Article abstract
Nature Medicine 15, 417 - 424 (2009)
Published online: 29 March 2009 | doi:10.1038/nm.1945
Estrogen-dependent and C-C chemokine receptor-2–dependent pathways determine osteoclast behavior in osteoporosis
Nikolaus B Binder1, Birgit Niederreiter1, Oskar Hoffmann2, Richard Stange3,4, Thomas Pap4, Thomas M Stulnig5, Matthias Mack6, Reinhold G Erben7, Josef S Smolen1 & Kurt Redlich1
Abstract
Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-
B (NF-B) and extracellular signal–related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-B and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-B (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.
- Division of Rheumatology, Medical University Vienna, Vienna, Austria.
- Institute of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
- Department of Trauma, Hand and Reconstructive Surgery, University of Muenster, Muenster, Germany.
- Institute of Experimental Musculoskeletal Medicine, University of Muenster, Muenster, Germany.
- Division of Endocrinology and Metabolism, Medical University Vienna, Vienna, Austria.
- Division of Nephrology, University of Regensburg, Regensburg, Germany.
- Institute of Pathophysiology, University of Veterinary Medicine Vienna, Vienna, Austria.
Correspondence to: Kurt Redlich1 e-mail: kurt.redlich@meduniwien.ac.at
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