TGF-BETA AND BFGF SYNTHESIS AND LOCALIZATION IN DUPUYTRENS DISEASE (NODULAR PALMAR FIBROMATOSIS) RELATIVE TO CELLULAR-ACTIVITY, MYOFIBROBLAST PHENOTYPE AND ONCOFETAL VARIANTS OF FIBRONECTIN

Nodular palmar fibromatosis is a self-limited proliferation of fibro-/ myofibroblasts associated with growth factor synthesis and abundant fi bronectin extracellular matrix deposition. bFGF and TGF beta are poten t modulators of fibro-/myofibroblast proliferation and differentiation . Moreover, in vitro investigations evidenced a TGF beta 1-dependent r egulation of alternative splicing of fibronectin mRNA. To investigate a possible implication of these growth factors in the tissue formation process of palmar fibromatosis, TGF beta 1/2 and bFGF synthesis, as w ell as TGF beta 1/3 and bFGF tissue distribution is demonstrated by RN A in situ hybridization and/or immunohistochemistry in relation to myo fibroblast phenotype development (alpha-smooth muscle actin, desmin im munohistochemistry), expression of different fibronectin isoforms (ED- A(+), ED-B+ and oncofetal glycosylated fibronectin immunohistochemistr y: fibronectin RNA in situ hybridization) and cellular activity (cycli n RNA in situ hybridization, Ki-67 immunolabelling). The myofibroblast phenotype (alpha-smooth muscle actin, desmin), the growth factor synt hesis (TGF beta 1 and 2, bFGF) fibronectin matrix synthesis (RNA in si tu hybridization with cDNA) and ED-A(+), ED-B+ and oncofetal glycosyla ted fibronectin immunostaining are exclusively localized in the active proliferative nodules (Ki-67 immunolabelling and cyclin mRNA demonstr ation). Whereas the growth factor synthesis is restricted to the proli ferative areas of the fibromatosis only, TGF beta 1, TGF beta 3 and bF GF proteins can also be detected immunohistochemically with a lower in tensity in the surrounding aponeurotic tissue. The spatial correlation of myofibroblast phenotype, TGF beta and bFGF synthesis and the occur rence of the oncofetal molecular fibronectin variants (ED-B+ and oncof etal glycosylated fibronectin) in the active proliferative fibromatosi s nodules suggests a pathogentic role of these growth factors and matr ix components in the tumorous tissue formation process. The presence o f the bFGF and TGF beta 1/3 proteins in fibroblasts neighbouring the p roliferative nodules may point to a recruitment of quiescent aponeurot ic fibroblasts in the fibromatous tissue formation process.