Osteopetrosis with micro-lacunar resorption because of defective integrin organization

Harry C. Blair, Beatrice B. Yaroslavskiy, Lisa J. Robinson, Markus Y. Mapara, Alessandra Pangrazio, Lida Guo, Ka Chen, Paolo Vezzoni, Jakub Tolar, Paul J. Orchard

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11 Scopus citations

Abstract

In vitro differentiated monocytes were used to characterize the cellular defect in a type of osteopetrosis with minimally functional osteoclasts, in which defects associated with common causes of osteopetrosis were excluded by gene sequencing. Monocytes from the blood of a 28-year-old patient were differentiated in media with RANKL and CSF-1. Cell fusion, acid compartments within cells, and tartrate resistant acid phosphatase (TRAP) activity were normal. However, the osteoclasts made abnormally small pits on the dentine. Phalloidin labeling showed that the cell attachments lacked the peripheral ring structure that supports lacunar resorption. Instead, the osteoclasts had clusters of podosomes near the center of cell attachments. Antibody to the αvβ3 integrin pair or to the C-terminal of β3 did not label podosomes, but antibody to αv labeled them. Western blots using antibody to the N-terminal of β3 showed a protein of reduced size. Integrins β1 and β5 were upregulated, but, in contrast to observations in β3 defects, α2 had not increased. The ρ-GTP exchange protein Vav3, a key attachment organizing protein, did not localize normally with peripheral attachment structures. Vav3 forms of 70 kD and 90 kD were identified on western blots. However, the proteins β3 integrin, Vav3, Plekhm1, and Src, implicated in attachment defects, had normal exon sequences. In this new type of osteopetrosis, the integrin-organizing complex is dysfunctional, and at least two attachment proteins may be partially degraded.

Original languageEnglish (US)
Pages (from-to)1007-1017
Number of pages11
JournalLaboratory Investigation
Volume89
Issue number9
DOIs
StatePublished - Sep 2009

Bibliographical note

Funding Information:
Supported in part by a NOBEL grant from Fondazione Cariplo, and by the Department of Veteran’s Affairs (USA) and the National Institutes of Health (USA) AR053976, AR055208, and AR053566.

Keywords

  • Bone resorption
  • Integrin assembly
  • Osteopetrosis
  • Receptor activator of NF-κB
  • ρ-GTPase

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