Insulin-like growth factors (IGFs) stimulate the proliferation and differentiation of a vast number of cell types. The action of the growth factors is mediated and controlled by a complex system of components, including several proteases that cleave the IGF-Binding Proteins. HtrA1 is a 480 aa protein that contains an N-terminus homologous to MAC25 (IGFBP7) with a conserved Kazal-type serine protease inhibitor motif, as well as a C-terminal PDZ domain. Semiquantitative RT-PCR and immunoblot analyses showed an approximately 7-fold increase of PRSS11 in osteoarthritis cartilage compared with controls. HTRA2 is released from mitochondria and inhibits the function of XIAP by direct binding in a way similar to SMAC. Moreover, when overexpressed extramitochondrially, HTRA2 induced atypical cell death, which was neither accompanied by a significant increase in caspase activity nor inhibited by caspase inhibitors, including XIAP. A catalytically inactive mutant of HTRA2, however, did not induce cell death. Suzuki et al. (2001) concluded that HTRA2 is a SMAC-like inhibitor of IAP (inhibitor of apoptosis proteins) activity with a serine protease-dependent cell death-inducing activity.