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- Title
Evidence of reciprocal regulation between the high extracellular calcium and RANKL signal transduction pathways in RAW cell derived osteoclasts.
- Authors
Jiake Xu; Cathy Wang; Renzhi Han; Nathan Pavlos; Tony Phan; James H. Steer; Anthony J. Bakker; David A. Joyce; Ming H. Zheng
- Abstract
During bone resorption, osteoclasts are exposed to high Ca2+ concentrations (up to 40 mM). The role of high extracellular Ca2+ in receptor activator of NF‐κB ligand (RANKL)‐mediated osteoclast survival and their functional interrelationship is unclear. In this study, we show that RANKL enhances osteoclast tolerance to high extracellular Ca2+ by protecting the cell from cell death in a dose dependent manner. We have provided evidence that RANKL does this by attenuating high extracellular Ca2+‐induced Ca2+ elevations. Moreover, we have found that high extracellular Ca2+‐induced cell death was partially inhibited by a caspase‐3 inhibitor, suggesting caspase‐3‐mediated apoptosis is involved. Conversely, using reporter gene assays and Western blot analysis, we have demonstrated that high extracellular Ca2+ desensitizes the RANKL‐induced activation of NF‐κB and c‐Jun N‐terminal kinase (JNK), and inhibits constitutive and RANKL‐stimulated ERK phosphorylation, indicating a negative feed‐back mechanism via specific RANKL signaling pathways. Taken together, this study provides evidence for a reciprocal regulation between high extracellular Ca2+ and RANKL signaling in RAW cell derived osteoclasts. Our data imply a cross talk mechanism of extracellular Ca2+ on osteoclast survival through the regulation of RANKL. © 2004 Wiley‐Liss, Inc.
- Subjects
CELLULAR control mechanisms; OSTEOCLASTS; CELLULAR signal transduction; BONE resorption
- Publication
Journal of Cellular Physiology, 2005, Vol 202, Issue 2, p554
- ISSN
0021-9541
- Publication type
Article
- DOI
10.1002/jcp.20159