Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Drives Activation of Bone Remodelling and Skeletal Metastasis

Mulholland, Bridie S; Forwood, Mark R.; Morrison, Nigel Alexander

doi:10.1007/s11914-019-00545-7

Cited by 74 publications

(61 citation statements)

References 79 publications

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“…To prevent exposure to PMA, seeding of osteogenic cells may be done directly after activation and attachment of the myeloid cells. Added osteogenic cells then have to provide a sufficient amount of CCL-2, M-CSF and RANKL to induce cell fusion and osteoclastogenesis [160,161]. Their effect may be even enhanced in the presence of IL-4 and/or vitamin D 3 [192], which is of advantage when replacing dexamethasone by cholecalciferol in the co-culture medium as suggested before [131,158].…”

Section: Choice Of Suitable Osteoclast Precursor Cellsmentioning

confidence: 99%

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Feasibility of Cell Lines for In Vitro Co-Cultures Models for Bone Metabolism

et al. 2020

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Today, over 70 diseases and health conditions are known that negatively affect the bone quality directly or indirectly by their medical treatment, establishing the term metabolic bone disease. Already every third hospitalized patient in Europe suffers from musculoskeletal injuries or diseases. Facing an ageing society and a more and more sedentary lifestyle the number of chronic diseases and consequently metabolic bone diseases are expected to continuously increase. In order to investigate the various disease constellations and/or develop new treatment strategies suitable models representing bone metabolism are required. Many in vivo, ex vivo and in vitro models have been described, which have their advantages and limits. We here summarize the advantages and challenges of frequently used models to investigate bone metabolism, focusing on in vitro co-cultures of bone forming osteoblasts and osteoclasts. Comparing own data with published models, we further elaborate the feasibility of commonly used cells lines for such in vitro co-culture models, in order to provide an easy, constantly available, and up-scalable model system for screening alterations in bone metabolism.

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Section: Choice Of Suitable Osteoclast Precursor Cellsmentioning

confidence: 99%

“…High levels of the C-C motif chemokine ligand 2 (CCL-2), a marker for cellular stress, are associated with increased osteoclast activation [160]. Therefore, we determined the expression levels of CCL-2 in these cells.…”

Section: Figure 3 Comparison Of the Cell Lines Mg-63 Cal-72 And Samentioning

confidence: 99%

Feasibility of Cell Lines for In Vitro Co-Cultures Models for Bone Metabolism

et al. 2020

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“…Ccl2 protein and mRNA expression may be found in most cells and virtually all tissues 16,17 , and this wide distribution suggests a coordinated role in adaptive responses to systemic injuries. Ccl2 signals through G protein-coupled receptors may strongly affect metabolism and have been accepted as a potential link between immune and metabolic functions underlying human chronic diseases [18][19][20][21][22][23] . High circulating levels of CCL2 correlate with biological age in mammals and are closely associated with a deleterious course of chronic diseases [24][25][26][27] .…”

Section: Discussionmentioning

confidence: 99%

Chemokine C–C motif ligand 2 overexpression drives tissue-specific metabolic responses in the liver and muscle of mice

Luciano-Mateo

Cabré

Fernández-Arroyo

et al. 2020

Sci Rep

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Chemokine (C-C motif) ligand 2 (CCL2) has been associated with chronic metabolic diseases. We aimed to investigate whether Ccl2 gene overexpression is involved in the regulation of signaling pathways in metabolic organs. Biochemical and histological analyses were used to explore tissue damage in cisgenic mice that overexpressed the Ccl2 gene. Metabolites from energy and one-carbon metabolism in liver and muscle extracts were measured by targeted metabolomics. Western blot analysis was used to explore the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin pathways. Ccl2 overexpression resulted in steatosis, decreased AMPK activity and altered mitochondrial dynamics in the liver. These changes were associated with decreased oxidative phosphorylation and alterations in the citric acid cycle and transmethylation. In contrast, AMPK activity and its downstream mediators were increased in muscle, where we observed an increase in oxidative phosphorylation and increased concentrations of different metabolites associated with ATP synthesis. In conclusion, Ccl2 overexpression induces distinct metabolic alterations in the liver and muscle that affect mitochondrial dynamics and the regulation of energy sensors involved in cell homeostasis. These data suggest that CCL2 may be a therapeutic target in metabolic diseases. Research on the factors that relate the immune system to metabolic alterations in chronic diseases is clinically important because it can allow the identification of therapeutic targets. It remains unclear how immunity affects systemic metabolism, but experimental evidence supports an intertwined relationship through interorgan metabolic crosstalk and mitochondrial dynamics 1-3. One of the consequences of these processes is metabolic stress leading to adaptive responses and altered cellular communication 4. Autophagy, a lysosomal degradation pathway, appears to be the most important effector in the adaptation to metabolic stress and removal of damaged organelles. Among the molecular sensors that modulate autophagy, the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR)-driven pathways play a crucial role in mitochondrial dysfunction and favor a bidirectional relationship between metabolism and inflammation 4,5. Chemokines, especially chemokine (C-C motif) ligand 2 (CCL2), have various functions that are involved in the maintenance of normal metabolism. CCL2 participates, directly and/or through the induced metabolic alterations, in the regulation of mitochondrial biogenesis and autophagy 6,7. This chemokine also affects immune and inflammatory reactions and may compromise cell homeostasis and energy requirements in metabolic organs 8,9. Growing evidence indicates that in both humans and experimental animals, the Ccl2 gene is overexpressed in noncommunicable diseases characterized by a low degree of systemic inflammation and various metabolic alterations 10-14. Recently, the relationships among mitochondrial dysfunction, autophagy and chronic diseases

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“…32 MCP-1 induces the proliferation of monocytes/macrophages and promotes the differentiation and activation of osteoclasts. 33 In a porcine model, byproducts of necrotic bone have been shown to upregulate numerous pro-inflammatory cytokines in a mechanism that is dependent on TLR4 activation by macrophages. 34 This observation has been confirmed in a rat model of steroid-associated ONFH, which demonstrated excessive activation of TLR4/NF-κB and suppression of the canonical Wnt/β-catenin pathway Figure 1 Pathophysiology of osteonecrosis.…”

Section: Relationship Between Chronic Inflammation and Osteonecrosismentioning

confidence: 99%