Evidence for species differences in the regulation of MMPs by all-trans retinoic acid in cytokine-stimulated chondrocytes.
In inflammatory conditions, chondrocytes produce large amounts of matrix metalloproteases (MMP) and nitric oxide (NO) thought to contribute to joint degradation. We tested the ability of all-trans retinoic acid (ATRA, a retinoic acid receptor (RAR) agonist) to modulate these inflammatory genes in chondrocytes from humans or rats, chosen as representative of animal models of arthritis. All RAR subtypes and RXR-alpha or -beta were expressed at the mRNA level in both species, although IL-1beta (10 ng/ml) inhibited RAR subtypes more markedly in rat than in human cells. ATRA (300 or 1000 nM) inhibited IL-1-induced expression of iNOS and nitrites level in both species, although the NO pathway was induced maximally in rat cells. ATRA displayed controversial effects on MMPs between rat and human chondrocytes, especially for MMP-9 expression. The effects of ATRA were irrelevant to the nuclear translocation of AP-1. The present data underlines that retinoids have a species-dependent impact on IL-1-induced responses in chondrocytes, suggesting that extrapolation of their pharmacological properties from animal cells has a poor relevance to clinical situation.
Laboratoire de Physiopathologie et Pharmacologie Articulaires, UMR 7561 CNRS-Nancy Université, Vandoeuvre-lès-Nancy, France.
M
M
Kirchmeyer
J
J
Deffaud
S
S
Sebillaud
D
D
Moulin
M
M
Koufany
P
P
Netter
A
A
Bianchi
J-Y
JY
Jouzeau
D000818:Animals; D001172:Arthritis, Rheumatoid; D018929:Cell Culture Techniques; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000187:drug effects / Q000378:metabolism*; D013045:Species Specificity; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
D053583:Interleukin-1beta; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D014212:Tretinoin; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D020782:Matrix Metalloproteinases