Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Protein kinase C inhibitor, GF109203X attenuates osteoclastogenesis, bone resorption and RANKL-induced NF-κB and NFAT activity

Language

English

Abstract

© 2014 Wiley Periodicals, Inc.Osteolytic bone diseases are characterized by excessive osteoclast formation and activation. Protein kinase C (PKC)-dependent pathways regulate cell growth, differentiation and apoptosis in many cellular systems, and have been implicated in cancer development and osteoclast formation. A number of PKC inhibitors with anti-cancer properties have been developed, but whether they might also influence osteolysis (a common complication of bone invading cancers) is unclear. We studied the effects of the PKC inhibitor compound, GF109203X on osteoclast formation and activity, processes driven by receptor activator of NFκB ligand (RANKL). We found that GF109203X strongly and dose dependently suppresses osteoclastogenesis and osteoclast activity in RANKL-treated primary mouse bone marrow cells. Consistent with this GF109203X reduced expression of key osteoclastic genes, including cathepsin K, calcitonin receptor, tartrate resistant acid phosphatase (TRAP) and the proton pump subunit V-ATPase-d2 in RANKL-treated primary mouse bone marrow cells. Expression of these proteins is dependent upon RANKL-induced NF-κB and NFAT transcription factor actions; both were reduced in osteoclast progenitor populations by GF109203X treatment, notably NFATc1 levels. Furthermore, we showed that GF109203X inhibits RANKL-induced calcium oscillation. Together, this study shows GF109203X may block osteoclast functions, suggesting that pharmacological blockade of PKC-dependent pathways has therapeutic potential in osteolytic diseases. J. Cell. Physiol. 230: 1235-1242, 2015.

Publication Date

2015

Source Publication Title

Journal of Cellular Physiology

Volume

230

Issue

6

Start Page

1235

End Page

1242

Publisher

Wiley

DOI

10.1002/jcp.24858

Link to Publisher's Edition

http://dx.doi.org/10.1002/jcp.24858

ISSN (print)

00219541

ISSN (electronic)

10974652

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