The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis.
BACKGROUND
Nephrogenic systemic fibrosis (NSF) occurs in patients with renal dysfunction and gadolinium exposure. Although little is known about the pathogenesis of this disease, increased expression of transforming growth factor-beta has been recently demonstrated. Other fibrosing conditions have been shown to express an imbalance in matrix metalloproteinase (MMP) expression and their corresponding inhibitors. Myofibroblast differentiation, in which cells often express alpha-smooth muscle actin and achieve the ability to contract, is also a hallmark of fibrosis.


OBJECTIVE
We theorized that NSF may overexpress tissue inhibitor of metalloproteinase-1 (TIMP-1), while simultaneously showing decreased expression of MMP-1. As a secondary aim, we sought to evaluate the presence of smooth muscle actin in our samples.


METHODS
We applied immunohistochemistry to 16 skin biopsies from 10 patients with NSF using antibodies to TIMP-1, MMP-1, MMP-2, MMP-9, and alpha-smooth muscle actin. Samples from normal skin, scar, keloid and scleroderma were stained for comparison.


RESULTS
TIMP-1 was strongly expressed in all NSF specimens compared to normal skin. MMP-1 expression was nearly absent in all tested samples. In all 16 NSF cases, the dermal spindle cells did not stain for alpha-smooth muscle actin. MMP-2 and MMP-9 expression was variable but was increased compared to normal skin.


CONCLUSIONS
The expression is semiquantitative and based on immunohistochemistry and unconfirmed by other techniques.


CONCLUSIONS
In NSF, TIMP-1 is strongly expressed and MMP-1 is nearly absent, characteristic of the MMP imbalances seen in other fibrosing processes. Using smooth muscle actin immunohistochemistry, there was no evidence of myofibroblast differentiation.
Kelly
Brent C
BC
Department of Dermatology, University of Texas Medical Branch, Galveston, Texas 77555-0783, USA. bckelly@utmb.edu
Markle
Leslie Scroggins
LS
Vickers
Jennifer L
JL
Petitt
Matthew S
MS
Raimer
Sharon S
SS
McNeese
Catherine
C
D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001707:Biopsy, Needle; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D008875:Middle Aged; D054989:Nephrogenic Fibrosing Dermopathy / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D012016:Reference Values; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D046509:Tissue Culture Techniques; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1