Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic <i>op/op</i> mice

• Yuko Nakamichi

  Division of Hard Tissue Research, Institute for Oral Science, and Departments of

• Toshihide Mizoguchi

  Division of Hard Tissue Research, Institute for Oral Science, and Departments of

• Atsushi Arai

  Division of Hard Tissue Research, Institute for Oral Science, and Departments of

• Yasuhiro Kobayashi

  Division of Hard Tissue Research, Institute for Oral Science, and Departments of

• Masahiro Sato

  Conservative Dentistry and

• Josef M. Penninger

  Institute of Molecular Biotechnology, Austrian Academy of Sciences, A-1030, Vienna, Austria;

• Hisataka Yasuda

  Oriental Yeast Co., Tokyo 174-8505, Japan;

• Shigeaki Kato

  Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan;

• Hector F. DeLuca

  Department of Biochemistry, University of Wisconsin, Madison, WI 53706; and

• Tatsuo Suda

  Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan

• Nobuyuki Udagawa

  Biochemistry, School of Dentistry, Matsumoto Dental University, Nagano 399-0781, Japan;

• Naoyuki Takahashi

  Division of Hard Tissue Research, Institute for Oral Science, and Departments of

抄録

Osteoclasts are generated from monocyte/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). CSF-1–mutated CSF-1 op/op mice as well as RANKL −/− mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in RANKL −/− mice. Here we show that OCPs do not exist in bone but in spleen in CSF-1 op/op mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in CSF-1 op/op mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1–induced osteoclastogenesis in CSF-1 op/op mice. Osteoclasts appeared in aged CSF-1 op/op mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20 S )-1α,25(OH) 2 D 3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D 3 , into CSF-1 op/op mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in CSF-1 op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 109 (25), 10006-10011, 2012-06-05

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1360848658888931584
• NII論文ID: 20001663325
• DOI: 10.1073/pnas.1207361109
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.1207361109
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