Drs Green and Lynch are full-time employees of Novartis, AG, and own stock in the company. All other authors have no conflicts of interest.
The Nitrogen-Containing Bisphosphonate, Zoledronic Acid, Influences RANKL Expression in Human Osteoblast-Like Cells by Activating TNF-α Converting Enzyme (TACE)†
Article first published online: 1 JAN 2004
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 1, pages 147–154, January 2004
How to Cite
Pan, B., Farrugia, A. N., To, L. B., Findlay, D. M., Green, J., Lynch, K. and Zannettino, A. C. (2004), The Nitrogen-Containing Bisphosphonate, Zoledronic Acid, Influences RANKL Expression in Human Osteoblast-Like Cells by Activating TNF-α Converting Enzyme (TACE). J Bone Miner Res, 19: 147–154. doi: 10.1359/jbmr.2004.19.1.147
- Issue published online: 2 DEC 2009
- Article first published online: 1 JAN 2004
- Manuscript Accepted: 5 SEP 2003
- Manuscript Revised: 8 AUG 2003
- Manuscript Received: 17 APR 2003
- zoledronic acid;
- osteoblast-like cells;
- TNF-α converting enzyme
Bisphosphonates are used to prevent osteoclast-mediated bone loss. Zoledronic acid inhibits osteoclast maturation indirectly by increasing OPG protein secretion and decreasing transmembrane RANKL expression in human osteoblasts. The decreased transmembrane RANKL expression seems to be related to the upregulation of the RANKL sheddase, TACE.
Introduction: Bisphosphonates (BPs) exhibit high affinity for hydroxyapatite mineral in bone and are used extensively to treat malignancy-associated bone disease and postmenopausal bone loss by inhibiting osteoclast (OC)-mediated bone resorption.
Materials and Methods: We examined the effect of the most potent nitrogen-containing BP available, zoledronic acid (ZOL), on the expression of RANKL and osteoprotegerin (OPG), critical factors in the regulation of OC formation and activation, in primary osteoblast (OB)-like cells derived from human bone, using flow cytometry, ELISA, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ immunofluorescence staining, and Western blotting.
Results: Our studies show that ZOL, while not significantly affecting RANKL or OPG gene expression, markedly increased OPG protein secretion and reduced transmembrane RANKL protein expression in OB-like cells. The reduction in transmembrane RANKL expression was preceded by a marked increase in the expression of the metalloprotease-disintegrin, TNF-α converting enzyme (TACE). In addition, the decreased transmembrane expression of RANKL could be partially reversed by a TACE inhibitor, TAPI-2.
Conclusions: Our studies indicate that ZOL, in addition to its direct effects on mature OCs, may inhibit the recruitment and differentiation of OCs by cleavage of transmembrane RANKL in OB-like cells by upregulating the sheddase, TACE.