Targeting the RANKL/RANK/OPG Axis for Cancer Therapy

Ming, Jie; Cronin, Shane J. F.; Penninger, Josef

doi:10.3389/fonc.2020.01283

Cited by 52 publications

(50 citation statements)

References 171 publications

(165 reference statements)

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“…OPG, a decoy receptor of RANKL with a higher affinity than RANK, negatively regulates osteoclastogenesis. RANKL production in cells, such as osteoblasts, osteocytes, and activated T cells, can be induced by numerous factors, including prostaglandin E2 (PGE2), parathyroid hormone, progesterone, IL-17, TNF-α, and vitamin D, whereas OPG production can be induced by IL-4, estrogen, and transforming growth factor beta ( 85 ). The RANKL/RANK/OPG axis may also be regulated by B cells and T cells ( 86 ).…”

Section: Mechanisms Of Bone Loss Related To Inflammasomesmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Section: Mechanisms Of Bone Loss Related To Inflammasomesmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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“…The Receptor Activator of Nuclear Factor Kappa B (RANK, TNFRSF11A) and its ligand RANKL play a key role in osteoclast activation and differentiation [ 74 ]. RANKL is a cytokine expressed by osteoblast lineage cells, including osteoblasts and osteocytes.…”

Section: Genetic Causes Of Bone Fragilitymentioning

confidence: 99%

“…Osteoblast also express a decoy receptor osteoprotegerin (OPG, TNFRSF11B) that competitively binds with the RANK receptor and inhibits the interaction with RANKL. Hence, osteoblasts and osteocytes regulate activation and differentiation of osteoclasts by the RANKL-RANK axis signaling pathway [ 74 , 75 ].…”

Section: Genetic Causes Of Bone Fragilitymentioning

confidence: 99%

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Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

El‐Gazzar

Högler

2021

IJMS

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Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.

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“…During malignancy, calcium homeostasis is progressively disrupted by the secretion of osteolytic factors such as parathyroid hormone-related protein (PTHrP) by tumor cells, which like PTH promotes osteolysis. With tumor progression, the increased circulating PTHrP stimulates the biosynthesis and secretion of receptor activator of nuclear factor κB ligand (RANKL) by osteoblasts that further activate preosteoclasts osteoclast driven osteolysis [ 10 ]. This bone resorption signaling is inhibited by osteoprotegerin (OPG), which binds to RANKL and inhibits RANK signaling and bone resorption [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies

Actkins

Beasley

Faucon

et al. 2021

JPM

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Dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry. Multivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms. Circulating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies. Our data suggest that expression of CaSR variants at rs1801725 is associated with a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part to cancer-induced hypercalcemia and/or tumor immune suppression. Screening of patients for CASR variants at this locus may lead to improved management of high calcium associated tumor progression.

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Targeting the RANKL/RANK/OPG Axis for Cancer Therapy

Cited by 52 publications

References 171 publications

Inflammasomes in Alveolar Bone Loss

Inflammasomes in Alveolar Bone Loss

Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis

Calcium-Sensing Receptor Polymorphisms at rs1801725 Are Associated with Increased Risk of Secondary Malignancies

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