Disease relevance of CTSK

• Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature [1].
• 9. Its capacity to efficiently degrade Type I collagen and its high expression in osteoclasts suggest that cathepsin O2 may play a major role in human osteoclastic bone resorption [2].
• Cathepsin O2, a human cysteine protease predominantly present in osteoclasts, has been functionally expressed in Spodoptera frugiperda Sf9 cells using the Autographa californica nuclear polyhedrosis virus [2].
• Our results show that cathepsin X is not involved in degradation of extracellular matrix, a proteolytic event leading to tumor cell invasion and metastasis [3].
• Protein level of cathepsin X did not differ significantly between matched pairs of lung tumor and adjacent lung tissue obtained from patients with lung cancer whereas that of cathepsin B was 9.6-fold higher in tumor compared to adjacent lung tissue [3].
• CTSK was up-regulated in the WAT of overweight/obese subjects, and it had a significant positive correlation with body mass index [4].
• Coculture of CTSK+ fibroblasts enhanced the invasion of CTSK- breast tumor epithelial cells and this was blocked by CTSK inhibitors [5].

High impact information on CTSK

• Primary lung fibroblasts derived from CTSK(-/-) mice showed a decreased collagenolytic activity indicating the role of catK in collagen degradation [6].
• The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes [1].
• Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus [1].
• However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population [1].
• We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al [1].

Biological context of CTSK

• Genomic organization and chromosome localization of the human cathepsin K gene (CTSK) [7].
• RESULTS AND CONCLUSIONS: We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (> 1% frequency), and found that three STRs at the immediate 5' end of the CTSK locus are highly polymorphic [1].
• The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced [8].
• From a model of the protease complexed with Cbz-FRF, the bound carboxypeptidase substrate is predicted to establish a number of favorable contacts within the cathepsin X binding site, in particular with residues His23 and Tyr27 from the mini-loop [9].
• Cathepsin X is a novel cysteine protease which was identified recently from the EST (expressed sequence tags) database [9].

Anatomical context of CTSK

• Cathepsin X mRNA was localized to multinucleated giant cells within the osteoclastoma tumor by in situ hybridization [10].
• Two cell lines with proven invasive behavior, MCF-10A neoT and MDA-MB 231, showed positive staining for cathepsin B, but negative for cathepsin X [3].
• Immunohistochemical analysis of lung tumor cathepsin X revealed very faint staining in tumor cells but positive staining in infiltrated histiocytes, alveolar macrophages, bronchial epithelial cells, and alveolar type II cells [3].
• Cathepsin X stained positive also in CD68+ cells in germinal centers of secondary follicles in lymph nodes, corresponding to tingible body macrophages [3].
• Cathepsin X was found in large amounts in the pro-monocytic U-937 cell line, in monocytes and in dendritic cells, generated from monocytes in vitro [3].

Associations of CTSK with chemical compounds

• The mononuclear cells resulting from high cyclosporin treatment (1,000 ng/ml) were cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) positive but expression of calcitonin receptor (CTR) was downregulated by more than 30-fold [11].
• INTRODUCTION: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation [1].
• Leucine in the P2 position was proven to be the most effective residue for cathepsin O2 and also for cathepsins S and L [12].
• Cathepsin X binds to cell surface heparan sulfate proteoglycans [13].
• The interaction between cathepsin X and heparin has been revealed by affinity chromatography using heparin-Sepharose [13].

Enzymatic interactions of CTSK

• Cathepsin L hydrolyzed the majority of them with similar or higher catalytic efficiency than cathepsin X, acting as an endopeptidase mimicking a carboxymonopeptidase (pseudo-carboxymonopeptidase) [14].

Other interactions of CTSK

• To verify this hypothesis, human procathepsin X was expressed in Pichia pastoris and converted to mature cathepsin X using small amounts of human cathepsin L. Cathepsin X was found to display excellent carboxypeptidase activity against the substrate Abz-FRF(4NO(2)), with a k(cat)/K(M) value of 1.23 x 10(5) M(-)(1) s(-)(1) at the optimal pH of 5 [9].
• Therefore, cathepsin X displays a stricter exopeptidase activity than cathepsin B. No inhibition of cathepsin X by cystatin C could be detected up to a concentration of 4 microM of inhibitor [9].

Analytical, diagnostic and therapeutic context of CTSK

• MATERIALS AND METHODS: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing [1].
• Moreover, fluorescently labeled cathepsin X was shown by confocal microscopy to be endocytosed by wild-type CHO cells, but not by CHO-745 cells [13].
• Using flow cytometry cathepsin X was shown to bind cell surface heparan sulfate proteoglycans in wild-type CHO cells but not in CHO-745 cells, which are deficient in glycosaminoglycan synthesis [13].
• Northern blot analysis indicates predominant levels of expression in osteoclastomas and ovary and therefore the enzyme was named cathepsin O2 [15].
• Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution [15].

References