723-5728 [Abstract] [Full Text]
Barille, S., Akhoundi, C., Collette, M., Mellerin, M.-P., Rapp, M.-J., Harousseau, J.-L., Bataille, R., Amiot, M. (1997). Metalloproteinases in Multiple Myeloma: Production of Matrix Metalloproteinase-9 (MMP-9), Activation of proMMP-2, and Induction of MMP-1 by Myeloma Cells. Blood 90: 1649-1655 [Abstract] [Full Text]