Characterization of cathepsins in cartilage.
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ABSTRACT:
SUBMITTER: Ali SY
PROVIDER: S-EPMC1198344 | biostudies-other | 1967 Nov
REPOSITORIES: biostudies-other
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Project description:Cathepsins are lysosomal peptidases belonging to the papain family, and based on their catalytic sites, these enzymes can be divided into serine, cysteine and aspartic proteases. The studies conducted to date have identified, 15 types of cathepsins that are widely distributed in intracellular and extracellular spaces. These proteases participate in various pathological activities, including the occurrence and development of human cancers. Several recent studies suggest that cathepsins, particularly cathepsins B, D, E and L, contribute to digestive tumorigenesis. Cathepsins were found to promote the development of most digestive cancers except liver cancer, in which they might have the opposite effects. Due to their important roles in digestive tumors, cathepsins might be therapeutic targets for the treatment of digestive cancers.
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Project description:Cathepsins are proteolytic enzymes with a broad spectrum of substrates. They are known to reside within endo-lysosomes where they acquire optimal conditions for proteolytic activity and substrate cleavage. However, cathepsins have been detected in locations other than the canonical compartments of the endocytotic pathway. They are often secreted from cells in either proteolytically inactive proform or as mature and active enzyme; this may happen in both physiological and pathological conditions. Moreover, cytosolic and nuclear forms of cathepsins have been described and are currently an emerging field of research aiming at understanding their functions in such unexpected cellular locations. This chapter summarizes the canonical pathways of biosynthesis and transport of cathepsins in healthy cells. We further describe how cathepsins can reach unexpected locations such as the extracellular space or the cytosol and the nuclear matrix. No matter where viruses and cathepsins encounter, several outcomes can be perceived. Thus, scenarios are discussed on how cathepsins may support virus entry into host cells, involve in viral fusion factor and polyprotein processing in different host cell compartments, or help in packaging of viral particles during maturation. It is of note to mention that this review is not meant to comprehensively cover the present literature on viruses encountering cathepsins but rather illustrates, on some representative examples, the possible roles of cathepsins in replication of viruses and in the course of disease.
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Project description:Heavy metal ions can disrupt biological functions via multiple molecular mechanisms, including inhibition of enzymes. We investigate the interactions of human papain-like cysteine endopeptidases cathepsins L, K, and S with gallium and cerium ions, which are associated with medical applications. We compare these results with zinc and lead, which are known to inhibit thiol enzymes. We show that Ga3+, Ce3+, and Ce4+ ions inhibit all tested peptidases with inhibition constants in the low micromolar range (between 0.5 µM and 10 µM) which is comparable to Zn2+ ions, whereas inhibition constants of Pb2+ ions are one order of magnitude higher (30 µM to 150 µM). All tested ions are linear specific inhibitors of cathepsin L, but cathepsins K and S are inhibited by Ga3+, Ce3+, and Ce4+ ions via hyperbolic inhibition mechanisms. This indicates a mode of interaction different from that of Zn2+ and Pb2+ ions, which act as linear specific inhibitors of all peptidases. All ions also inhibit the degradation of insoluble elastin, which is a common target of these peptidases in various inflammatory diseases. Our results suggest that these ions and their compounds have the potential to be used as cysteine cathepsin inhibitors in vitro and possibly in vivo.
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Project description:Osteoarthritis is characterized by a loss of extracellular matrix that leads to cartilage degradation and joint space narrowing. Specific proteases, including the aggrecanases ADAMTS-4 and matrix metalloproteinase 3, are important in initiating and promoting cartilage degradation in osteoarthritis. This study investigated protease-specific and disease-specific cleavage patterns of particular extracellular matrix proteins by comparing new peptide fragments, neopeptides, in specific exogenous protease-driven digestion of a crude cartilage proteoglycan extract and an in-vitro model of early osteoarthritis. Additionally, equine cartilage explants were treated with interleukin-1 and the media collected. Proteolytic cleavage products following trypsin digestion were then identified using tandem mass spectrometry. Complete sequences of proteolytically cleaved neopeptides were determined for the major cartilage proteoglycans aggrecan, biglycan, decorin, fibromodulin plus cartilage oligomeric matrix protein. The generation of neopeptides varied with enzyme specificity; however, some peptides were common to all samples. Previous known and novel cleavage sites were identifies. The identification of novel peptide fragments provides a platform for the development of antibodies that could assist in the identification of biomarkers for osteoarthritis (OA), as well as the identification of basic biochemical processes underlying OA.
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Project description:Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context.
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