Deficiency of Chemokine Receptor CCR1 Causes Osteopenia Due to Impaired Functions of Osteoclasts and Osteoblasts

Abstract

Chemokines are characterized by the homing activity of leukocytes to targeted inflammation sites. Recent research indicates that chemokines play more divergent roles in various phases of pathogenesis as well as immune reactions. The chemokine receptor, CCR1, and its ligands are thought to be involved in inflammatory bone destruction, but their physiological roles in the bone metabolism in vivo have not yet been elucidated. In the present study, we investigated the roles of CCR1 in bone metabolism using CCR1-deficient mice. Chemokines are initially identified as small cytokines that direct the homing of circulating leukocytes into sites of inflammation (1). Chemokines are now recognized to be major factors in inflammation and immune development as well as tumor growth, angiogenesis, and osteolysis. Chemokine receptors are expressed in a well organized spatiotemporal manner in various types of leukocytes, including lymphocytes, granulocytes, and macrophages. They facilitate the recruitment of these cells into inflammatory sites during the appropriate phase of inflammation.Recent findings indicate that chemokine receptors, including CCR1 7 and its related chemokines, CCL3 and CCL9, are involved in the pathogenesis of a variety of diseases. In particular, CCL3 (also called MIP-1␣), a major pro-inflammatory chemokine produced at inflammatory sites, appears to play a crucial role in pathological osteoclastogenesis (2, 3). In osteolytic bone inflammation (e.g. rheumatoid arthritis-associated bone destruction), CCL3 induces ectopic osteoclastogenesis (4) * This work was supported in part by Grant H19-nano-012 from the Ministry of Health, Labor and Welfare (to K. Y.) and by a research fellowship from the Japan Society for the Promotion of Science for Young Scientists (2007Scientists ( -2009 ( The abbreviations used are: CCR, C-C chemokine receptor; M-CSF, macrophage-colony stimulation factor; BALP, bone-specific alkaline phosphatase; CCL, C-C chemokine ligand; MCP-1, macrophage chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; CT, computed tomography; PTX, pertussis toxin from Bordetella pertussis; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; RANTES, regulated upon activation normal T expression and secreted; TRAP, tartrate-resistant acid phosphatase; NTx, N-telopeptides.

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

“…Future studies will elucidate whether autocrine EBI2 signaling is constitutive or inducible in OCPs and whether it is altered during pathological conditions. Although EBI2 contributes and is sufficient to promote OCP movement and differentiation in vivo, EBI2-deficient Hoshino et al, 2010). Our study revealed that autocrine EBI2 signaling accelerated OCP movement in vitro, which presumably maximized cell-cell interactions that precede cell fusion.…”

Roles of chemokine receptor CX3CR1 in maintaining murine bone homeostasis through the regulation of both osteoblasts and osteoclasts

“…2E), since we had previously reported critical roles of the CCR1 axis involving CCL5 and CCL9 in the differentiation and function of both osteoblasts and osteoclasts by observing Ccr1-deficient mice (Hoshino et al, 2010). Interestingly, the expression of Cx3cl1, Ccr1 and Ccl9 was almost completely eliminated, and CX3CR1-CX3CL1 axis in bone metabolism 1033 the level of Ccl5 was significantly downregulated in the bones from Cx3cr1-deficient mice (Fig.…”

“…Bone cells derived from Ccr1 2/2 mice show diminished expression levels of several chemokine ligands, thus suggesting that hierarchal networks of chemokines participate in bone metabolism (Hoshino et al, 2010). Therefore, in the present study, we investigated the bone features of Cx3cr1-deficient mice to further assess the roles of the chemokine receptors in bone metabolism.…”

CCL5/RANTES is important for inducing osteogenesis of human mesenchymal stem cells and is regulated by dexamethasone

“…The profile of chemokine receptors was analyzed by flow cytometry of human MSCs, and the results revealed that at least 70% of MSCs express CCR1, while none express CCR3 or CCR5 (9). Moreover, modulating the receptor activator of nuclear factor-κB ligand (RANKL)/RANK mediated interaction and osteoclast/osteoblast function in a mouse model (10), and osteopenia occur within CCR1-deficienct mice where they have fewer and thinner trabecular bones.…”