Dominant Negative <scp>MCP</scp>‐1 Blocks Human Osteoclast Differentiation

Morrison, Nigel Alexander; Day, Christopher J.; Nicholson, Geoffrey C.

doi:10.1002/jcb.24663

Cited by 29 publications

(35 citation statements)

References 39 publications

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“…Three cytokines were identified by the model as positive regulators of osteoclast and monocyte nuclei: IL-8, MCP-1 and VEGF. Of these cytokines, MCP-1 (Miyamoto et al, 2009; Morrison et al, 2014) and VEGF (Trebec-Reynolds et al, 2010; Zhang et al, 2008) were previously implicated as autocrine regulators of osteoclast formation and function consistent with model predictions. In contrast to previous reports demonstrating that TNFα plays a positive role as an autocrine regulator of osteoclast differentiation from mouse precursors (Nakao et al, 2007; Zou et al, 2001), we did not observe strong correlation of this factor with formation of human osteoclasts.…”

Section: Discussionsupporting

confidence: 69%

Autocrine signaling is a key regulatory element during osteoclastogenesis

et al. 2014

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Osteoclasts are responsible for bone destruction in degenerative, inflammatory and metastatic bone disorders. Although osteoclastogenesis has been well-characterized in mouse models, many questions remain regarding the regulation of osteoclast formation in human diseases. We examined the regulation of human precursors induced to differentiate and fuse into multinucleated osteoclasts by receptor activator of nuclear factor kappa-B ligand (RANKL). High-content single cell microscopy enabled the time-resolved quantification of both the population of monocytic precursors and the emerging osteoclasts. We observed that prior to induction of osteoclast fusion, RANKL stimulated precursor proliferation, acting in part through an autocrine mediator. Cytokines secreted during osteoclastogenesis were resolved using multiplexed quantification combined with a Partial Least Squares Regression model to identify the relative importance of specific cytokines for the osteoclastogenesis outcome. Interleukin 8 (IL-8) was identified as one of RANKL-induced cytokines and validated for its role in osteoclast formation using inhibitors of the IL-8 cognate receptors CXCR1 and CXCR2 or an IL-8 blocking antibody. These insights demonstrate that autocrine signaling induced by RANKL represents a key regulatory component of human osteoclastogenesis.

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Section: Discussionsupporting

confidence: 69%

Autocrine signaling is a key regulatory element during osteoclastogenesis

et al. 2014

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“…Consistent with that phenotype, ITGBL1-overexpressing cancer cells showed elevated levels of RANKL and decreased expression of osteoprotegerin. Moreover, ITGBL1 positively regulated the secretion of the osteoclast differentiation activators GM-CSF (34), GRO (35), IL1a (36), MCPs (37), and MSP-a (38) in cancer cells, providing additional evidence supporting the role of ITGBL1 in cancer cell-triggered osteolytic lesions in bone metastatic events.…”

Section: Discussionmentioning

confidence: 82%

ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway

et al. 2015

Cancer Research

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Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin b-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFb signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer.

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“…In addition, our previous study showed that 7ND protein prevents not only particle-induced macrophage chemotaxis, but also particle-induced inflammation in vitro [16]. Furthermore, 7ND has been shown to inhibit osteoclast differentiation of human colony forming unit-granulocyte macrophages (CFU-GM) in vitro [36]. Taken together 7ND coating reduced both the number of infiltrating macrophages and possibly the amount of particle-induced secretion of pro-inflammatory factors.…”

Section: Discussionmentioning

confidence: 99%

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

et al. 2017

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Wear particle-induced osteolysis limits the long-term survivorship of total joint replacement (TJR). Monocyte/macrophages are the key cells of this adverse reaction. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) is the most important chemokine regulating trafficking of monocyte/macrophages in particle-induced inflammation. 7ND recombinant protein is a mutant of CCL2 that inhibits CCL2 signaling. We have recently developed a layer-by-layer (LBL) coating platform on implant surfaces that can release biologically active 7ND. In this study, we investigated the effect of 7ND on wear particle-induced bone loss using the murine continuous polyethylene (PE) particle infusion model with 7ND coating of a titanium rod as a local drug delivery device. PE particles were infused into hollow titanium rods with or without 7ND coating implanted in the distal femur for 4 weeks. Specific groups were also injected with RAW 264.7 as the reporter macrophages. Wear particle-induced bone loss and the effects of 7ND were evaluated by microCT, immunohistochemical staining, and bioluminescence imaging. Local delivery of 7ND using the LBL coating decreased systemic macrophage recruitment, the number of osteoclasts and wear particle-induced bone loss. The development of a novel orthopaedic implant coating with anti-CCL2 protein may be a promising strategy to mitigate peri-prosthetic osteolysis.

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Dominant Negative MCP‐1 Blocks Human Osteoclast Differentiation

Cited by 29 publications

References 39 publications

Autocrine signaling is a key regulatory element during osteoclastogenesis

Autocrine signaling is a key regulatory element during osteoclastogenesis

ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

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