Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
J Immunol. 2009 Dec 15;183(12):7825-31. doi: 10.4049/jimmunol.0803627.
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.
破骨细胞前体细胞向成骨细胞的募集以及随后的细胞-细胞相互作用对于破骨细胞分化至关重要。趋化因子已知可调节细胞迁移和黏附。CX3CL1（也称为 fractalkine）是一种独特的膜结合趋化因子，对表达其受体 CX3CR1 的细胞具有双重功能：可溶性形式下是一种有效的趋化因子，膜结合形式下是一种有效的细胞黏附分子。在本文中，我们证明了 CX3CL1 在成骨细胞诱导的破骨细胞分化中的新作用。我们发现破骨细胞前体细胞选择性表达 CX3CR1，而 CX3CL1 则由成骨细胞表达。我们证实，可溶性 CX3CL1 诱导含有破骨细胞前体细胞的骨髓细胞迁移，而固定化的 CX3CL1 介导破骨细胞前体细胞的牢固黏附。此外，针对 CX3CL1 的阻断 mAb 可有效抑制与成骨细胞共培养的小鼠骨髓细胞中的破骨细胞分化。抗-CX3CL1 还通过减少骨吸收成熟破骨细胞的数量，显著抑制新生小鼠的骨吸收。总之，成骨细胞表达的 CX3CL1 在破骨细胞分化中发挥重要作用，可能通过其作为趋化因子和 CX3CR1 表达的破骨细胞前体的黏附分子的双重功能。CX3CL1-CX3CR1 轴可能是治疗类风湿关节炎、骨质疏松症和癌症骨转移等骨吸收疾病的新靶点。
