RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Glasnović, Anton; Stojić, Maristela; Dežmalj, Lidija; Tudorić-Đeno, Ivana; Romić, Dominik; Jeleč, Vjekoslav; Vrca, Anđelko; Vuletić, Vladimira; Grčević, Danka

doi:10.1159/000488988

Cited by 12 publications

(9 citation statements)

References 39 publications

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“…RANK RANKL (TNFSF11) is produced by activated T cells, osteoblasts and stromal cells and binds to RANK, or to a decoy receptor osteoprotegerin (OPG). The ratio of RANKL/OPG has been shown to be altered in the cerebrospinal fluid of MS patients at clinical onset and mRNA levels of RANK, RANKL and OPG are elevated in PBMC from individuals with relapsing-remitting MS 271 . Given the role of RANKL in bone erosion, attempts have been made to target this pathway in rheumatoid arthritis.…”

Section: Tnfmentioning

confidence: 99%

Targeting co-stimulatory molecules in autoimmune disease

Edner

Carlesso

Rush

et al. 2020

Nat Rev Drug Discov

120

109

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Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, and efforts have focused in particular on the CD28 family members CTLA-4 and PD-1. In autoimmunity, these same pathways can be targeted to opposite effect, to curb the overexuberant immune response. The CTLA-4 checkpoint serves as an exemplar, whereby CTLA-4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA-4 in autoimmunity. Here we review the targeting of costimulatory molecules in autoimmune disease, focusing in particular on the CD28 family and TNFR family members. We present the state-of-the-art in costimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.

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Section: Tnfmentioning

confidence: 99%

Targeting co-stimulatory molecules in autoimmune disease

Edner

Carlesso

Rush

et al. 2020

Nat Rev Drug Discov

120

109

View full text Add to dashboard Cite

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“…Using a cytokine array, the levels of astrocyte-derived secreted factors were quantified in supernatants from astrocytes exposed to melanoma CM in the presence or absence of Aβ. This analysis revealed that Aβ both stimulates astrocyte secretion of anti-inflammatory cytokines and suppresses astrocyte secretion of cytokines with known pro-inflammatory activity in the central nervous system (Figure 5g) 30–39 , thus demonstrating that melanoma-secreted Aβ stimulates astrocytes to an anti-inflammatory phenotype.…”

Section: Mainmentioning

confidence: 89%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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26Brain metastasis is a significant cause of morbidity and mortality in multiple cancer 27 types and represents an unmet clinical need. The mechanisms that mediate metastatic 28 cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the 29 highest rate of brain metastasis among common cancer types, is an ideal model to 30 study how cancer cells adapt to the brain parenchyma. We performed unbiased 31 proteomics analysis of melanoma short-term cultures, a novel model for the study of 32 brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative 33 pathologies are differentially expressed in melanoma cells explanted from brain 34 metastases compared to those derived from extracranial metastases. This raised the 35 exciting hypothesis that molecular pathways implicated in neurodegenerative disorders 36 are critical for metastatic adaptation to the brain. 37 38Here, we show that melanoma cells require amyloid beta (Ab), a polypeptide heavily 39 implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. 40Melanoma cells produce and secrete Ab, which activates surrounding astrocytes to a 41 pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that 42 pharmacological inhibition of Ab decreases brain metastatic burden. 43 44Our results reveal a mechanistic connection between brain metastasis and Alzheimer's 45 disease -two previously unrelated pathologies, establish Ab as a promising therapeutic 46 target for brain metastasis, and demonstrate suppression of neuroinflammation as a 47 critical feature of metastatic adaptation to the brain parenchyma. 48 49 3 Main 50 51Brain metastasis is the most common form of adult intracranial malignancy 1 and results 52 in severe morbidity and mortality. 40-75% of Stage IV melanoma patients develop brain 53 metastasis 2,3 , reflecting melanoma's striking ability to colonize the brain. Brain 54 metastases are less responsive than extracranial metastases to current cancer 55 therapies 4-6 , and the majority of patients succumb to disease in less than one year 7 . 56 Furthermore, patients with brain metastasis are often excluded from clinical trials and 57 urgently need new clinical options. In recent years, research has started to elucidate the 58 molecular mechanisms contributing to the multi-step process of brain metastasis. Most 59 findings have focused on cancer extravasation across the blood-brain barrier (BBB), 60 which cannot be leveraged therapeutically given that the vast majority of brain 61 metastasis patients will present with extravasated cancer cells at the time of cancer 62 diagnosis. The main bottleneck in the brain metastatic process has been shown to be 63 the successful expansion of a single cell in the brain parenchyma to form a macro-64 metastasis 8 . Recent studies have begun to demonstrate the role of the brain 65 microenvironment in this process. In particular, reactive astrocytes have been shown to 66 interact with cancer cells in the brain 9,10 and exhibit both pro-and anti-...

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“…These data indicate the initial RRO dysregulation at intrathecal sites already at the outset of the disease. Additional analysis of plasma samples and peripheral blood mononuclear cells from patients with RR-MS revealed upregulation of chemokines CCL2 and CXCL12 as well as increase in sRANKL and sRANKL/OPG ratio with the disease progression (70). Another clinical study on MS patients found higher OPG and lower RANKL levels in serum of patients with RR-MS compared to those with SP-MS.…”

Section: Rro Axis and Multiple Sclerosismentioning

confidence: 94%

“…Through the parallel profiling of peripheral blood and cerebrospinal fluid (CSF), our group was the first to compare the levels of RANKL and OPG in control subjects and MS patients at clinical onset (70). It is important to stress that these naïve patients were excluded from the use of any immunomodulatory or immunosuppressive agents known to interfere with the RRO axis (71).…”

Section: Rro Axis and Multiple Sclerosismentioning

confidence: 99%

RANK/RANKL/OPG Signaling in the Brain: A Systematic Review of the Literature

et al. 2020

Self Cite

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Together with its dominant immunological and bone remodeling involvement, RRO axis, comprising of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling, is as well-implicated in CNS functioning and corresponding pathologies. The CNS aspects of RANKL/RANK/OPG (RRO) axis were systematically reviewed. With search 10 databases, and 7 additional resources from first article publication to July 2019, resulted in total 2,222 hits, from which 33 relevant articles were selected. The elements of RRO axis in CNS include cells involved in neuroinflammation, predominantly in microglia, but as well in resident macrophages and inflammatory cells migrating across the blood-brain barrier. The expression in neurons and oligodendrocytes is mainly confined to processes of differentiation and cell death. RRO axis tunes the neuroinflammatory response, depending on the molecular, cellular and pathological context. RANK/RANKL signaling is neuroprotective in TLR-mediated inflammation, while OPG seems detrimental in stroke, but beneficial in multiple sclerosis. The levels of RRO axis elements can serve as biomarkers in the blood and cerebrospinal fluid. They act as neuroprotectant after brain damage even being implicated in body weight-and thermo-regulation. As derivatives of RRO axis already exist as therapeutic agents in bone remodeling, it would be intriquing to see if these or new RRO-based pharmaceuticals would appear effective in CNS therapies.

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RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Cited by 12 publications

References 39 publications

Targeting co-stimulatory molecules in autoimmune disease

Targeting co-stimulatory molecules in autoimmune disease

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

RANK/RANKL/OPG Signaling in the Brain: A Systematic Review of the Literature

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