UNLIKE TENASCIN-X, TENASCIN-C IS HIGHLY UP-REGULATED IN PIG CUTANEOUSAND UNDERLYING MUSCLE-TISSUE DEVELOPING FIBROSIS AFTER NECROSIS INDUCED BY VERY HIGH-DOSE GAMMA-RADIATION

Fibrosis is characterized by proliferation of fibroblasts and depositi on of extracellular matrix (ECM). As alterations in the composition of ECM may account for its chronic extension, we studied the expression of the tenascin-C (TN-C) and tenascin-X (TN-X) ECM glycoproteins in ou r pig model of the effects of accidental exposures to radiation, in wh ich cutaneous and muscle fibrosis developed after the induction of nec rosis after a high single dose (160 Gy at the skin surface) of gamma r ays. We found that, in the healed fibrotic dermis and underlying muscl e fibrosis, the amount of TN-C mRNA was increased up to 18- and 39-fol d, respectively, compared to normal dermis, whereas the level of TN-X mRNA remained almost unchanged. In analyses by Western blotting, the t wo main TN-C isoforms of 235-240 and 190-200 kDa increased up to 45- a nd 105-fold in fibrotic tissues, respectively. The large isoform was e xpressed more strongly than the smaller, although in healed fibrotic s car tissues their ratio was lower in protein than in RNA. Compared to unirradiated skin, an immunohistological study revealed stronger TN-C staining at the dermo-epidermal junction and in areas of remodeling in healed skin. An intense extracellular staining was observed around my ofibroblasts in muscle fibrosis. Therefore, the gene encoding TN-C is highly up-regulated in fibrotic tissues, and mechanisms regulating the levels of TN-C variants occur at both the RNA and protein levels. Eac h isoform might play a distinct role in the chronic activation of fibr osis by differentially regulating mechanisms like cell adhesion, migra tion or proliferation. (C) 1998 by Radiation Research Society.