Universität zu Köln

Klapproth, Sarah, Richter, Karsten, Tuerk, Clara, Bock, Theresa ORCID: 0000-0002-8308-4021, Bromberger, Thomas, Dominik, Julian, Huck, Kathrin, Pfaller, Kristian, Hess, Michael W., Reichel, Christoph A., Krueger, Marcus, Nakchbandi, Inaam A. and Moser, Markus (2021). Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones. J. Cell Sci., 134 (22). CAMBRIDGE: COMPANY BIOLOGISTS LTD. ISSN 1477-9137

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Abstract

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 Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Klapproth, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Richter, Karsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuerk, Clara UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Theresa UNSPECIFIED orcid.org/0000-0002-8308-4021 UNSPECIFIED Bromberger, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dominik, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Huck, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfaller, Kristian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, Michael W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichel, Christoph A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Nakchbandi, Inaam A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moser, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-596877
DOI:	10.1242/jcs.259040
Journal or Publication Title:	J. Cell Sci.
Volume:	134
Number:	22
Date:	2021
Publisher:	COMPANY BIOLOGISTS LTD
Place of Publication:	CAMBRIDGE
ISSN:	1477-9137
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTEGRIN ACTIVATION; ADHESION; PLATELET; PODOSOME; LOCALIZATION; PAXILLIN; BINDING; MATRIX; ACTIN Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59687