Monocytes have the potential to differentiate to either macrophages, dendritic cells, or to osteoclasts. The microenvironment, particularly cytokines, directs the monocyte differentiation. Receptors of NF B (RANK) ligand, tumor necrosis factor (TNF) , or interleukin- (IL-) 8 have be identified as inducers of osteoclastogenesis, whereas others, such as IL-10 or transforming growth factor (TGF) inhibit osteoclast generation or induce differentiation towards a dendritic cell type. We now describe that bone morphogenetic protein (BMP) 7/osteogenic protein- (OP-) 1 inhibited the differentiation of human CD14+ monocytes to osteoclasts. In the presence of BMP7/OP-1 the transcription factors c-Fos and NFATc1, though upregulated and translocated to the nucleus in response to either RANKL or IL-8, did not persist. In parallel, MafB, a transcription factor expressed by monocytes and required for differentiation to macrophages but inhibiting osteoclast generation, was preserved. Because both persistence of NFATc1 and downregulation of MafB are crucial for osteoclastogenesis, we conclude that BMP7/OP-1 inhibits the generation of osteoclasts by interfering with signalling pathways. 1. Introduction Physiological bone turnover, fracture healing, or repair of large bone defects depends on a well-balanced action of bone forming osteoblasts and bone resorbing osteoclasts [1]. A shift towards enhanced osteoclast formation is invariably associated with localized bone loss, as it is seen in patients with periodontitis, osteomyelitis, or implant-associated infections [2–7]. Presumably, the proinflammatory microenvironment created by persistent infections favors the generation of bone resorbing osteoclasts. Indeed, leukocytes recovered from inflamed site expressed increased levels of cytokines or cytokine specific mRNA, respectively [7, 8], which could promote the differentiation of monocytes to osteoclasts. Moreover, in biopsies of patients with osteomyelitis, the density of infiltrating leukocytes correlated with the number of osteoclasts [9]. Differentiation of monocytes to osteoclasts is induced by exogenous stimuli, which activate transcription factors for osteoclast-specific genes. Best studied in the context of osteoclast generation is the receptor activator of Nf B ligand (RANKL), which binds to its receptor RANK, resulting in translocation and upregulation of NF B, c-Fos, and NFATc1, transcription factors required for osteoclastogenesis [10–14]. RANKL also induces the transcription of a repressor for MafB [15]. MafB is expressed by myeloid cells, and its
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