Abstract 3

Protein Kinase C delta (PKC-o) mediates Receptor Activator of NF-kB Ligand (RANKL)- induced signaling pathways required for osteoclastogenesis

Cathy Wang, Ming-Hao Zheng and Jiake Xu

¹Molecular Orthopaedic Laboratory, School of Surgery and Pathology, University of Western Australia, Nedlands, WA 6009, Australia.

Increased formation and activation of osteoclasts underlie many bone lytic disorders such as osteoporosis and Paget's disease. The Protein Kinase C pathway has been suggested to be an important regulator of osteoclastic bone formation, however, the role and subtypes of PKC in RANKL-induced osteoclastogenesis is unknown. In this study, we have screened several PKC inhibitors and found that PKC delta mediates RANKL-induced signaling and osteoclast formation. PKC delta inhibitor, Rottlerin dose dependently inhibited RANKL-induced osteoclast formation, as well as the expression of osteoclast specific genes, calcitonin receptor and cathepsin K. Using nuclear translocation and reporter gene assays, we showed that Rottlerin, inhibited RANKL-induced NF-kB activations in a dose dependent manner. Interestingly, PKC delta activator, Bryostatin 1, enhanced RANKL-induced osteoclastogenesis in a dose dependent manner and partially compensated the inhibitory effect of Rottlerin on osteoclastogenesis. This was achieved by increasing RANKL-induced activation of NF-kB. Furthermore, we showed that overexpression of PKC delta wild type enhanced the NF-kB activation mediated by RANK. In contrast, overexpression of PKC delta dominant negative form reduced the NF-kB activation. In short, our data indicate that PKC delta plays a role in RANKL-induced osteoclast formation. Selective modulation of RANKL signaling pathways by PKC delta may have important therapeutic implications for the treatment of bone diseases associated with enhanced bone resorption.

Return to Listing of 2004 Abstracts
View Listing of 2005 Abstracts