Differential calcium independent regulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases by interleukin-1beta and transforming growth factor-beta in Peyronie's plaque fibroblasts.
OBJECTIVE
Peyronie's disease is a fibrotic disorder of the tunica albuginea characterized by the localized formation of an inelastic plaque. We characterized matrix metalloproteinases and TIMPs (tissue inhibitors of matrix metalloproteinase) in Peyronie's disease tissue.


METHODS
Matrix metalloproteinases and TIMPs were investigated in Peyronie's disease plaque tunica removed from patients with stable Peyronie's disease. Immunological methods were used to characterize the matrix metalloproteinases and TIMPs produced by cell cultures stimulated with transforming growth factor-beta or interleukin-1beta (PreproTech, Rocky Hill, New Jersey). Enzyme activity was quantified with a fluorescent substrate and correlated with mRNA levels using real-time polymerase chain reaction.


RESULTS
Interleukin-1beta significantly induced (p <0.01) matrix metalloproteinase-1, 3, 10 and 13 protein production, endogenous matrix metalloproteinase-13 activity (12-fold) and matrix metalloproteinase-13 mRNA expression (11.2-fold) through a Ca(2+) independent mechanism in cultured fibroblasts. Transforming growth factor-beta stimulation failed to induce any detectable matrix metalloproteinase protein production or activity and conditioned culture medium even had the capacity to inhibit (p <0.01) the activity of purified recombinant human matrix metalloproteinase-13. Intact Peyronie's disease plaques were highly enriched with TIMP-1 to 4 compared to donor matched perilesional tunica.


CONCLUSIONS
These data show that, while interleukin-1beta strongly induces matrix metalloproteinase expression, transforming growth factor-beta strongly induces TIMP expression without any effect on matrix metalloproteinases and may represent an important downstream biochemical mechanism that leads to the progression of Peyronie's disease. The localized accumulation of TIMPs together with decreased matrix metalloproteinase activity in the Peyronie's disease lesion may be the biochemical consequence of the transforming growth factor-beta over expression that has been reported in many fibrotic disorders, including Peyronie's disease.
Del Carlo
Marcello
M
Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, USA.
Cole
Ada A
AA
Levine
Laurence A
LA
D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D010411:Penile Induration / Q000201:enzymology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D053583:Interleukin-1beta; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases