Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5)

TY - JOUR

T1 - Impaired bone formation and increased osteoclastogenesis in mice lacking chemokine (C-C motif) ligand 5 (Ccl5)

AU - Wintges, Kristofer

AU - Beil, F Timo

AU - Albers, Joachim

AU - Jeschke, Anke

AU - Schweizer, Michaela

AU - Claass, Benjamin

AU - Tiegs, Gisa

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - © 2013 American Society for Bone and Mineral Research.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Chemokines play crucial roles in the recruitment of specific hematopoietic cell types, and some of them have been suggested to be involved in the regulation of bone remodeling. Because we have previously observed that chemokine (C-C motif) ligand 2 (Ccl2) and Ccl5 are direct target genes of noncanonical Wnt signaling in osteoblasts, we analyzed the skeletal phenotypes of Ccl2-deficient and Ccl5-deficient mice. In line with previous studies, Ccl2-deficient mice display a moderate reduction of osteoclastogenesis at the age of 6 months. In contrast, 6-month-old Ccl5-deficient mice display osteopenia associated with decreased bone formation and increased osteoclastogenesis. Moreover, unlike in wild-type and Ccl2-deficient mice, large areas of their trabecular and endocortical bone surfaces are not covered by osteoblasts or bone-lining cells, and this is associated with a severe reduction of endosteal bone formation. Although this phenotype diminishes with age, it is important that we could further identify a reduced number of osteal macrophages in 6-month-old Ccl5-deficient mice, because this cell type has previously been reported to promote endosteal bone formation. Because Ccl5-deficient mice also display increased osteoclastogenesis, we finally addressed the question of whether osteal macrophages could differentiate into osteoclasts and/or secrete inhibitors of osteoclastogenesis. For that purpose we isolated these cells by CD11b affinity purification from calvarial cultures and characterized them ex vivo. Here we found that they are unable to differentiate into osteoblasts or osteoclasts, but that their conditioned medium mediates an antiosteoclastogenic effect, possibly caused by interleukin-18 (IL-18), an inhibitor of osteoclastogenesis expressed by osteal macrophages. Taken together, our data provide in vivo evidence supporting the previously suggested role of Ccl5 in bone remodeling. Moreover, to the best of our knowledge, Ccl5-deficient mice represent the first model with a spontaneous partial deficiency of osteal macrophages, a recently identified cell type, whose impact on bone remodeling is just beginning to be understood.

AB - Chemokines play crucial roles in the recruitment of specific hematopoietic cell types, and some of them have been suggested to be involved in the regulation of bone remodeling. Because we have previously observed that chemokine (C-C motif) ligand 2 (Ccl2) and Ccl5 are direct target genes of noncanonical Wnt signaling in osteoblasts, we analyzed the skeletal phenotypes of Ccl2-deficient and Ccl5-deficient mice. In line with previous studies, Ccl2-deficient mice display a moderate reduction of osteoclastogenesis at the age of 6 months. In contrast, 6-month-old Ccl5-deficient mice display osteopenia associated with decreased bone formation and increased osteoclastogenesis. Moreover, unlike in wild-type and Ccl2-deficient mice, large areas of their trabecular and endocortical bone surfaces are not covered by osteoblasts or bone-lining cells, and this is associated with a severe reduction of endosteal bone formation. Although this phenotype diminishes with age, it is important that we could further identify a reduced number of osteal macrophages in 6-month-old Ccl5-deficient mice, because this cell type has previously been reported to promote endosteal bone formation. Because Ccl5-deficient mice also display increased osteoclastogenesis, we finally addressed the question of whether osteal macrophages could differentiate into osteoclasts and/or secrete inhibitors of osteoclastogenesis. For that purpose we isolated these cells by CD11b affinity purification from calvarial cultures and characterized them ex vivo. Here we found that they are unable to differentiate into osteoblasts or osteoclasts, but that their conditioned medium mediates an antiosteoclastogenic effect, possibly caused by interleukin-18 (IL-18), an inhibitor of osteoclastogenesis expressed by osteal macrophages. Taken together, our data provide in vivo evidence supporting the previously suggested role of Ccl5 in bone remodeling. Moreover, to the best of our knowledge, Ccl5-deficient mice represent the first model with a spontaneous partial deficiency of osteal macrophages, a recently identified cell type, whose impact on bone remodeling is just beginning to be understood.

KW - Animals

KW - Bone Marrow Cells

KW - Bone Remodeling

KW - Cell Differentiation

KW - Cell Separation

KW - Cells, Cultured

KW - Chemokine CCL2

KW - Chemokine CCL5

KW - Culture Media, Conditioned

KW - Hematopoiesis

KW - Interleukin-18

KW - Macrophages

KW - Mice

KW - Mice, Inbred C57BL

KW - Osteoclasts

KW - Osteogenesis

KW - Spine

KW - Stem Cells

KW - Tibia

U2 - 10.1002/jbmr.1937

DO - 10.1002/jbmr.1937

M3 - SCORING: Journal article

C2 - 23553711

VL - 28

SP - 2070

EP - 2080

JO - J BONE MINER RES

JF - J BONE MINER RES

SN - 0884-0431

IS - 10

ER -