Retinoic acid and oncostatin M combine to promote cartilage degradation via matrix metalloproteinase-13 expression in bovine but not human chondrocytes.
OBJECTIVE
Retinoic acid (RetA) and oncostatin M (OSM) have both been shown to mediate potent effects with respect to extracellular matrix integrity. This study assesses the effects of a RetA + OSM combination on cartilage catabolism.


METHODS
Animal and human cartilage samples were used to assess the ability of RetA + OSM to promote the release of collagen and proteoglycan fragments, which was determined by measuring glycosaminoglycan and hydroxyproline, respectively. Total collagenolytic and tissue inhibitor of metalloproteinases (TIMP) inhibitory activities were determined by bioassay, whilst gene expression of matrix metalloproteinases (MMPs) and TIMP-1 were determined by northern blotting. Immunohistochemistry was used to assess the presence of MMP-1 and -13 in resorbing cartilage explants.


RESULTS
Both agents alone induced proteoglycan release from bovine cartilage, whilst RetA-induced collagen release was variable. Reproducible and synergistic collagenolysis was observed with RetA + OSM, which appeared to be due to MMP-13. Similar collagen release was observed from porcine cartilage. Conversely, no collagen release was seen with human articular cartilage. In primary human chondrocytes, RetA + OSM failed to induce MMP-1 or -13 but caused a significant increase in TIMP-1 expression.


CONCLUSIONS
These novel observations show that the combination of RetA + OSM has profound effects on cartilage matrix turnover, but these effects are species-specific. A better understanding of the mechanism by which this combination differentially regulates MMP and TIMP expression in human chondrocytes could provide valuable insight into new therapeutic strategies aimed at the prevention of cartilage destruction.
Musculoskeletal Research Group, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
W D
WD
Shingleton
D
D
Jones
X
X
Xu
T E
TE
Cawston
A D
AD
Rowan
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D053683:Oncostatin M; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D016207:Cytokines; D018836:Inflammation Mediators; C508351:OSM protein, human; D011509:Proteoglycans; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D053683:Oncostatin M; D014212:Tretinoin; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13