Monocyte chemoattractant protein-1 (MCP-1) is associated with various inflammatory diseases involving bone loss, and is expressed along with its receptor by bone marrow-derived macrophages (BMM), which are osteoclast (OC) precursors. To investigate the role of MCP-1 in bone remodeling, we compared MCP-1-knockout (KO) mice with wild-type (WT) mice. The absence of MCP-1 increased bone mass and lowered serum collagen type I fragments (CTX-1) and TRACP 5b, but had no significant effect on the N-terminal propeptide of type I procollagen, suggesting that OCs are primarily responsible for the bone phenotype observed in the absence of MCP-1. MCP-1 deficiency resulted in reduced numbers and activity of OCs in vitro. It also led to a reduced level of c-Fms and receptor activator of nuclear factor-κB receptor and impaired actin ring formation. Activation of ERK, Akt, Rac1, and Rho upon M-CSF stimulation was also reduced and our evidence suggests that the aberrant actin ring formation was partly due to reduced activation of these molecules. Our findings point to a role of osteoclast MCP-1 in regulating bone remodeling. The higher bone mass in the femurs of MCP-1-KO mice could be, at least in part, due to decreased osteoclastogenesis and bone resorption resulting from aberrant M-CSF signaling in OCs.

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BackgroundLoss of ovarian function is highly associated with an elevated risk of metabolic disease. Monocyte chemoattractant protein-1 (MCP-1, C-C chemokine ligand 2) plays critical roles in the development of inflammation, but its role in ovariectomy (OVX)-induced metabolic disturbance has not been known.Methodology and Principal FindingsWe investigated the role of MCP-1 in OVX-induced metabolic perturbation using MCP-1-knockout mice. OVX increased fat mass, serum levels of MCP-1, macrophage-colony stimulating factor (M-CSF), and reactive oxygen species (ROS), whereas MCP-1 deficiency attenuated these. OVX-induced increases of visceral fat resulted in elevated levels of highly inflammatory CD11c-expressing cells as well as other immune cells in adipose tissue, whereas a lack of MCP-1 significantly reduced all of these levels. MCP-1 deficiency attenuated activation of phospholipase Cγ2, transforming oncogene from Ak strain, and extracellular signal-regulated kinase as well as generation of ROS, which is required for up-regulating CD11c expression upon M-CSF stimulation in bone marrow-derived macrophages.Conclusions/SignificanceOur data suggested that MCP-1 plays a key role in developing metabolic perturbation caused by a loss of ovarian functions through elevating CD11c expression via ROS generation.

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