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Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption

The blood cell–specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abn...

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Autores principales: Schmidt, Sarah, Nakchbandi, Inaam, Ruppert, Raphael, Kawelke, Nina, Hess, Michael W., Pfaller, Kristian, Jurdic, Pierre, Fässler, Reinhard, Moser, Markus
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051823/
https://www.ncbi.nlm.nih.gov/pubmed/21357746
http://dx.doi.org/10.1083/jcb.201007141
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author Schmidt, Sarah
Nakchbandi, Inaam
Ruppert, Raphael
Kawelke, Nina
Hess, Michael W.
Pfaller, Kristian
Jurdic, Pierre
Fässler, Reinhard
Moser, Markus
author_facet Schmidt, Sarah
Nakchbandi, Inaam
Ruppert, Raphael
Kawelke, Nina
Hess, Michael W.
Pfaller, Kristian
Jurdic, Pierre
Fässler, Reinhard
Moser, Markus
author_sort Schmidt, Sarah
collection PubMed
description The blood cell–specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3–deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.
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spelling pubmed-30518232011-09-07 Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption Schmidt, Sarah Nakchbandi, Inaam Ruppert, Raphael Kawelke, Nina Hess, Michael W. Pfaller, Kristian Jurdic, Pierre Fässler, Reinhard Moser, Markus J Cell Biol Research Articles The blood cell–specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3–deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis. The Rockefeller University Press 2011-03-07 /pmc/articles/PMC3051823/ /pubmed/21357746 http://dx.doi.org/10.1083/jcb.201007141 Text en © 2011 Schmidt et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Schmidt, Sarah
Nakchbandi, Inaam
Ruppert, Raphael
Kawelke, Nina
Hess, Michael W.
Pfaller, Kristian
Jurdic, Pierre
Fässler, Reinhard
Moser, Markus
Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title_full Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title_fullStr Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title_full_unstemmed Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title_short Kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
title_sort kindlin-3–mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051823/
https://www.ncbi.nlm.nih.gov/pubmed/21357746
http://dx.doi.org/10.1083/jcb.201007141
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