{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:07:08Z","timestamp":1790831228634,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1996,11,26]]},"abstract":"<jats:p>\n                    Tetracyclines have recently been shown to have \u201cchondroprotective\u201d effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline &gt; minocycline blocked and reversed both spontaneous and interleukin 1\u03b2-induced OA-NOS activity in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    conditions. Similarly, minocycline \u2265 doxycycline inhibited both lipopolysaccharide- and interferon-\u03b3-stimulated iNOS in RAW 264.7 cells\n                    <jats:italic>in vitro<\/jats:italic>\n                    , as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of\n                    <jats:sc>l<\/jats:sc>\n                    -arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for \u03b2-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of \u03b2-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.93.24.14014","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:16Z","timestamp":1027679656000},"page":"14014-14019","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":378,"title":["A novel mechanism of action of tetracyclines: Effects on nitric\u2009oxide\u2009synthases"],"prefix":"10.1073","volume":"93","author":[{"given":"Ashok\u2009R.","family":"Amin","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of Medicine and Pathology, and Kaplan Cancer Research Center, New York University Medical Center, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukundan\u2009G.","family":"Attur","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of Medicine and Pathology, and Kaplan Cancer Research Center, New York University Medical Center, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geeta\u2009D.","family":"Thakker","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of Medicine and Pathology, and Kaplan Cancer Research Center, New York University Medical Center, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash\u2009D.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of Medicine and Pathology, and Kaplan Cancer Research Center, New York University Medical Center, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranav\u2009R.","family":"Vyas","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; 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