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

Content Provider	PubMed Central
Author	Nakamichi, Yuko Mizoguchi, Toshihide Arai, Atsushi Kobayashi, Yasuhiro Sato, Masahiro Penninger, Josef M. Yasuda, Hisataka Kato, Shigeaki Deluca, Hector F. Suda, Tatsuo Udagawa, Nobuyuki Takahashi, Naoyuki
Abstract	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-1op/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-1op/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-1op/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-1op/op mice. Osteoclasts appeared in aged CSF-1op/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-(20S)-1α,25(OH)2D3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D3, into CSF-1op/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-1op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D.
Related Links	http://dx.doi.org/10.1073/pnas.1207361109
Ending Page	10011
Page Count	6
Starting Page	10006
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-06-19
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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