Role of CX3CL1/fractalkine in osteoclast differentiation and bone resorption.
The recruitment of osteoclast precursors toward osteoblasts and subsequent cell-cell interactions are critical for osteoclast differentiation. Chemokines are known to regulate cell migration and adhesion. CX3CL1 (also called fractalkine) is a unique membrane-bound chemokine that has dual functions for cells expressing its receptor CX3CR1: a potent chemotactic factor in its soluble form and a type of efficient cell adhesion molecule in its membrane-bound form. In this paper, we demonstrate a novel role of CX3CL1 in osteoblast-induced osteoclast differentiation. We found that osteoclast precursors selectively expressed CX3CR1, whereas CX3CL1 is expressed by osteoblasts. We confirmed that soluble CX3CL1 induced migration of bone marrow cells containing osteoclast precursors, whereas immobilized CX3CL1 mediated firm adhesion of osteoclast precursors. Furthermore, a blocking mAb against CX3CL1 efficiently inhibited osteoclast differentiation in mouse bone marrow cells cocultured with osteoblasts. Anti-CX3CL1 also significantly suppressed bone resorption in neonatal mice by reducing the number of bone-resorbing mature osteoclasts. Collectively, CX3CL1 expressed by osteoblasts plays an important role in osteoclast differentiation, possibly through its dual functions as a chemotactic factor and adhesion molecule for osteoclast precursors expressing CX3CR1. The CX3CL1-CX3CR1 axis may be a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis, osteoporosis, and cancer bone metastasis.
Koizumi
Keiichi
K
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan. kkoizumi@inm.u-toyama.ac.jp
Saitoh
Yurika
Y
Minami
Takayuki
T
Takeno
Nobuhiro
N
Tsuneyama
Koichi
K
Miyahara
Tatsuro
T
Nakayama
Takashi
T
Sakurai
Hiroaki
H
Takano
Yasuo
Y
Nishimura
Miyuki
M
Imai
Toshio
T
Yoshie
Osamu
O
Saiki
Ikuo
I
D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D001862:Bone Resorption / Q000276:immunology*; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine