Dynamic visualization of RANKL and Th17-mediated osteoclast function

Kikuta, Junichi; Wada, Yoh; Kowada, Toshiyuki; Wang, Ze; Sun-Wada, Ge Hong; Nishiyama, Issei; Mizukami, Shin; Maiya, Nobuhiko; Yasuda, Hisataka; Kumanogoh, Atsushi; Kikuchi, Kazuya; Germain, Ronald N.; Ishii, Masaru

doi:10.1172/jci65054

Cited by 124 publications

(157 citation statements)

References 38 publications

(40 reference statements)

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“…Male AS patients are known to experience greater radiographic progression compared with female patients (5). Th17 cells are known to mediate murine arthritis directly through RANKL expression and indirectly through IL-17A-mediated osteoclastogenesis (24,25). Thus, it is plausible that the elevated Th17 axis observed in male AS patients contributes to their increased radiographic progression compared with female AS patients.…”

Section: Discussionmentioning

confidence: 99%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

139

101

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ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

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Section: Discussionmentioning

confidence: 99%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

139

101

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“…C57BL/6 mice were obtained from The Jackson Laboratory. The generation of Ebi2 GFP/GFP mice was described previously (Pereira et al, 2009b Kikuta et al, 2013). TRA-P Red mice were intercrossed with Ebi2 GFP/GFP and with Ch25h / mice to generate TRAP Red Ebi2 GFP/GFP and TRAP Red Ch25h / and littermate control mice.…”

Section: Methodsmentioning

confidence: 99%

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Nevius¹,

Pinho²,

Dhodapkar³

et al. 2015

J Cell Biol

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Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gi protein-coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7,25-dihydroxycholesterol (7,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell-cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age-and estrogen deficiency-induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential.

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“…RANKL is produced by osteoblasts, marrow stromal cells and T cells. [160][161][162] Disruption of the balance between RANKL and the decoy receptor osteoprotegerin results in the deregulation of bone homeostasis. Most inflammatory cytokines including TNFa, IL-1 and IL-6 potentiate osteoclastogenesis by inducing RANKL expression in marrow stromal cells, osteoblasts or by stimulating RANK expression in myeloid-lineage cells (osteoclast precursors).…”

Section: Molecular Pathways Of Metastasis-promoting Inflammationmentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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Dynamic visualization of RANKL and Th17-mediated osteoclast function

Cited by 124 publications

References 38 publications

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Inflammation and skeletal metastasis

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