Quantitative analysis of type I collagen fibril regulation by lumican and decorin using AFM

Stamov, Dimitar R.; Müller, Anna Ophelia; Wegrowski, Yanusz; Brézillon, Stéphane; Franz, Clemens M.

doi:10.1016/j.jsb.2013.05.022

Cited by 49 publications

(29 citation statements)

References 69 publications

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“…This rotation indicates that an extended GAG chain would run down the length of the tropocollagen, either twirling around it or crossing over to neighboring triple helices in the fibril. Both GAG binding modes have been demonstrated via biochemical means and by electron microscopy (23)(24)(25). The CatK dimer-GAG complex interaction with the collagen sheds light on a potential mechanism of collagen uncoiling and cleaving.…”

Section: Resultsmentioning

confidence: 96%

Structural basis of collagen fiber degradation by cathepsin K

Aguda¹,

Panwar²,

Du³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

126

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Cathepsin K is the major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation. Despite its key role in bone remodeling and for being a highly sought-after drug target for the treatment of osteoporosis, the mechanism of collagen fiber degradation by cathepsin K remained elusive. Here, we report the structure of a collagenolytically active cathepsin K protein dimer. Cathepsin K is organized into elongated C-shaped protease dimers that reveal a putative collagen-binding interface aided by glycosaminoglycans. Molecular modeling of collagen binding to the dimer indicates the participation of nonactive site amino acid residues, Q21 and Q92, in collagen unfolding. Mutations at these sites as well as perturbation of the dimer protein-protein interface completely inhibit cathepsin-K-mediated fiber degradation without affecting the hydrolysis of gelatin or synthetic peptide. Using scanning electron microscopy, we demonstrate the specific binding of cathepsin K at the edge of the fibrillar gap region of collagen fibers, which suggest initial cleavage events at the N-and C-terminal ends of tropocollagen molecules. Edman degradation analysis of collagen fiber degradation products revealed those initial cleavage sites. We propose that one cathepsin K molecule binds to collagen-bound glycosaminoglycans at the gap region and recruits a second protease molecule that provides an unfolding and cleavage mechanism for triple helical collagen. Removal of collagen-associated glycosaminoglycans prevents cathepsin K binding and subsequently fiber hydrolysis. Cathepsin K dimer and glycosaminoglycan binding sites represent novel targeting sites for the development of nonactive site-directed secondgeneration inhibitors of this important drug target.cathepsin K | collagen | glycosaminoglycan | enzyme mechanism

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Section: Resultsmentioning

confidence: 96%

Structural basis of collagen fiber degradation by cathepsin K

Aguda¹,

Panwar²,

Du³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

126

View full text Add to dashboard Cite

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“…Similar endocytosis pathways cannot be excluded as a mechanism of the regulation of the lumican effect on EMT/MET process. A quantitative analysis of type I collagen fibril regulation by lumican and decorin by Atomic Force Microscopy was reported42. The results showed that lumican or decorin core proteins alone have a strong potential to regulate the spacing and connectivity of collagen I fibrils.…”

Section: Discussionmentioning

confidence: 99%

Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition

Καραμάνου

Franchi

Piperigkou

et al. 2017

Sci Rep

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Lumican is a small leucine-rich proteoglycan that has been shown to contribute in several physiological processes, but also to exert anticancer activity. On the other hand, it has been recently shown that knockdown of the estrogen receptor α (ERα) in low invasive MCF-7 (ERα+) breast cancer cells and the suppression of ERβ in highly aggressive MDA-MB-231 (ERβ+) cells significantly alter the functional properties of breast cancer cells and the gene expression profile of matrix macromolecules related to cancer progression and cell morphology. In this report, we evaluated the effects of lumican in respect to the ERs-associated breast cancer cell behaviour, before and after suppression of ERs, using scanning electron and confocal microscopies, qPCR and functional assays. Our data pinpointed that lumican significantly attenuated cell functional properties, including proliferation, migration and invasion. Furthermore, it modified cell morphology, inducing cell-cell junctions, evoked EMT/MET reprogramming and suppressed the expression of major matrix effectors (matrix metalloproteinases and EGFR) implicated in breast cancer progression. The effects of lumican were found to be related to the type of breast cancer cells and the ERα/β type. These data support the anticancer activity of lumican and open a new area for the pharmacological targeting of the invasive breast cancer.

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“…DCN may increase water diffusivity through direct modulation (softening) of the extracellular matrix (ECM), as DCN acts to modulate the rigidity and stiffness of the ECM by binding with various ECM macromolecules and activating specific matrix metalloproteinases (MMPs)(36). The protein core of DCN is known to bind with a variety of collagen molecules, fibrils, and other macromolecules, acting to significantly increase interfibrillary spacing(37). Since ADC is inversely correlated with fluid viscosity (38, 39) and tortuosity of the ECM (40–44), it is conceivable that high DCN expression results in softer, less viscous tumors with decreased boundaries to fluid within the extracellular space from DCM remodeling, ultimately resulting in a higher measured ADC L .…”

Section: Discussionmentioning

confidence: 99%

Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials

Ellingson

Gerstner

Smits

et al. 2017

Clinical Cancer Research

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Purpose Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine. Experimental Design Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate Phase II clinical trials were included: 1) cediranib (NCT00035656); 2) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); 3) cabozantinib (XL184-201; NCT00704288); 4) aflibercept (VEGF Trap; NCT00369590); and 5) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate “ADCL”, the mean of the lower ADC distribution. Pre-treatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS. Results The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P=0.4537). An ADCL threshold of 1.24 um2/ms produced the largest OS differences between patients (HR~0.5) and patients with an ADCL>1.24 um2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not lomustine, after accounting for age and baseline enhancing tumor volume. Conclusions Pre-treatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse.

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Quantitative analysis of type I collagen fibril regulation by lumican and decorin using AFM

Cited by 49 publications

References 69 publications

Structural basis of collagen fiber degradation by cathepsin K

Structural basis of collagen fiber degradation by cathepsin K

Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition

Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials

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