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Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones

Osteoclasts form special integrin-mediated adhesion structures called sealing zones that enable them to adhere to and resorb bone. Sealing zones consist of densely packed podosomes tightly interconnected by actin fibers. Their formation requires the presence of the hematopoietic integrin regulator k...

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Main Authors: Klapproth, Sarah (Author) , Richter, Karsten (Author) , Türk, Clara (Author) , Bock, Theresa (Author) , Bromberger, Thomas (Author) , Dominik, Julian (Author) , Huck, Katrin (Author) , Pfaller, Kristian (Author) , Hess, Michael W. (Author) , Reichel, Christoph A. (Author) , Krüger, Marcus (Author) , Nakchbandi, Inaam (Author) , Moser, Markus (Author)
Format: Article (Journal)
Language:English
Published: 26 November 2021
In: Journal of cell science
Year: 2021, Volume: 134, Issue: 22, Pages: 1-11
ISSN:1477-9137
DOI:10.1242/jcs.259040
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1242/jcs.259040
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Author Notes:Sarah Klapproth, Karsten Richter, Clara Türk, Theresa Bock, Thomas Bromberger, Julian Dominik, Kathrin Huck, Kristian Pfaller, Michael W. Hess, Christoph A. Reichel, Marcus Krüger, Inaam A. Nakchbandi and Markus Moser
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Summary:Osteoclasts form special integrin-mediated adhesion structures called sealing zones that enable them to adhere to and resorb bone. Sealing zones consist of densely packed podosomes tightly interconnected by actin fibers. Their formation requires the presence of the hematopoietic integrin regulator kindlin-3 (also known as Fermt3). In this study, we investigated osteoclasts and their adhesion structures in kindlin-3 hypomorphic mice expressing only 5-10% of the kindlin-3 level of wild-type mice. Low kindlin-3 expression reduces integrin activity, results in impaired osteoclast adhesion and signaling, and delays cell spreading. Despite these defects, in vitro-generated kindlin-3-hypomorphic osteoclast-like cells arrange their podosomes into adhesion patches and belts, but their podosome and actin organization is abnormal. Remarkably, kindlin-3-hypomorphic osteoclasts form sealing zones when cultured on calcified matrix in vitro and on bone surface in vivo. However, functional assays, immunohistochemical staining and electron micrographs of bone sections showed that they fail to seal the resorption lacunae properly, which is required for secreted proteinases to digest bone matrix. This results in mild osteopetrosis. Our study reveals a new, hitherto understudied function of kindlin-3 as an essential organizer of integrin-mediated adhesion structures, such as sealing zones.
Item Description:Richtiger Name vom 7. Autor: Katrin Huck
Gesehen am 04.05.2022
Physical Description:Online Resource
ISSN:1477-9137
DOI:10.1242/jcs.259040

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