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 a-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 a-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 a-smooth muscle actin. MMP-2 and MMP-9 expression was variable but was increased compared to normal skin. Limitations: 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. (J Am Acad Dermatol 2010;63:483-9.)