Institute for Oral Science, Matsumoto Dental University, Nagano 399-0781, Japan.
J Cell Sci. 2012 Jun 15;125(Pt 12):2910-7. doi: 10.1242/jcs.099986. Epub 2012 Mar 27.
Fos plays essential roles in the osteoclastic differentiation of precursor cells generated by colony-stimulating factor 1 (CSF-1) and receptor activator of NF-κB ligand (RANKL; also known as tumor necrosis factor ligand superfamily member 11, Tnsf11). RANKL-deficient (RANKL(-/-)) mice and Fos(-/-) mice exhibit osteopetrosis due to an osteoclast deficiency. We previously reported that RANK-positive osteoclast precursors are present in bone of RANKL(-/-) mice but not Fos(-/-) mice. Here we report the role of Fos in RANK expression in osteoclast precursors. Medullary thymic epithelial cells and intestinal antigen-sampling microfold cells have been shown to express RANK. High expression of RANK was observed in some epithelial cells in the thymic medulla and intestine but not in osteoclast precursors in Fos(-/-) mice. RANK mRNA and protein levels in bone were lower in Fos(-/-) mice than RANKL(-/-) mice, suggesting that Fos-regulated RANK expression is tissue specific. When wild-type bone marrow cells were inoculated into Fos(-/-) mice, RANK-positive cells appeared along bones. RANK expression in wild-type macrophages was upregulated by coculturing with RANKL(-/-) osteoblasts as well as wild-type osteoblasts, suggesting that cytokines other than RANKL expressed by osteoblasts upregulate RANK expression in osteoclast precursors. CSF-1 receptor-positive cells were detected near CSF-1-expressing osteoblastic cells in bone in Fos(-/-) mice. CSF-1 upregulated RANK expression in wild-type macrophages but not Fos(-/-) macrophages. Overexpression of Fos in Fos(-/-) macrophages resulted in the upregulation of RANK expression. Overexpression of RANK in Fos(-/-) macrophages caused RANKL-induced signals, but failed to recover the RANKL-induced osteoclastogenesis. These results suggest that Fos plays essential roles in the upregulation of RANK expression in osteoclast precursors within the bone environment.
Fos 在由集落刺激因子 1（CSF-1）和核因子-κB 受体激活配体（RANKL；也称为肿瘤坏死因子配体超家族成员 11，Tnsf11）生成的前体细胞的破骨细胞分化中发挥重要作用。由于破骨细胞缺乏，RANKL 缺陷（RANKL(-/-)）小鼠和 Fos(-/-) 小鼠表现出骨质增生。我们之前报道过，RANK 阳性的破骨细胞前体存在于 RANKL(-/-) 小鼠的骨骼中，但不存在于 Fos(-/-) 小鼠中。在这里，我们报告了 Fos 在破骨细胞前体中 RANK 表达中的作用。已经表明，骨髓胸腺上皮细胞和肠道抗原取样微褶细胞表达 RANK。在胸腺髓质和肠道的一些上皮细胞中观察到 RANK 的高表达，但在 Fos(-/-) 小鼠的破骨细胞前体中没有观察到。与 RANKL(-/-) 小鼠相比，Fos(-/-) 小鼠骨骼中的 RANK mRNA 和蛋白水平较低，这表明 Fos 调节的 RANK 表达是组织特异性的。当将野生型骨髓细胞接种到 Fos(-/-) 小鼠中时，RANK 阳性细胞出现在骨骼周围。与 RANKL(-/-) 成骨细胞以及野生型成骨细胞共培养可上调野生型巨噬细胞中的 RANK 表达，这表明成骨细胞表达的除 RANKL 以外的细胞因子可上调破骨细胞前体中的 RANK 表达。在 Fos(-/-) 小鼠的骨骼中，检测到 CSF-1 表达的成骨细胞附近存在 CSF-1 受体阳性细胞。CSF-1 上调野生型巨噬细胞中的 RANK 表达，但不影响 Fos(-/-) 巨噬细胞。在 Fos(-/-) 巨噬细胞中过表达 Fos 可上调 RANK 表达。在 Fos(-/-) 巨噬细胞中过表达 RANK 可导致 RANKL 诱导的信号，但未能恢复 RANKL 诱导的破骨细胞生成。这些结果表明，Fos 在骨骼环境中破骨细胞前体中 RANK 表达的上调中发挥重要作用。
