INFLUENCE OF EXTRACELLULAR-MATRIX MACROMOLECULES ON NORMAL HUMAN KERATINOCYTE PHENOTYPE AND PARATHYROID HORMONE-RELATED PROTEIN SECRETION AND EXPRESSION IN-VITRO

Parathyroid hormone-related protein (PTHrP) is produced by a wide rang e of neoplastic and normal cells, including keratinocytes where it mag be involved in the regulation of cellular growth and differentiation, There is evidence that the nature of the extracellular matrix (ECM) i nfluences gene expression and cell phenotype, The objective of this st udy was to investigate the phenotype of normal human keratinocytes gro wn on different types of ECM (basement membrane components or collagen type I), as well as the expression and secretion of PTHrP. Normal ker atinocytes grown on basement membrane extract (Matrigel) actively reor ganized the matrix and formed networks of cells with traction of the m atrix. This was associated with linear arrays of intracellular microtu bules and formation of prominent actin stress fibers and was suppresse d by treatment with colchicine or cytochalasin B, confirming the role of the cytoskeleton in this process. In addition, growth on Matrigel w as associated with increased PTHrP nuclear translocation, secretion, a nd mRNA expression compared to growth on collagen where keratinocytes exhibited decreased proliferation and increased differentiation, PTHrP , as a paracrine keratinocyte factor, did not appear to mediate the mo rphologic changes, since they were not altered by treatment with neutr alizing anti-PTHrP antibodies. It was concluded that different types o f ECM influenced the morphologic, functional, and proliferative charac teristics of keratinocytes, as well as the level of PTHrP expression a nd secretion in vitro. (C) 1998 Academic Press.