Mevastatin reduces cartilage degradation in rabbit experimental osteoarthritis through inhibition of synovial inflammation.
OBJECTIVE
To examine the therapeutic efficacy of an HMG-CoA reductase inhibitor (statin) in rabbit osteoarthritis (OA) in vitro and in vivo.


METHODS
In the presence or absence of mevastatin, rabbit chondrocytes and synoviocytes were incubated with Interleukin-1beta (IL-1beta), and analyzed by biochemical methods. Thirty-two mature rabbits that underwent bilateral anterior cruciate ligament transaction (ACLT) received six consecutive weekly intra-articular injections of mevastatin at three different concentrations or a control solution. All animals were sacrificed 6 weeks after ACLT, and the knee joints were assessed by morphological, histological, immunohistochemical, and biochemical methods.


RESULTS
Mevastatin inhibited IL-1beta stimulation of gene expression of monocyte chemoattractant protein-1 (MCP-1) and matrix-metalloproteinases 3 (MMP-3), in synoviocytes but not chondrocytes. The levels of MCP-1 and MMP-3 productions in synoviocytes were significantly reduced by statin-treatment. In rabbit with OA, intra-articular injection of mevastatin significantly reduced cartilage degradation, as assessed by morphological and histological examinations. Synovial tissues of knees treated with mevastatin showed less severe inflammatory responses with reduced thickness of synovial cell lining and less infiltration of subsynovial CD68+monocyte lineage cells compared to untreated control knees. Relative mRNA expressions of MCP-1, IL-1beta, MMP-3, and MMP-13 were reduced in synovial tissues, but not articular cartilage, of knees treated with mevastatin compared with untreated control knees.


CONCLUSIONS
During the development of experimental OA, intra-articular administration of HMG-CoA reductase inhibitor (statin) reduces inflammatory cell infiltration and matrix-degrading enzyme expression, thus limiting cartilage degradation.
Akasaki
Y
Y
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Matsuda
S
S
Nakayama
K
K
Fukagawa
S
S
Miura
H
H
Iwamoto
Y
Y
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D019902:Chondrocytes / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; C012258:mevastatin; D008148:Lovastatin; D019278:Matrix Metalloproteinase 3