This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DIBATTISTA, J. A. Articles by PELLETIER, J.-P. Search for Related Content PubMed PubMed Citation Articles by DIBATTISTA, J. A. Articles by PELLETIER, J.-P.

Glucocorticoid Receptor Mediated Inhibition of Interleukin-1 Stimulated Neutral Metalloprotease Synthesis in Normal Human Chondrocytes^*

JOHN A. DIBATTISTA, JOHANNE MARTEL-PELLETIER, LEONARD O. WOSU, THOMAS SANDOR, TONY ANTAKLY and JEAN-PIERRE PELLETIER

Rheumatic Disease Unit (J.D.B., J.M.P., L.O. W., J-P.P.) and Endocrine Laboratory (T.S.), Notre-Dame Hospital; Department of Medicine, University of Montreal H2L 4K8; and Department of Anatomy (T.A.), McGill University H3A 2B2 Montréal, Québec, Canada

Address requests for reprints to: Dr. J.-P. Pelletier, Rheumatic Disease Unit, Notre-Dame Hospital, P.O. Box 1560, Station C, Montréal, Québec, Canada H2L 4K8.

Glucocorticoids play an important role in the therapy of arthritic diseases. We sought, firstly, to identify, characterize and localize glucocorticoid receptors (GR) in normal human chondrocytes and, secondly, to determine whether glucocorticoid suppression of human recombinant interleukin-1β (rhIL-lβ)-stimulated metalloproteases (MPs) synthesis by chondrocytes requires GR occupancy. Radioligand binding studies with cultured chondrocytes revealed the presence of high affinity-low capacity [³H]dexamethasone (DEX) binding sites with the following kinetic parameters: K_b = 12.5 ± 1.4 nmol/L, N_max = 57,560 ± 3,960 sites per cell. Competition studies indicated that the DEX binding site was glucocorticoid specific and the competitive hierarchy established was: DEX > RU-26988 > RU-486 > cortisol > progesterone >> testosterone > estradiol-17β. Immunocytochemical studies using a specific anti-human GR antiserum identified immunoreactive material primarily in the cytoplasm with cells cultured in the absence of glucocorticoids. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis-Western immunoblotting analysis of chondrocyte cytosol detected the presence of a macromolecular species comigrating with a standard protein possessing a molecular weight of 94 kilodalton. rhIL-1β provoked the synthesis and secretion of the MPs stromelysin and collagenase from human chondrocytes in a saturable, coordinate, and dose-dependent fashion. DEX and cortisol inhibited the cytokine-stimulated MP synthesis in similar dose-dependent fashions: DEX, IC₅₀ for stromelysin and collagenase suppression was 1.12 x 10^–8 mol/L and 1.26 x 10^–9 mol/L, respectively and the IC₅₀ for cortisol was 6.3 x 10^–7 mol/L and 4.9 x 10^–8 mol/L, respectively rhIL-1β failed to stimulate metalloprotease synthesis and release from chondrocytes pretreated with 10 nmol/L DEX, even after 20 days of incubation. The antiglucocorticoid, RU-486 CDmpletely reversed the DEX induced suppression of MP synthesis at 10^–7 mol/L. RU-486 alone had no effect on MP synthesis. We believe there is a biochemical rationale for the therapeutic efficacy of glucocorti-coid administration in the management of arthritic diseases such as osteoarthritis and rheumatoid arthritis, and cytokines such as IL-1 are likely to be involved in the increase in MP synthesis. (J Clin Endocrinol Metub 72: 316–326, 1991)

^* This work was supported by grants from the Canadian Arthritis Society (C.A.S.) and the Medical Research Council of Canada (M.R.C.).

Postdoctoral Fellow of the C.A.S.

Career Investigator of the M.R.C.

Received January 30, 1990.

This article has been cited by other articles:

				H. Jarvelainen, A. Sainio, M. Koulu, T. N. Wight, and R. Penttinen Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy Pharmacol. Rev., June 1, 2009; 61(2): 198 - 223. [Abstract] [Full Text] [PDF]

				R. H. Oakley, J. C. Webster, M. Sar, C. R. Parker Jr., and J. A. Cidlowski Expression and Subcellular Distribution of the {beta}-Isoform of the Human Glucocorticoid Receptor Endocrinology, November 1, 1997; 138(11): 5028 - 5038. [Abstract] [Full Text] [PDF]