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Estrogen-dependent and C-C chemokine receptor-2–dependent pathways determine osteoclast behavior in osteoporosis

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-κB (NF-κB) 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-κB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-κB (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.

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Figure 1: Ccr2−/− mice show increased bone mass and stability.
Figure 2: Osteoclasts but not osteoblasts are affected by the absence of CCR2.
Figure 3: Osteoclast generation and function is decreased in BMMs from Ccr2−/− mice.
Figure 4: CCR2−/− mice show lower RANK levels.
Figure 5: MCP-1 and MCP-3 act via CCR2 to affect RANK expression.
Figure 6: Ccr2−/− mice are protected from osteoporosis.

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Acknowledgements

We are grateful to B.R. Binder, L. Bakiri and E.F. Wagner for critical comments and suggestions to the manuscript. We thank the laboratory of P.K. Zysset for their help with microcomputed tomography images as well as C.W. Steiner, M. Tryniecki and A. Raffetseder for their technical assistance and J. Zaujec for performing the ovariectomies. This work was supported by Austrian Science Fund (FWF) grant 18223 and by the Center for Musculoskeletal Diseases of the Medical University Vienna.

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Contributions

N.B.B. designed and performed all experiments and wrote the manuscript; B.N. and R.S. helped with the experiments; M.M. performed CCR2 surface expression analysis; R.G.E. and T.P. performed the biomechanical analysis; O.H. performed the resorption assays; T.M.S. provided and analyzed the Ccl2−/− mice; J.S.S. participated in evaluating data and writing the manuscript; and K.R. directed the project, designed the experiments and wrote the manuscript. All authors approved the final manuscript.

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Correspondence to Kurt Redlich.

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Binder, N., Niederreiter, B., Hoffmann, O. et al. Estrogen-dependent and C-C chemokine receptor-2–dependent pathways determine osteoclast behavior in osteoporosis. Nat Med 15, 417–424 (2009). https://doi.org/10.1038/nm.1945

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