c-Fos plays an essential role in the up-regulation of RANK expression in osteoclast precursors within the bone microenvironment

Author:

Arai Atsushi,Mizoguchi Toshihide,Harada Suguru,Kobayashi Yasuhiro,Nakamichi Yuko,Yasuda Hisataka,Penninger Josef M.,Yamada Kazuhiro,Udagawa Nobuyuki,Takahashi Naoyuki

Abstract

c-Fos plays essential roles in the osteoclastic differentiation of precursors generated by colony-stimulating factor 1 (CSF-1) and receptor activator of NF-κB ligand (RANKL). RANKL-deficient (RANKL−/−) mice and c-Fos−/− mice exhibit osteopetrosis due to an osteoclast deficiency. We previously reported that RANK-positive osteoclast precursors existed in bone in RANKL−/− mice but not c-Fos−/− mice. Here we examined the role of c-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 c-Fos−/− mice. RANK mRNA and protein levels in bone were lower in c-Fos−/− mice than RANKL−/− mice, suggesting that c-Fos-regulated RANK expression is tissue specific. When wild-type bone marrow cells were inoculated into c-Fos−/− mice, RANK-positive cells appeared along bones. RANK expression in wild-type macrophages was up-regulated by coculturing with RANKL−/− osteoblasts as well as wild-type osteoblasts, suggesting that cytokines other than RANKL expressed by osteoblasts up-regulate RANK expression in osteoclast precursors. CSF-1 receptor-positive cells were detected near CSF-1-expressing osteoblastic cells in bone in c-Fos−/− mice. CSF-1 up-regulated RANK expression in wild-type macrophages but not c-Fos−/− macrophages. Overexpression of c-Fos in c-Fos−/− macrophages resulted in the up-regulation of RANK expression. Overexpression of RANK in c-Fos−/− macrophages caused RANKL-induced signals, but failed to recover the RANKL-induced osteoclastogenesis. These results suggest that c-Fos plays essential roles in the up-regulation of RANK expression in osteoclast precursors within the bone environment.

Publisher

The Company of Biologists

Subject

Cell Biology

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