{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:13:26Z","timestamp":1790936006626,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2003,6,3]],"date-time":"2003-06-03T00:00:00Z","timestamp":1054598400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2003,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen\u2010activated protein kinase kinase 1\/2 (MEK\u20101\/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal\u2013regulated kinase 1\/2 (phospho\u2013ERK\u20101\/2) and matrix metalloproteinase 1 (MMP\u20101; collagenase 1) in OA chondrocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>After surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg\/kg\/day or 30 mg\/kg\/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho\u2013ERK\u20101\/2 and MMP\u20101 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>OA rabbits treated with the highest dosage of MEK\u20101\/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (<jats:italic>P<\/jats:italic> &lt; 0.002) and in osteophyte width on the lateral condyles (<jats:italic>P<\/jats:italic> = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (<jats:italic>P<\/jats:italic> &lt; 0.02). In cartilage from placebo\u2010treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho\u2013ERK\u20101\/2 and MMP\u20101 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose\u2010dependent reduction in the level of phospho\u2013ERK\u20101\/2 and a lower level of MMP\u20101.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK\u20101\/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho\u2013ERK\u20101\/2 in OA chondrocytes, which probably explains the action of the drug.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.11014","type":"journal-article","created":{"date-parts":[[2003,6,4]],"date-time":"2003-06-04T10:07:16Z","timestamp":1054721236000},"page":"1582-1593","source":"Crossref","is-referenced-by-count":112,"title":["In vivo selective inhibition of mitogen\u2010activated protein kinase kinase 1\/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes"],"prefix":"10.1002","volume":"48","author":[{"given":"Jean\u2010Pierre","family":"Pelletier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio 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