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Cathepsin K in Lymphangioleiomyomatosis: LAM Cell-Fibroblast Interactions Enhance Protease Activity by Extracellular Acidification

Lookup NU author(s): Professor Andrew FisherORCiD

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Abstract

Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells and fibroblasts form lung nodules and it is hypothesized that LAM nodule-derived proteases cause cyst formation and tissue damage. On protease gene expression profiling in whole lung tissue, cathepsin K gene expression was 40-fold overexpressed in LAM compared with control lung tissue (P ≤ 0.0001). Immunohistochemistry confirmed cathepsin K protein was expressed in LAM but not control lungs. Cathepsin K gene expression and protein and protease activity were detected in LAM-associated fibroblasts but not the LAM cell line 621-101. In lung nodules, cathepsin K immunoreactivity predominantly co-localized with LAM-associated fibroblasts. In vitro, fibroblast extracellular cathepsin K activity was minimal at pH 7.5 but significantly enhanced at pH 7 and 6. 621-101 cells reduced extracellular pH with acidification dependent on 621-101 mechanistic target of rapamycin activity and net hydrogen ion exporters, particularly sodium bicarbonate co-transporters and carbonic anhydrases, which were also expressed in LAM lung tissue. In LAM cell-fibroblast co-cultures, acidification paralleled cathepsin K activity, and both were reduced by sodium bicarbonate co-transporter (P ≤ 0.0001) and carbonic anhydrase inhibitors (P = 0.0021). Our findings suggest that cathepsin K activity is dependent on LAM cell-fibroblast interactions, and inhibitors of extracellular acidification may be potential therapies for LAM.

Publication metadata

Author(s): Dongre A, Clements D, Fisher AJ, Johnson SR

Publication type: Article

Publication status: Published

Journal: The American Journal of Pathology

Year: 2017

Volume: 187

Issue: 8

Pages: 1750-1762

Print publication date: 01/08/2017

Online publication date: 15/06/2017

Acceptance date: 26/04/2017

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: Elsevier

URL: https://doi.org/10.1016/j.ajpath.2017.04.014

DOI: 10.1016/j.ajpath.2017.04.014

PubMed id: 28623674

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