Reduced collagenolytic activity of matrix metalloproteinases and development of liver fibrosis in the aging rat.
Although moderate fibrosis is a histological hallmark of the aging liver, the molecular mechanisms underlying this phenomenon are little known. Here, we provide a comprehensive description of hepatic collagen expression and metabolism during natural aging in rats. Interstitial collagen accumulated significantly in the oldest animals, mainly in the periportal area (P<0.05, 19- vs. 2-month-old rats). This was ascribed to COL-III protein deposition (P<0.05 vs. 2-month-old rats), rather than COL-I. Conversely, the transcription activity of COL-III gene decreased (P<0.05) during the considered lifespan (2-19-months), whereas COL-I and transforming growth fator-beta1 (TGF-beta1) mRNA content was substantially unchanged. In the aged rats, hepatic matrix metalloproteinases (MMP) activity, (both MMP-1 and MMP-2) dropped significantly (P<0.05), with a concomitant increase of the inactive tissue inhibitor of MMP (TIMP-1)/MMP-1 complex (P<0.05). MMP-2 and TIMP-1 levels were weakly affected. All together, these results suggest that during natural aging, (i) COL III is the protein that accumulates preferentially in the liver; (ii) liver fibrosclerosis is mainly explained by a reduced proteolytic activity of matrix MMP, in which TIMP-1 seems to be a major regulating factor.
Gagliano
Nicoletta
N
Department of Internal Medicine and Geriatrics, Milan University and Ospedale Maggiore IRCCS, Via Pace 9, 20122, Milan, Italy.
Arosio
Beatrice
B
Grizzi
Fabio
F
Masson
Serge
S
Tagliabue
Jacopo
J
Dioguardi
Nicola
N
Vergani
Carlo
C
Annoni
Giorgio
G
D000375:Aging / Q000378:metabolism*; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006909:Hydroxyproline / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D024061:Collagen Type III; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D006909:Hydroxyproline