Journal
CLINICAL SCIENCE
Volume 112, Issue 11-12, Pages 567-575Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20060274
Keywords
bone resorption; C-terminal telopeptide degradation product of type I collagen (CTX-I); cathepsin K; metalloproteinase (MMP); osteoclast; receptor activator of nuclear factor kappa B ligand (RANKL)
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Funding
- Wellcome Trust Funding Source: Medline
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Although much has been learned recently of the mechanisms that regulate osteoclastic differentiation, much less is known of the means through which their resorptive activity is controlled. This is especially so for human osteoclasts. We have recently developed an assay that allows us to measure resorptive activity while minimizing confounding effects on differentiation by optimizing osteoclastogenesis, so that measurable resorption occurs over a short period, and by relating resorption in each culture during the test period to the resorption that had occurred in the same culture in a prior control period. In the present study, we found that RANKL (receptor activator of nuclear factor KB ligand) strongly stimulated the release of CTX-I (C-terminal telopeptide degradation product of type I collagen) by osteoclasts over a similar range to that over which it induces osteoclastic differentiation, consistent with a distinct action on osteoclastic function. CT (calcitonin) dose-dependently inhibited bone resorption, whereas PTH (parathyroid hormone), IL (interleukin)-I, TNF-alpha (tumour necrosis factor-alpha), IL-6, IL-8, VEGF (vascular endothelial growth factor), MCP-I (monocyte chemoattractant protein-I), MIP-ly (macrophage inflammatory protein-I gamma), IFN (interferon)-gamma and dibutyryl cGMP had no significant effect. Ca (2+), cyclosporin A, IFN-P and dibutyryl cAMP all strongly suppressed resorption. Bone resorption was also strongly suppressed by alendronate, the cysteine protease inhibitor E64 and the cathepsin K inhibitor MV061 194. Inhibitors of MMPs (matrix metal loproteinases) had no effect on CTX-I release. Moreover, the release of the MMP-derived collagen fragment ICTP (C-terminal crosslinked telopeptide of type I collagen) represented less that 0.01 % of the quantity of CTX-I released in our cultures. This suggests that MMPs make, at most, a very small contribution to the bone-resorptive activity of osteoclasts.
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