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The effect of calcium channel blockers and calmodulin inhibitors on the macrophage factor-stimulated synthesis of collagenase by rabbit chondrocytes

  • Immunosuppression and Inflammations
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Abstract

Macrophages and monocytes secrete a factor(s) which can stimulate the synthesis of collagenase in synovial cells and in chondrocytes. Incubation of rabbit chondrocytes with macrophage conditioned medium (MCM) and with the calcium channel blockers, nifedipine, verapamil or diltiazem (up to 200 μM) had no effect on collagenase synthesis. However, TMB-8 (8-[N, N-diethylamino]-octyl 3,4,5,-trimethoxybenzoate hydrochloride), an inhibitor of internal calcium movement, did inhibit the process with an IC50 of approximately 130 μM. The calmodulin antagonists, trifluoperazine, chlorpromazine and calmidazolium (R-24571) were effective inhibitors of the process with IC50's of 40 μM, 18 μM and 3.5μM, respectively. Collagenase activity itself was not affected by these agents. The data suggests that calmodulin and/or internal calcium movement may play a role in the macrophage factor-stimulated synthesis of collagenase in rabbit chondrocytes.

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References

  1. J. B. McCarthy, S. M. Wahl, J. C. Rees, C. E. Olsen, A. L. Sandberg and L. M. Wahl,Mediation of macrophage collagenase production by 3′–5′ cyclic adenosine monophosmpate. J. Imm.124 (5), 2405–2409 (1980).

    Google Scholar 

  2. S. M. Wahl and L. M. Wahl,Regulation of macrophage collagenase, prostaglandin, and fibroblast-activating-factor production by antiinflammatory agents: different regulatory mechanisms for tissue injury and repair. Cell. Imm.92, 302–312 (1985).

    Article  Google Scholar 

  3. A. L. Oronsky, R. J. Perper and H. C. Schroder,Phagocytic release and activation of human leukocyte procollagenase. Nature246 (5433), 417–419 (1973).

    Article  PubMed  Google Scholar 

  4. E. Wojtecka-Lukasik andA. M. Donecewicz, Inhibition of human leukocyte collagenase by some drugs used in the therapy of rheumatic diseases. Biochem. Pharm.23, 2077–2081 (1974).

    Article  PubMed  Google Scholar 

  5. G. M. Kammer, A. I. Sapolsky and C. J. Malemud,Secretion of an articular cartilage proteoglycan-degrading enzyme activity by murine T lymphocytes in vitro. J. Clin. Invest.76, 395–402 (1985).

    PubMed  Google Scholar 

  6. J. M. Dayer, R. G. G. Russell and S. M. Krane,Collagenase production by rheumatoid synovial cells, Stimulation by a human lymphocyte factor. Science195, 181–183 (1977).

    PubMed  Google Scholar 

  7. P. A. McCroskery, S. Arai, E. P. Amento and S. M. Krane,Stimulation of procollagenas synthesis in human rheumatoid synovial fibroblasts by monouclear cell factor/interleukin 1. FEBS Letters191 (1), 7–12 (1985).

    Article  PubMed  Google Scholar 

  8. C. E. Brinckerhoff, R. M. McMillan, J. M. Dayer and E. D. Harris, Jr.,Inhibition by retinoic acid of collagenase production in rheumatoid synovial cells. New Engl. J. Med.303, 432–436 (1980).

    PubMed  Google Scholar 

  9. S. C. Ridge, A. L. Oronsky and S. S. Kerwar,Induction of the synthesis of latent collagenase and latent neutral protease in chondrocytes by a factor synthesized by activated macrophages. Arth. Rheum.23, 448–454 (1980).

    Google Scholar 

  10. E. D. Harris, Jr.,Pathogenesis of rheumatoid arthritis. Am. J. Med.80 (Suppl. 4BB), 4–10 (1986).

    Article  PubMed  Google Scholar 

  11. J. M. Dayer and S. Demcyuk,Cytokines and other mediators in rheumatoid arthritis. Springer Semin. Immunopathol.7, 387–413 (1984).

    Article  PubMed  Google Scholar 

  12. S. M. Krane and E. P. Amento,Cellular interactions and control of collagenase secretion in the synovium. J. Hheum. Suppl.11, 7–12 (1983).

    Google Scholar 

  13. E. E. Golds, V. Santer, J. Killackey and P. J. Roughley,Mononuclear cell factors stimulate the concomitant secretion of distinct latent proteoglycon, gelatin and collagen degrading enzymes from human skin fibroblasts and synovial cells. J. Rheum.10 (6), 861–871 (1983).

    PubMed  Google Scholar 

  14. C. Peeters-Joris and G. Vaes,Degradation of cartilage proteoglycan and collagen by synovial cells-stimulation by macrophages under activation by phagocytosis, lymphocyte factors, bacterial products or other inflammatory stimuli. Biochem. Biophys. Acta804, 474–486 (1984).

    Article  PubMed  Google Scholar 

  15. S. B. Mizel, J. M. Dayer, S. M. Krane and S. E. Mergenhagen,Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin-1). Proc. Natl. Acad. Sci. USA78 (4), 2474–2477 (1981).

