The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

Jimi, Eijiro; Shin, Masashi; Furuta, Haruhiko; Tada, Yukiyo; Kusukawa, Jingo

doi:10.3892/ijo.2013.1794

Cited by 42 publications

(44 citation statements)

References 55 publications

(97 reference statements)

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“…52 The infiltrative pattern has a lower rate of 3-year disease-free status compared with the erosive bone invasion pattern. High expression levels of PTHrP, RANKL, interleukin (IL)-6, and tumor necrosis factor–α (TNF-α) were detected in bone-invasive HNSCCs.…”

Section: Animal Modelsmentioning

confidence: 97%

“…High expression levels of PTHrP, RANKL, interleukin (IL)-6, and tumor necrosis factor–α (TNF-α) were detected in bone-invasive HNSCCs. 52 The majority of bone-invasive HNSCCs are suspected to be mediated by PTHrP and RANKL, similar to cancers that metastasize to bone. 52,76,133 PTHrP contributes to bone lysis by inducing RANKL expression in osteoblasts, resulting in binding of RANKL to its receptor, RANK, on osteoclasts and stimulating osteoclastogenesis.…”

Section: Animal Modelsmentioning

confidence: 99%

“…52 The majority of bone-invasive HNSCCs are suspected to be mediated by PTHrP and RANKL, similar to cancers that metastasize to bone. 52,76,133 PTHrP contributes to bone lysis by inducing RANKL expression in osteoblasts, resulting in binding of RANKL to its receptor, RANK, on osteoclasts and stimulating osteoclastogenesis. 133 Osteoprotegerin (OPG), the soluble decoy receptor of RANKL, is regulated by the Wnt/β-catenin signaling pathway and counterbalances the actions of RANKL.…”

Section: Animal Modelsmentioning

confidence: 99%

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Animal Models of Bone Metastasis

et al. 2015

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Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone.

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Section: Animal Modelsmentioning

confidence: 97%

Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

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Animal Models of Bone Metastasis

et al. 2015

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“…An altered RANKL/osteoprotegerin ratio can cause bone resorption or enhanced bone formation . It is well recognized that alterations in the RANKL/osteoprotegerin system play an important role in the pathogenesis of diseases of bone metabolism, such as rheumatoid arthritis , Paget's disease and postmenopausal osteoporosis , as well as in different types of cancer . Infiltrating leukocytes and macrophages release proinflammatory cytokines, such as interleukin‐1, interleukin‐6 and prostaglandin E 2 , which affect the expression of RANKL and osteoprotegerin by osteoblasts, as well as by periodontal ligament fibroblasts and gingival fibroblasts .…”

Section: Changes In the Periodontal Tissuesmentioning

confidence: 99%

Local inflammatory reactions in patients with diabetes and periodontitis

Sonnenschein¹,

Meyle²

2015

Periodontology 2000

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The impact of diabetes mellitus on the prevalence, severity and progression of periodontal disease has been known for many years and intense efforts have been made to elucidate the underlying mechanisms. It is widely reported that hyperglycemia causes numerous systemic changes, including altered innate immune‐cell function and metabolic changes. The aim of this review was to summarize and discuss the evidence for mechanisms that probably play a role in the altered local inflammatory reactions in the periodontium of patients with diabetes, focusing on local changes in cytokine levels, matrix metalloproteinases, reactive oxygen species, advanced glycation end‐products, immune‐cell functions, the RANKL/osteoprotegerin axis and toll‐like receptors. Apart from the systemic effects of diabetes, recent evidence suggests that local changes in the periodontal tissues are characterized by enhanced interactions between leukocytes and endothelial cells and by altered leukocyte functions [resulting in increased levels of reactive oxygen species and of proinflammatory cytokines (interleukin‐1β, interleukin‐6 and tumor necrosis factor‐α)]. These local changes are amplified by the enhanced accumulation of advanced glycation end‐products and their interaction with receptors for advanced glycation end‐products. Furthermore, the increased levels of proinflammatory cytokines lead to an up‐regulation of RANKL in periodontal tissues, stimulating further periodontal tissue breakdown.

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“…The RANKL/RANK interaction induces osteoclastogenesis, while OPG prevents this process in vitro and in vivo [16,17]. Although these proteins are known to be involved in normal bone development, they have also been shown to contribute to pathological bone metabolic processes, such as osteolysis, which is associated with the progression of malignant tumors at the bone site [18,19]. Binding of RANKL to RANK activates several intracellular signaling pathways, and activation of NF-B is an important step for RANKLinduced osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%

NF‐κB acts as a multifunctional modulator in bone invasion by oral squamous cell carcinoma

Jimi¹,

Kokabu²,

Matsubara³

et al. 2015

Oral Science International

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a b s t r a c tOral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral cavity and the head and neck region. Gingival squamous cell carcinomas (SCCs) frequently invade the maxilla or the mandibular bone and are associated with poor prognosis. Recent findings suggest that osteoclasts, rather than OSCC cells, mediate invasion to the bone. Nuclear factor-B (NF-B) is constitutively activated in OSCCs and is involved in promoting the invasive characteristics of OSCC. NF-B activation is also important for receptor activator of NF-B ligand (RANKL)-induced osteoclastogenesis. NF-B inhibitors suppress proliferation and stimulate apoptosis of OSCC cells in vitro and in vivo, as well as inhibit matrix metalloproteinase (MMP) production in OSCC. Furthermore, NF-B inhibitors have been shown to suppress osteoclastogenesis by reducing RANKL expression in animal models. Thus, inhibition of NF-B activity may constitute a promising therapeutic approach to treat bone-invasive OSCC. In this review, we discuss recent findings, which suggest that bone invasion in OSCC is mediated via NF-B signaling and may be successfully prevented by NF-B inhibition.

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The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

Cited by 42 publications

References 55 publications

Animal Models of Bone Metastasis

Animal Models of Bone Metastasis

Local inflammatory reactions in patients with diabetes and periodontitis

NF‐κB acts as a multifunctional modulator in bone invasion by oral squamous cell carcinoma

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