APOPTOSIS AND PROLIFERATION OF FIBROBLASTS DURING POSTNATAL SKIN DEVELOPMENT AND SCLERODERMA IN THE TIGHT-SKIN MOUSE

Tight-skin (Tsk) is a dominant gene mutation that causes a fibrotic sk in disease in mice, similar to human scleroderma. Both conditions are characterized by increased numbers of dermal fibroblasts containing hi gh levels of procollagen mRNA. Whether this fibroblast population aris es from fibroblast growth or fibroblast transcriptional activation is debated. Proliferation and apoptosis of fibroblasts of normal and Tsk mice were studied in skin sections before, at onset, and in establishe d fibrosis. Tissue sections were immunostained with proliferating cell nuclear antigen (PCNA) as proliferation marker. Apoptosis was investi gated by in situ end-labeling of fragmented DNA and nuclear staining w ith propidium iodide. The expression of the apoptosis inhibitor Bcl-2 was investigated by immunohistochemistry. We demonstrate differences i n fibroblast proliferation and apoptosis related to postnatal skin gro wth and development. Neonatal skin exhibits the highest levels of prol iferation and apoptosis in fibroblasts. In contrast, low proliferation and absence of apoptosis characterizes adult fibroblasts. Skin fibrob lasts express Bcl-2 only in newborns, and at other ages Bcl-2 was rest ricted to epithelial cells. Our results also suggest that neither incr eased fibroblast proliferation nor defective apoptosis accounts for th e fibrotic phenotype of Tsk. Therefore, transcriptional activation of extracellular matrix genes appears PCNA more relevant in the pathogene sis of Tsk fibrosis.