    PubMed  Google Scholar 

  16. J. M. Dayer, B. de Rochemonteix, B. Burrus, S. Demczuk and C. A. Dinarello, Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells. J. Clin. Invest.77, 645–648 (1986).

    PubMed  Google Scholar 

  17. A. E. Postlethwaite, L. B. Lachman, C. L. Mainardi and A. H. Kang,Interleukin 1 stimulation of collagenase production by cultured fibroblasts. J. Exp. Med.157, 801–806 (1983).

    Article  PubMed  Google Scholar 

  18. H. J. Richardson, P. R. Elford, R. M. Sharrad, J. E. Meats and R. G. G. Russell,Modulation of connective tissue metabolism by partially purified human interleukin 1. Cell Immun.90, 41–51 (1985).

    Article  Google Scholar 

  19. G. DiPasquale, R. Caccese, R. Pasternak, J. Conaty, S. Hubbs and K. Perry,Proteoglycan- and collagen-degrading enzymes from human interleukin-1 stimulated chondrocytes from several species: proteoglycanase and collagenase inhibitors as potentially new disease-modifying antiarthritic agents. Proc. Soc. Exp. Biol. Med.183, 262–267 (1986).

    PubMed  Google Scholar 

  20. P. Hasselbacher,Stimulation of synovial fibroblasts by calcium oxallate and monosodium urate monohydrate. J. Lab. Clin. Med.100 (6), 977–985 (1982).

    PubMed  Google Scholar 

  21. C. E. Brinckerhoff, R. M. McMillan, J. V. Fahey and E. D. Harris Jr.,Collagenase production by synovial fibroblasts treated with phorbol myristate acetate. Arthr. Rheum.22, 1109–116 (1979).

    Google Scholar 

  22. L. M. C. Pilsworth, J. Saklatvala,The cartilage-resorbing protein catabolin is made by synovial fibroblasts and its production is increased by phorbol myristate acetate. Biochem. J.216, 481–489 (1983).

    PubMed  Google Scholar 

  23. J. M. Dayer, M. S. Roelke and S. M. Krane,Effects of prostaglandin E 2,ndomethacin, trifluoperazine and drugs affecting the cytoskeleton on collagenase production by cultured adherent rheumatoid synovial cells. Biochem. Pharm.33 (18), 2893–2899 (1984).

    Article  PubMed  Google Scholar 

  24. N. Moskowitz, L. Shapiro, W. Schook and S. Puszkin,Phospholipase A 2 modulation by calmodulin, prostaglandins, and cyclic nucleotides. Biochem. Biophys. Res. Commun.115 (1), 94–99 (1983).

    Article  PubMed  Google Scholar 

  25. J. L. Seltzer, H. G. Welgus, J. J. Jeffrey and A. Z. Eisen,The function of Ca 2+ in the action of mammalian collagenase. Arch. Biochem. Biophys.173, 355–361 (1976).

    Article  PubMed  Google Scholar 

  26. P. D. Benya, S. R. Padella and M. E. Nimni,The Progeny of rabbit articular chondrocytes synthesize collagen Type I and III and Type I trimer but not Type II. Biochemistry16, 865–872 (1977).

    Article  PubMed  Google Scholar 

  27. M. T. Gisslow and B. C. McBride,A rapid sensitive collagenase assay. Anal. Biochem.68, 70–78 (1975).

    Article  PubMed  Google Scholar 

  28. R. J. Smith and S. S. Iden,Phorbol myristate acetate-induced release of granule enzymes from human neutrophils: inhibition by the calcium antagonist, 8-(N, N-diethylamino)-octyl 3,4,5-trimethoxybenzoate hydrochloride. Biochem. Biophys. Res. Commun.91 (1), 263–271 (1979).

    Article  PubMed  Google Scholar 

  29. A. B. Stavisty, J. R. Dasch and L. Astrachon,Effects of trifluoperazine, a calmodulin antagonist, on rabbit T- and B-cell responses to mitogens and antigen. Cell. Imm.87, 411–423 (1984).

    Article  Google Scholar 

  30. B. Wright, I. Zeidman, R. Greig and G. Poste,Inhibition of macrophage activation by calcium channel blockers and calmodulin antagonists. Cell. Imm.95, 46–53 (1985).

    Article  Google Scholar 

  31. J. C. Nolan and W. C. Pickett,Studies on the effects of cyclo-oxygenase and lipoxygenase inhibitors on the macrophage stimulated synthesis of collagenase by rabbit chondrocytes. Agents Actions17, 73–76 (1985).

    Article  PubMed  Google Scholar 

  32. J. Aggeler, S. M. Frisch and Z. Werb,Changes in cell shape correlate with collagenase gene expression in rabbit synovial fibroblasts. J. Cell Biol.98, 1662–1671 (1984).

    Article  PubMed  Google Scholar 

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  1. Department of Pharmacology, A. H. Robins Company, 1211 Sherwood Avenue, 23220, Richmond, VA, USA

    J. C. Nolan, C. E. Gathright & L. E. Wagner

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  3. L. E. Wagner
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Nolan, J.C., Gathright, C.E. & Wagner, L.E. The effect of calcium channel blockers and calmodulin inhibitors on the macrophage factor-stimulated synthesis of collagenase by rabbit chondrocytes. Agents and Actions 25, 71–76 (1988). https://doi.org/10.1007/BF01969097

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