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Molecular Changes in Human Osteoarthritic Cartilage After 3 Weeks of Oral Administration of BAY 12-9566, a Matrix Metalloproteinase Inhibitor
RICHARD L. LEFF, ILEANA ELIAS, MIRELA IONESCU, AGNES REINER, and A. ROBIN POOLE
ABSTRACT. Methods. Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage. Results. Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected. Conclusion. BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content. (J Rheumatol 2003;30:544-9) Key Indexing Terms:
OSTEOARTHRITIS
From the Bayer Corporation, West Haven, Connecticut, USA; Bayer, Inc., Toronto, Ontario; Joint Diseases Laboratory, Shriners Hospital for Children, Montreal, Quebec; and Departments of Surgery and Medicine, McGill University, Montreal, Quebec, Canada. Supported by an unrestricted research grant from Bayer Inc. in addition to funding from Shriners Hospitals for Children, the Canadian Institutes of Health Research, the Council of Canada, the Canadian Arthritis Network, and the National Institute of Ageing, National Institutes of Health. R.L. Leff, MD, Astra Zeneca Pharmaceuticals, Wilmington, DE, USA; I. Elias, PhD, Aventis Pasteur Limited, Toronto, Canada; M. Ionescu, MSc; A. Reiner, MSc; A.R. Poole, PhD, DSc, Shriners Hospital for Children, McGill University. Address reprint requests to Dr. A.R. Poole, Joint Diseases Laboratory, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, Quebec H3G 1A6, Canada. E-mail: rpoole@shriners.mcgill.ca Submitted February 28, 2002; revision accepted August 21, 2002. |