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 κB 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)-1, TNF-α (tumour necrosis factor-α), IL-6, IL-8, VEGF (vascular endothelial growth factor), MCP-1 (monocyte chemoattractant protein-1), MIP-1γ (macrophage inflammatory protein-1γ), IFN (interferon)-γ and dibutyryl cGMP had no significant effect. Ca2+, cyclosporin A, IFN-β 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 MV061194. Inhibitors of MMPs (matrix metalloproteinases) had no effect on CTX-I release. Moreover, the release of the MMP-derived collagen fragment ICTP (C-terminal cross-linked 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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June 2007
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Research Article|
May 01 2007
Regulation and enzymatic basis of bone resorption by human osteoclasts
Karen Fuller;
Karen Fuller
1Department of Cellular Pathology, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, U.K.
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Barrie Kirstein;
Barrie Kirstein
1Department of Cellular Pathology, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, U.K.
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Timothy J. Chambers
1Department of Cellular Pathology, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, U.K.
Correspondence: Dr Timothy J. Chambers (email [email protected]).
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Publisher: Portland Press Ltd
Received:
September 26 2006
Revision Received:
November 23 2006
Accepted:
January 23 2007
Accepted Manuscript online:
January 23 2007
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2007 Biochemical Society
2007
Clin Sci (Lond) (2007) 112 (11): 567–575.
Article history
Received:
September 26 2006
Revision Received:
November 23 2006
Accepted:
January 23 2007
Accepted Manuscript online:
January 23 2007
Citation
Karen Fuller, Barrie Kirstein, Timothy J. Chambers; Regulation and enzymatic basis of bone resorption by human osteoclasts. Clin Sci (Lond) 1 June 2007; 112 (11): 567–575. doi: https://doi.org/10.1042/CS20060274
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