A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines.
OBJECTIVE
To address the effects of a novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), on the induction of matrix metalloproteinases 1 and 13 (MMP-1, MMP-13) by inflammatory cytokines.


METHODS
Human chondrosarcoma cells stimulated with inflammatory cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor alpha) were used to study the effects of CDDO on the induction of MMPs and the invasion of cells through a collagen matrix.


RESULTS
CDDO selectively reduced the induction of MMP-1 and MMP-13 at the levels of messenger RNA and protein. Treatment with CDDO prior to cytokine stimulation enhanced this inhibition, and we demonstrated that CDDO functions at the level of transcription. Additionally, CDDO reduced IL-1beta-mediated invasion of cells through a collagen matrix.


CONCLUSIONS
This study demonstrates that CDDO is a novel inhibitor of MMP-1 and MMP-13 gene expression mediated by inflammatory cytokines. Thus, CDDO may have therapeutic potential for the inhibition of joint degradation in osteoarthritis.
Mix
K S
KS
Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Mengshol
J A
JA
Benbow
U
U
Vincenti
M P
MP
Sporn
M B
MB
Brinckerhoff
C E
CE
D001859:Bone Neoplasms; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002813:Chondrosarcoma; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000235:genetics; D005109:Extracellular Matrix / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053509:Matrix Metalloproteinase 13; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015138:RNA, Nuclear / Q000032:analysis; D013379:Substrate Specificity / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D007375:Interleukin-1; D012333:RNA, Messenger; D015138:RNA, Nuclear; D009828:Oleanolic Acid; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1