Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors

Arai, Fumio; Miyamoto, Takeshi; Onodera, Osamu; Inada, Tornohisa; Sudo, Tetsuo; Brasel, Kenneth; Miyata, Takashi; Anderson, D; Suda, Toshio

doi:10.1084/jem.190.12.1741

Cited by 647 publications

(596 citation statements)

References 53 publications

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“…53 Bone marrow cells (1x10 6 cells/well) were cultured with wild-type primary OBs (calvarial bone derived) (1x10 5 cells/well) in α-MEM containing 10% FBS, 10 − 7 M dexamethasone and 10 − 8 M 1α, 25-dihydroxyvitamin D 3 (Sigma, D1530) in 24-well plates for 6-7 days. 26,54 For rescue experiments, ca-NFAT2 retrovirus was generated with ca-NFAT2 vector (Addgene plasmid 11102, Cambridge, MA, USA) and phoenix Eco packaging cells (Garry Nolan, Stanford University, Stanford, CA, USA) as previously described. 55 Nonadherent bone marrow cells were cultured with M-CSF for another 24 h and incubated with viral supernatant for 8 h in the presence of 8 μg/ml polybrene.…”

Section: Methodsmentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca 2+ oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12 fl/fl cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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Section: Methodsmentioning

confidence: 99%

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

et al. 2015

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“…(4,(32)(33)(34)(35) Typically, these cells are cultured together with stromal cells or osteoblasts in the presence of 1,25-dihydroxyvitamin D 3 and dexamethasone. (35,36) Recently, these two factors were shown to stimulate osteoclastogenesis by inducing osteoblasts to produce RANKL.…”

Section: Discussionmentioning

confidence: 99%

“…As in other developmental systems, decisions on cell fate and differentiation are regulated by the sequential expression of lineage-specifying transcription factors. (3,4) On the other hand, some ubiquitously expressed transcription factors have been shown to have unique functions largely confined to osteoclasts, for example, c-Fos, PU.1, and NF-B, all of which are required for osteoclast differentiation. (2) The c-myc oncogene has been implicated in the control of cell proliferation, differentiation, and programmed cell death as well as in neoplastic transformation.…”

Section: Introductionmentioning

confidence: 99%

c-myc Is Required for Osteoclast Differentiation

Battaglino¹,

D²,

Fu³

et al. 2002

Journal of Bone and Mineral Research

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The role of the receptor activator of nuclear factor B (NF-B) ligand (RANKL)-a tumor necrosis factor (TNF)-related cytokine-in osteoclast formation has been established clearly. However, the downstream signaling pathways activated by this cytokine remain largely unknown. To identify genes that play a role in osteoclastogenesis, we used RAW 264.7 mouse monocytes as a model system for the differentiation of multinucleated osteoclasts from mononucleated precursors. RAW 264.7 cells were induced with RANKL to form multinucleated giant osteoclast-like cells (OCLs) that expressed a number of osteoclast-specific markers and were able to form resorption pits on both calcium phosphate films and bone slices. This system was used to identify genes that are regulated by RANKL and may play a role in osteoclast differentiation.

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“…Despite the fact that myeloid precursor cells respond to RANK-L signaling, 33 surface expression of the RANK receptor has to date only been significantly detected on in vitro cultured primary cells. 34 We have also not been able to detect significant surface RANK ex vivo on the surface of myeloid cells from mouse BM (data not shown). Although it is likely that RANK mediates IL-6 induction, we cannot formally exclude the involvement of another receptor in the process.…”

Section: Il-6-mediated Hematopoietic Deviation During MM Developmentmentioning

confidence: 81%

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

Matthes

Manfroi

Zeller³

et al. 2015

Leukemia

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Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells

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Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors

Cited by 647 publications

References 53 publications

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

c-myc Is Required for Osteoclast Differentiation

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow

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