Pathology-associated expression and function of the metalloproteases meprin α and meprin β
By proteolysis, the enzymatic cleavage of peptide bonds, proteins undergo an irreversible posttranslational modification which is used for protein maturation, signaling and cellular adhesion. The work of this thesis approaches the role of the extracellular metalloproteases meprin α and meprin β in physiological and pathological conditions, especially in skin and inflammation related diseases. The first part of this thesis addresses the meprin expression in murine skin and their resulting role in wound healing and deposition of extracellular matrix in this organ. Based on previous findings that meprins are over-expressed in fibrotic and hyperkeratotic skin diseases, we analyzed mouse models over-expressing meprin β in skin in order to study its contribution to the onset of disease. Fra2 transgenic mice develop skin fibrosis and over-express meprin β in skin. Since Fra2 activates several other genes besides the meprin β gene, mouse models directly over-expressing meprin β in skin were generated. Epidermal over-expression of meprin β led to a pigmentary phenotype and hyperproliferation of keratinocytes. On the other hand, a dermal over-expression of meprin β did not show an obvious phenotype or development of fibrosis. The second part focused on proteolytic processing of the adhesion molecule CD99. Cleavage of CD99 by meprin β had an effect on transendothelial migration of cancer cells and inhibition of meprin β delayed infiltration of immune cells in an acute inflammation model. Finally, altered localization of meprin α was investigated during pathological conditions. Under normal conditions, soluble meprin α was observed to bind to epithelial cells via heparan sulphate, which had impact on infiltration of immune cells and epithelial barrier integrity. Moreover, covalent binding of meprin α to meprin β on the secretory pathway could also tether soluble meprin α to the plasma membrane. The altered localization of meprin α contributed to inflammatory disease progression.