Cathepsin K in thyroid epithelial cells

Extracellular proteolysis is a cellular activity of central importance as it is a key event for the modulation of the extracellular matrix during cell migration, epithelial morphogenesis and tumor metastasis. In recent years, thyrocytes have proved to be a useful model to study extracellular proteolysis mainly through the degradation of thyroglobulin (Tg) (Brix et al., 1996). Tg (Mercken et al., 1985), the major secretory product of thyroid epithelial cells, is stored in the extracellular lumen of thyroid follicles at high concentrations of up to 800 mg/ml (Hayden et al., 1970; Smeds, 1972; Herzog et al., 1992; Berndorfer et al., 1996). Luminal Tg occurs in a soluble or covalently cross-linked form (Herzog et al., 1992; Berndorfer et al., 1996; Saber-Lichtenberg et al., 2000). Because covalently cross-linked Tg can fill the entire follicle lumen, thereby forming globules of 20-120 μm, an extracellular solubilization process before endocytosis of Tg by thyroid epithelial cells has been postulated (Herzog et al., 1992). First evidence for luminal proteolysis came from Robertis, 1941. Later, with the discovery of lysosomes, the concept was conceived that storage and degradation of Tg are separated in time and space. Recently, we showed that limited proteolysis of Tg at the surface of thyroid epithelial cells precedes its endocytosis (Brix et al., 1996), which might also account for the solubilization of covalently cross-linked Tg. The process of extracellular proteolysis of Tg is largely mediated by secreted cysteine proteases, e.g. cathepsins B and L, and results in the rapid liberation of thyroxine (T4) from the prohormone Tg (Brix et al., 1996). Finally, Tg is internalized by thyroid epithelial cells for complete degradation and triiodothyronine (T3) liberation within lysosomes (Brix et al., 1996). Despite the importance of lysosomal protein degradation, thyroid epithelial cells can be regarded as a physiologically important example of lysosomal cysteine proteases being involved in extracellular proteolysis under non-pathological conditions. In order to identify the spectrum of participating enzymes we were interested in other cysteine proteases involved in this process. Whereas the lysosomal cysteine proteases cathepsins B, H and L are assumed to occur ubiquitously, expression of the cathepsins S and K is believed to be restricted to certain tissues or cell types (Wiederanders et al., 1992; Drake et al., 1996; Chapman et al., 1997; Uchiyama et al., 1989; Brix et al., 1996). Cathepsin S has been detected in rat FRTand FRTL-5 cell lines (Petanceska and Devi, 1992), but is not expressed by epithelial cells of the porcine thyroid (K. B. and B. Wiederanders, unpublished observation). Cathepsin K, a new member of the family of lysosomal cysteine proteases, is primarily expressed in ovary and in 4487 Journal of Cell Science 113, 4487-4498 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS1678