A Putative Role for Cathepsin K in Degradation of AA and AL Amyloidosis

Röcken, Christoph; Stix, Barbara; Brὂmme, Dieter; Ansorge, Siegfried; Roessner, Albert; Bühling, Frank

doi:10.1016/s0002-9440(10)64050-3

Cited by 49 publications

(50 citation statements)

References 42 publications

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“…Augmented CatK proteolysis in atherosclerosis further links CatK to adverse vascular remodeling. Additional applications of the CatK-activatable imaging agent could include disorders of bone remodeling, 31,32 Gaucher's disease, 33 amyloidosis, 34 thyroid function, 35 prostate cancer, 36 and lung fibrosis. 37 Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor

et al. 2007

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Background-Cathepsin K (CatK), a potent elastinolytic and collagenolytic cysteine protease, likely participates in the evolution and destabilization of atherosclerotic plaques. To assess better the biology of CatK activity in vivo, we developed a novel near-infrared fluorescence (NIRF) probe for imaging of CatK and evaluated it in mouse and human atherosclerosis. Methods and Results-The NIRF imaging agent consists of the CatK peptide substrate GHPGGPQGKC-NH 2 linked to an activatable fluorogenic polymer. In vitro, CatK produced a 2-to 14-fold activation of the agent over other cysteine and matrix metalloproteinases (PϽ0.0001), as well as a Ͼ8-fold activation over a control imaging agent (PϽ0.001). Optical imaging of atheroma revealed Ͼ100% NIRF signal increases in apolipoprotein E Ϫ/Ϫ mice in vivo (nϭ13; PϽ0.05, CatK imaging agent versus control agent) and in human carotid endarterectomy specimens ex vivo (nϭ14; PϽ0.05).Fluorescence microscopy of plaque sections demonstrated that enzymatically active CatK (positive NIRF signal) localized primarily in the vicinity of CatK-positive macrophages. Augmented NIRF signal (reflecting CatK activity) colocalized with disrupted elastin fibers within the media underlying plaques. Conclusions-Use of this novel protease-activatable NIRF agent for optical imaging in vivo demonstrated preferential localization of enzymatically active CatK to macrophages, consistent with their known greater elastinolytic capabilities compared with smooth muscle cells. Augmented CatK proteolysis in atheromata further links CatK to vascular remodeling and plaque vulnerability.

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Section: Discussionmentioning

confidence: 99%

Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor

et al. 2007

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“…Auto -PBSCT treatment is capable of promptly suppressing production of M -protein and organ deposition of amyloid fibril proteins, but the elimination of the amyloid fibril proteins that have already been deposited in organs is required for the improvement of organ damage seen in the present patient. Amyloid fibril proteins deposited in tissue are surrounded by multi -nucleated giant cells, and cathepsin K, found within these cells, is known to degrade amyloid fibril proteins 17) . In addition to cathepsin K, the macrophage -derived cysteine proteases cathepsin B and cathepsin L have also been reported as degrading amyloid fibril proteins 18) .…”

Section: Discussionmentioning

confidence: 99%

A Long-Term Remission of Renal Amyloidosis With Nephrotic Syndrome After Autologous Peripheral Blood Stem-Cell Transplantation

Ogawa

Ikeda

Furukawa

et al. 2010

FJMS

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: Renal amyloidosis is typically characterized by nephrotic syndrome, often with massive proteinuria and refractory peripheral edema. We report the case of a patient with renal amyloidosis associated with nephrotic syndrome who maintained remission for 6 years after undergoing highdose chemotherapy followed by autologous peripheral blood stem -cell transplantation (auto -PBSCT). The patient was a man aged in his 50s who had developed nephrotic syndrome. Bone marrow aspiration and kidney biopsy determined that the cause of the nephrotic syndrome was renal amyloidosis due to multiple myeloma, and the patient was admitted to our department in July 2003. After one course of chemotherapy, auto -PBSCT was performed in March 2004. Following transplantation, serum M -protein was no longer detectable from March 2005, and the patient achieved complete hematological remission. Subsequently, proteinuria decreased, serum albumin levels normalized, and nephrotic syndrome improved. As of 6 years after transplantation, in March 2010, the patient remained in remission, meaning that auto -PBSCT proved extremely effective as a treatment for renal amyloidosis in this case.

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“…Cathepsins C and S have been found to have the highest pH stability [54,88], while cathepsins K and V display intermediate pH stability [27,55]. In vitro investigations have shown that cathepsin K can degrade fibril proteins at neutral pH [93].…”

Section: Cysteine Proteases In Matrix Remodelling Of the Lungmentioning

confidence: 99%

“…Similar mechanisms may be involved in matrix remodelling by lung macrophages and may also contribute to the pathogenesis of granulomatous lung diseases, which are characterised by the appearance of multinucleated giant cells (MGC). Recently it was shown that MGC express and release large amounts of cathepsin K [29,93,95]. Conversely, it was shown that MGC can enclose foreign materials, micro-organisms or other extracellular components.…”

Section: Cysteine Proteases In Matrix Remodelling Of the Lungmentioning

confidence: 99%

Lysosomal cysteine proteases in the lung: role in protein processing and immunoregulation

Bühling¹,

Waldburg²,

Reisenauer³

et al. 2004

Eur Respir J

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Lysosomal cysteine proteases are a family comprising w10 enzymes. For many years it was believed that these enzymes catalyse protein breakdown unselectively, are highly redundant in their substrate specificity and are also expressed ubiquitously.This view has changed dramatically since a number of new lysosomal cysteine proteases with restricted expression and outstanding enzymatic activity have been described. In addition, knockout mice and selective protease inhibitors have been used to characterise specific functions of single proteases.In this review, some of these functions are discussed in relation to the lungs, especially the role of lysosomal cysteine proteases in matrix remodelling, immunoregulation and surfactant protein processing.

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A Putative Role for Cathepsin K in Degradation of AA and AL Amyloidosis

Cited by 49 publications

References 42 publications

Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor

Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor

A Long-Term Remission of Renal Amyloidosis With Nephrotic Syndrome After Autologous Peripheral Blood Stem-Cell Transplantation

Lysosomal cysteine proteases in the lung: role in protein processing and immunoregulation

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