Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization

Miyamoto, Kana; Yoshida, Shigeyuki; Kawasumi, Miyuri; Hashimoto, Kazuaki; Kimura, Tokuhiro; Sato, Yuiko; Kobayashi, Tami; Miyauchi, Yoshiteru; Hoshi, Hiroko; Iwasaki, Ryuichiro; Miyamoto, Hiroaki; Wu, Hao; Morioka, Hideo; Chiba, Kazuhiro; Kobayashi, Takashi; Yasuda, Hisataka; Penninger, Josef; Toyama, Yoshiaki; Suda, Toshio; Miyamoto, Takeshi

doi:10.1084/jem.2010189020813c

Cited by 34 publications

(59 citation statements)

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“…This suggests that spleen acts as the reservoir of hematopoietic precursors under pathological conditions such as osteopetrosis. Recently, Miyamoto et al (36) reported that the mobilization of hematopoietic stem and progenitor cells (HSPCs) occurring after granulocyte colony-stimulating factor (G-CSF) injection was comparable or even increased in osteopetrotic CSF-1 op/op , RANKL −/− and c-Fos −/− mice, compared with that in WT mice. Contrary to OCPs, the mobilization of HSPCs was not suppressed by SPX in CSF-1 op/op mice in the G-CSF treatment (36).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Miyamoto et al (36) reported that the mobilization of hematopoietic stem and progenitor cells (HSPCs) occurring after granulocyte colony-stimulating factor (G-CSF) injection was comparable or even increased in osteopetrotic CSF-1 op/op , RANKL −/− and c-Fos −/− mice, compared with that in WT mice. Contrary to OCPs, the mobilization of HSPCs was not suppressed by SPX in CSF-1 op/op mice in the G-CSF treatment (36). These results suggest that spleen cannot act as the reservoir of HSPCs in CSF-1 op/op mice, although HSPCs exist in the enlarged spleen.…”

Section: Discussionmentioning

confidence: 99%

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

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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-(20S)-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. CSF-1 is the most potent growth factor for monocytes/macrophages (3), but its synthesis by osteoblasts occurs independently of PTH and 1α,25(OH) 2 D 3 (2). CSF-1 op/op mice cannot produce a functionally active CSF-1 (4), and therefore, exhibit monocytopenia and osteopetrosis (OP) (5, 6). However, several curious phenomena have been observed in CSF-1 op/op mice. First, osteoclasts are totally absent in young CSF-1 op/op mice, but appear in aged CSF-1 op/op mice (7). Second, osteopetrotic characteristics of CSF-1R −/− mice are more severe than those of CSF-1 op/op mice (8). Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9, 10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11, 12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).Recently, Lin et al. (14) discovered IL-34, as a new ligand for CSF-1R. The amino acid sequence of IL-34 was quite different from that of CSF-1, but IL-34 promoted macrophage colony formation like CSF-1 did. IL-34 was specifically expressed in splen...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This result indicates that active osteoclasts are indispensable for endosteal HSC/ HPC niche formation. Another group reported that osteopetrotic mice models, op/op, c-Fos-deficient, and receptor activator of nuclear factor kappa B ligand-deficient mice, in which osteoclasts are deficient and BM cavity is absent, have normal capacity for HSC/HPC mobilization induced by granulocyte colony-stimulating factor (G-CSF) [27]. Therefore, the role of osteoclasts in hematopoietic system remains a matter of debate.…”

Section: Osteoblast Progenitor (Pre-osteoblast) and Osteoblastmentioning

confidence: 99%

Regulation of hematopoiesis in endosteal microenvironments

Asada

Katayama

2014

Int J Hematol

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After birth, the hematopoietic system develops along with bone formation in mammals. Osteolineage cells are derived from mesenchymal progenitor cells, and differentiate into several types of bone-forming cells. Of the various types of cell constituents in bone marrow, osteolineage cells have been shown to play important roles in hematopoiesis. Early studies have identified osteoblasts as a hematopoietic stem cell niche component. Since that time, the role of endosteal microenvironment as a critical regulator of hematopoietic stem/progenitor cell (HSC/ HPC) behavior has been appreciated particularly under stress conditions, such as cytokine-induced HSC/HPC mobilization, homing/engraftment after bone marrow transplantation, and disease models of leukemia/myelodysplasia. Recent studies revealed that the most differentiated osteolineage cells, i.e., osteocytes, play important roles in the regulation of hematopoiesis. In this review, we provide an overview of recent advances in knowledge of regulatory hematopoietic mechanisms in the endosteal area.

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“…Macrophage depletion strategies using clodronate liposome and the macrophage-Fas-induced apoptosis (Mafia) models both reduced osteoclast numbers, yet resulted in robust HSC mobilization [28]. Administration of bisphosphonates and anti-RANKL antibody to suppress OC activity instead enhanced mobilization of HSPCs in response to G-CSF [28,29,44]. Furthermore, the timing of G-CSF-induced elevation in osteoclast number and activity seems to occur after the peak of HSPC mobilization [28,29].…”

Section: Osteoclastsmentioning

confidence: 99%

“…Furthermore, the timing of G-CSF-induced elevation in osteoclast number and activity seems to occur after the peak of HSPC mobilization [28,29]. Studies utilising gene knockout models with defective OCs at birth are confounded by a perturbed BM niche, including osteopetrosis, leading to abnormal levels and response of HSPCs depending on the severity of the OC defect [44,45]. A recent study by Daniel Link's group employing two mouse models with selective OC depletion without osteopetrosis again found no effect on G-CSF-induced HSPC mobilization [46].…”

Section: Osteoclastsmentioning

confidence: 99%

Cellular players of hematopoietic stem cell mobilization in the bone marrow niche

Tay

Levesque

2016

Int J Hematol

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Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization

Cited by 34 publications

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

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

Regulation of hematopoiesis in endosteal microenvironments

Cellular players of hematopoietic stem cell mobilization in the bone marrow niche

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