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Klapproth S, Richter K, Türk C, et al. Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones. J Cell Sci. 2021;134(22)doi: 10.1242/jcs.259040.
Klapproth, S., Richter, K., Türk, C., Bock, T., Bromberger, T., Dominik, J., Huck, K., Pfaller, K., Hess, M. W., Reichel, C. A., Krüger, M., Nakchbandi, I. A., & Moser, M. (2021). Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones. Journal of cell science, 134(22), . https://doi.org/10.1242/jcs.259040
Klapproth, Sarah, et al. "Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones." Journal of cell science vol. 134,22 (2021). doi: https://doi.org/10.1242/jcs.259040
Klapproth S, Richter K, Türk C, Bock T, Bromberger T, Dominik J, Huck K, Pfaller K, Hess MW, Reichel CA, Krüger M, Nakchbandi IA, Moser M. Low kindlin-3 levels in osteoclasts of kindlin-3 hypomorphic mice result in osteopetrosis due to leaky sealing zones. J Cell Sci. 2021 Nov 15;134(22). doi: 10.1242/jcs.259040. Epub 2021 Nov 26. PMID: 34704600.
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J Cell Sci. 2021 Nov 15;134(22). doi: 10.1242/jcs.259040. Epub 2021 Nov 26.

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

Journal of cell science

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, Markus Moser

Affiliations

  1. Institute of Experimental Hematology, School of Medicine, Technical University Munich, D-81675 Munich, Germany.
  2. Central Unit Electron Microscopy, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
  3. CECAD Research Center, Institute for Genetics, University of Cologne, D-50931 Cologne, Germany.
  4. Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  5. Department of Otorhinolaryngology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  6. Institute of Immunology, University of Heidelberg, D-69120 Heidelberg, Germany.
  7. Institute of Histology and Embryology, Medical University Innsbruck, A-6020 Innsbruck, Austria.
  8. Center for Molecular Medicine (CMMC), University of Cologne, D-50931 Cologne, Germany.
  9. Max-Planck Institute of Biochemistry, D-82152 Martinsried, Germany.

PMID: 34704600 DOI: 10.1242/jcs.259040

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.

© 2021. Published by The Company of Biologists Ltd.

Keywords: Bone resorption; Integrin; Kindlin-3; Osteoclast; Podosome; Sealing zone

Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

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