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Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts.

Authors
  • Cremasco, Viviana
  • Decker, Corinne E
  • Stumpo, Deborah
  • Blackshear, Perry J
  • Nakayama, Keiichi I
  • Nakayama, Keiko
  • Lupu, Traian S
  • Graham, Daniel B
  • Novack, Deborah V
  • Faccio, Roberta
Type
Published Article
Journal
Journal of Bone and Mineral Research
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2012
Volume
27
Issue
12
Pages
2452–2463
Identifiers
DOI: 10.1002/jbmr.1701
PMID: 22806935
Source
Medline
License
Unknown

Abstract

Bone homeostasis requires stringent regulation of osteoclasts, which secrete proteolytic enzymes to degrade the bone matrix. Despite recent progress in understanding how bone resorption occurs, the mechanisms regulating osteoclast secretion, and in particular the trafficking route of cathepsin K vesicles, remain elusive. Using a genetic approach, we describe the requirement for protein kinase C-delta (PKCδ) in regulating bone resorption by affecting cathepsin K exocytosis. Importantly, PKCδ deficiency does not perturb formation of the ruffled border or trafficking of lysosomal vesicles containing the vacuolar-ATPase (v-ATPase). Mechanistically, we find that cathepsin K exocytosis is controlled by PKCδ through modulation of the actin bundling protein myristoylated alanine-rich C-kinase substrate (MARCKS). The relevance of our finding is emphasized in vivo because PKCδ-/- mice exhibit increased bone mass and are protected from pathological bone loss in a model of experimental postmenopausal osteoporosis. Collectively, our data provide novel mechanistic insights into the pathways that selectively promote secretion of cathepsin K lysosomes independently of ruffled border formation, providing evidence of the presence of multiple mechanisms that regulate lysosomal exocytosis in osteoclasts.

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