Evidence of reciprocal regulation between the high extracellular calcium and RANKL signal transduction pathways in RAW cell derived osteoclasts
✍ Scribed by Jiake Xu; Cathy Wang; Renzhi Han; Nathan Pavlos; Tony Phan; James H. Steer; Anthony J. Bakker; David A. Joyce; Ming H. Zheng
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 251 KB
- Volume
- 202
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
During bone resorption, osteoclasts are exposed to high Ca^2+^ concentrations (up to 40 mM). The role of high extracellular Ca^2+^ 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 Ca^2+^ by protecting the cell from cell death in a dose dependent manner. We have provided evidence that RANKL does this by attenuating high extracellular Ca^2+^‐induced Ca^2+^ elevations. Moreover, we have found that high extracellular Ca^2+^‐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 Ca^2+^ 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 Ca^2+^ and RANKL signaling in RAW cell derived osteoclasts. Our data imply a cross talk mechanism of extracellular Ca^2+^ on osteoclast survival through the regulation of RANKL. © 2004 Wiley‐Liss, Inc.