Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts.
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.
Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA.
Viviana
V
Cremasco
Corinne E
CE
Decker
Deborah
D
Stumpo
Perry J
PJ
Blackshear
Keiichi I
KI
Nakayama
Keiko
K
Nakayama
Traian S
TS
Lupu
Daniel B
DB
Graham
Deborah V
DV
Novack
Roberta
R
Faccio
D000818:Animals; D001862:Bone Resorption / Q000503:physiopathology*; D001842:Bone and Bones / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000172:deficiency*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; D056657:Cathepsin K; D025262:Vacuolar Proton-Translocating ATPases