Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice

Dauth, Stephanie; Schmidt, Maike; Rehders, Maren; Dietz, Frank; Kelm, Sørge; Dringen, Ralf; Brix, Klaudia

doi:10.1515/hsz-2012-0145

Cited by 11 publications

(9 citation statements)

References 49 publications

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“… 19 Similar results have been reported for the cysteine cathepsin L by Strojnik and co-workers 47 , showing high cathepsin L expression in astrocytomas and GBM, but these high levels were not predictive. We have also shown that cathepsin K is expressed in normal brain cells as has been reported for all brain regions of wild type mice 48 where it has been associated with neurobe-havioral disorders such as schizophrenia. 49 At the protein level, cathepsin K was detected in vesicles of neuronal and non-neuronal cells throughout the mouse brain and its deficiency was associated with a marked decrease in differentiated astrocytes, indicating a possible role of cathepsin K in stem cell differentiation.…”

Section: Discussionsupporting

confidence: 76%

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Breznik

Limback

Porčnik

et al. 2018

Radiology and Oncology

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BackgroundGlioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.Materials and methodsGene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.ResultsHighest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.ConclusionsThe presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

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Section: Discussionsupporting

confidence: 76%

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Breznik

Limback

Porčnik

et al. 2018

Radiology and Oncology

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“…Because of its involvement in pycnodysostosis [51], osteoporosis [52], [53] and invasive carcinomas and their metastasis, a series of small inhibitory compounds have been developed for clinical application [53]. CatK knockdown animals show considerable neural defects indicating its role in normal brain functioning [54], [55], which is in contrast to CatB or CatL-deficient animals [56], although in CatB −/− and CatL −/− double knock-out mice, brain atrophy due to massive apoptosis of neurons is lethal [52]. In astroglia-rich primary cultures from CatK-deficient mice it appeared that CatK plays a role in differentiation of oligodendrocytes [52].…”

Section: Discussionmentioning

confidence: 99%

Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma

et al. 2014

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BackgroundCancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in glioblastoma multiforme (GBM), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression.MethodsComparisons were performed between the transcriptomics of primary GBM tumors and unmatched non-malignant brain tissue, and between GBM cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells.ResultsOf the 311 protease genes identified to be differentially expressed in both GBM tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues transferrin receptor (TFRC) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and cathepsin K (CTSK), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in GBM cell lines. CTSK overexpression was validated using RT-qPCR in GBM tissues as well. Cathepsin K immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of cathepsin K were overexpressed in GBM tissues and cells.ConclusionsThe presence of high levels of inactive proforms of cathepsin K in GBM tissues and cells indicate that in GBM the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role.

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“…In the current study, we found that diabetes may potentiate cathepsin K expression. Moreover, cathepsin K deficiency in mice is associated with a marked decrease in differentiated astrocytes and learning and memory deficits [48]. Sema3A is also positively involved in the regulation of the central and peripheral nervous systems.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats

Wang

Zhao

et al. 2017

Cell Physiol Biochem

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Purpose: Increasing evidence supported that semaphorin 3A (Sema3A), insulin-like growth factor (IGF)-1 and β-catenin were involved in the development of osteoporosis and diabetes. This study is aimed to evaluate whether Sema3A/IGF-1/β-catenin is directly involved in the alterations of bone microarchitecture and bone strength of diabetic rats. Methods: Diabetic rats were induced by streptozotocin and high fat diet exposure. Bone microarchitecture and strength in the femurs were evaluated by micro-CT scanning, three-point bending examination and the stainings of HE, alizarin red S and safranin O/fast green, respectively. The alterations of lumbar spines microarchitecture were also determined by micro-CT scanning. Western blot and immunohistochemical analyses were used to examine the expression of Sema3A, β-catenin, IGF-1, peroxisome proliferator-activated receptor γ (PPARγ) and cathepsin K in rat tibias. Results: Diabetic rats exhibited decreased trabecular numbers and bone formation, but an increased trabecular separation in the femurs and lumbar spines. Moreover, the increased bone fragility and decreased bone stiffness were evident in the femurs of diabetic rats. Diabetic rats also exhibited a pronounced bone phenotype which manifested by decreased expression of Sema3A, IGF-1 and β-catenin, as well as increased expression of cathepsin K and PPARγ. Conclusions: This study suggests that diabetes could perturb bone loss through the Sema3A/IGF-1/β-catenin pathway. Sema3A deficiency in bone may contribute to upregulation of PPARγ and cathepsin K expression, which further disrupts bone remodeling in diabetic rats.

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Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice

Cited by 11 publications

References 49 publications

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Localization patterns of cathepsins K and X and their predictive value in glioblastoma

Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma

Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats

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