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

Viviana Cremasco, Corinne E. Decker, Deborah Stumpo, Perry J. Blackshear, Keiichi Nakayama, Keiko Nakayama, Traian S. Lupu, Daniel B. Graham, Deborah V. Novack, Roberta Faccio

研究成果: ジャーナルへの寄稿記事

31 引用 (Scopus)

抄録

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. © 2012 American Society for Bone and Mineral Research.

元の言語英語
ページ(範囲)2452-2463
ページ数12
ジャーナルJournal of Bone and Mineral Research
27
発行部数12
DOI
出版物ステータス出版済み - 12 1 2012

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Cathepsin K
Protein Kinase C-delta
Osteoclasts
Exocytosis
Homeostasis
Bone and Bones
Bone Resorption
Vacuolar Proton-Translocating ATPases
Postmenopausal Osteoporosis
Bone Matrix
Lysosomes
Actins
Peptide Hydrolases
Theoretical Models
Proteins

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

これを引用

Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts. / Cremasco, Viviana; Decker, Corinne E.; Stumpo, Deborah; Blackshear, Perry J.; Nakayama, Keiichi; Nakayama, Keiko; Lupu, Traian S.; Graham, Daniel B.; Novack, Deborah V.; Faccio, Roberta.

:: Journal of Bone and Mineral Research, 巻 27, 番号 12, 01.12.2012, p. 2452-2463.

研究成果: ジャーナルへの寄稿記事

Cremasco, V, Decker, CE, Stumpo, D, Blackshear, PJ, Nakayama, K, Nakayama, K, Lupu, TS, Graham, DB, Novack, DV & Faccio, R 2012, 'Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts', Journal of Bone and Mineral Research, 巻. 27, 番号 12, pp. 2452-2463. https://doi.org/10.1002/jbmr.1701
Cremasco, Viviana ; Decker, Corinne E. ; Stumpo, Deborah ; Blackshear, Perry J. ; Nakayama, Keiichi ; Nakayama, Keiko ; Lupu, Traian S. ; Graham, Daniel B. ; Novack, Deborah V. ; Faccio, Roberta. / Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts. :: Journal of Bone and Mineral Research. 2012 ; 巻 27, 番号 12. pp. 2452-2463.
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