title: 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-kappaB (NF-kappaB) 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-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (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.
authors.affiliation: Division of Rheumatology, Medical University Vienna, Vienna, Austria.
authors.forename: Nikolaus B
authors.initials: NB
authors.lastname: Binder
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.forename: Oskar
authors.initials: O
authors.lastname: Hoffmann
authors.forename: Richard
authors.initials: R
authors.lastname: Stange
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich