Multifunctional Properties of RANKL/RANK in Cell Differentiation, Proliferation and Metastasis

Kukita, Akiko; Kukita, Toshio

doi:10.2217/fon.13.115

Cited by 22 publications

(13 citation statements)

References 123 publications

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“…Mice deficient in RANK are not capable of lactation owing to lack of functional mammary gland formation during pregnancy (19). RANKL is also important to the formation of mammary glands by stimulating the proliferation of epithelial cells through nuclear factor kappa B (NF-kB); progesterone was important for this process through induction of RANKL (20). In a mouse mammary tumor virus model, direct action of RANKL was observed in tumorigenesis, which was accelerated by progesterone (21).…”

Section: Cell Growth and Differentiationmentioning

confidence: 99%

Role of the RANK/RANKL Pathway in Multiple Myeloma

Raje

Bhatta

Terpos

2019

Clinical Cancer Research

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Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.

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Section: Cell Growth and Differentiationmentioning

confidence: 99%

Role of the RANK/RANKL Pathway in Multiple Myeloma

Raje

Bhatta

Terpos

2019

Clinical Cancer Research

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“…RANKL‐RANK interaction induces activation of the TNF receptor‐associated factor 6 (TRAF6), which leads to activation of MAPKs (ERK, JNK, and p38) and several transcription factors including c‐fos. (Kukita & Kukita, ; Takayanagi, ). This signaling results in the activation of nuclear factor of activated T cells (NFAT) c1, a master regulator of osteoclastogenesis (Asagiri & Takayanagi, ; Ishida et al, ; Takayanagi et al, ).…”

Section: Introductionmentioning

confidence: 99%

Pmepa1 induced by RANKL‐p38 MAPK pathway has a novel role in osteoclastogenesis

Funakubo

Kukita

et al. 2017

Journal Cellular Physiology

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Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here, we have analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-β and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsin K and c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling.

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“…The formation of osteoclasts involves several factors such as receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) and macrophage colony-stimulating factor (Novack, 2011). Many researchers have shown that RANKL is directly involved in the differentiation of macrophages into osteoclasts (Wang et al, 2003;Kukita and Kukita, 2013). RANKL is able to activate mature osteoclasts (Burgess et al, 1999), and induce osteoclast polarization and hypercalcemia (Xu et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of andrographolide in RAW 264.7 murine macrophage osteoclastogenesis by downregulating the nuclear factor-kappaB signaling pathway

Ren

Yuan

2015

Genet. Mol. Res.

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ABSTRACT. This study aims to investigate the effects of andrographolide (AGP) on osteoclast formation in RAW 264.7 murine macrophage cells. The effects of AGP on cell viability were determined in RAW 264.7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of AGP on osteoclast formation were tested by osteoclast staining with tartrate-resistant acid phosphatase (TRAP). The effects of AGP on receptor activator of nuclear factor-kappaB (NFkappaB) ligand (RANKL)-induced, NF-kappaB-dependent transcription in RAW 264.7 cells were assessed using luciferase reporter assays. The results demonstrated that the viability of osteoclast precursor RAW 264.7 cells was not affected by AGP treatment at a concentration of 0.4 to 10 μM. Additionally, the number of TRAP-positive osteoclasts was significantly reduced by the same concentrations of AGP treatment. AGP also inhibited RANKL-induced NF-kappaB activation in a dose-dependent 15955-15961 (2015) fashion as evidenced by luciferase reporter assays. In summary, this study demonstrates that AGP inhibits osteoclastogenesis in RAW 264.7 murine macrophage cells through downregulation of the NF-kappaB signaling pathway.

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Multifunctional Properties of RANKL/RANK in Cell Differentiation, Proliferation and Metastasis

Cited by 22 publications

References 123 publications

Role of the RANK/RANKL Pathway in Multiple Myeloma

Role of the RANK/RANKL Pathway in Multiple Myeloma

Pmepa1 induced by RANKL‐p38 MAPK pathway has a novel role in osteoclastogenesis

Inhibition of andrographolide in RAW 264.7 murine macrophage osteoclastogenesis by downregulating the nuclear factor-kappaB signaling pathway

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