VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor, Rhiannon; Kashima, Takeshi; Knowles, Helen J.; Athanasou, Nicholas A.

doi:10.1038/labinvest.2012.108

Cited by 40 publications

(32 citation statements)

References 35 publications

(59 reference statements)

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“…All of these not only are potent chemoattractants for the preosteoclast monocytes (47,48), but also directly stimulate osteoclast differentiation (48,49). These mechanisms were consistent with the phenotype that bortezomib inhibited the NSCinduced monocyte migration, osteoclast differentiation, formation, and resorption.…”

Section: Discussionsupporting

confidence: 71%

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Luo

Jin

et al. 2016

Molecular Cancer Therapeutics

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Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-kB signaling-related cytokines, including TNFa, MCP-1, IL1a, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-kB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cellinduced bone destruction in vivo. As a result, bortezomib suppressed NF-kB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-kB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB.

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Section: Discussionsupporting

confidence: 71%

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Luo

Jin

et al. 2016

Molecular Cancer Therapeutics

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“…31 An HGF-dependent downregulation of miR-27b and upregulation of the target ST14/matriptase is proposed. 37 Since HGF substitutes for M-CSF to support osteoclastogenesis, 38, 39 decitabine treatment might intervene halting this mechanism and reducing osteolysis in bone metastasis. HGF is known to trigger TGF β 1-signaling pathway also involved in osteoclast activation 4, 15 and to activate Twist, 4 which facilitates establishment of osteolytic metastases through miR-10b.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma

et al. 2017

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Our translational research deals with the influence of microenvironment on the phenotype and colonization of bone metastases from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model, DNA methyltransferase blockade using the chemotherapic drug 5-aza-2′-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of bone metastases. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis and Wwox, as therapy of bone metastasis.

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“…29 These observations with VEGF, FLT3 ligand and HGF have been corroborated in human osteoclastogenesis assays. 37 …”

Section: Pathological Osteoclastogenesismentioning

confidence: 99%

Alternative pathways of osteoclastogenesis in inflammatory arthritis

2014

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Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on macrophage colony-stimulating factor 1 (CSF-1, also known as M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). However, an emerging hypothesis is that alternative pathways of osteoclast generation might be active during inflammatory arthritis. In this Perspectives article, we summarize the physiological pathway of osteoclastogenesis and then focus on experimental findings that support the hypothesis that infiltrating inflammatory cells and the cytokine milieu provide multiple routes to bone destruction. The precise identity of osteoclast precursor(s) is not yet known. We propose that myeloid cell differentiation during inflammation could be an important contributor to the differentiation of osteoclast populations and their associated pathologies. Understanding the dynamics of osteoclast differentiation in inflammatory arthritis is crucial for the development of therapeutic strategies for inflammatory joint disease in children and adults.

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VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Cited by 40 publications

References 35 publications

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

RETRACTED ARTICLE: Epigenetic regulation of HGF/Met receptor axis is critical for the outgrowth of bone metastasis from breast carcinoma

Alternative pathways of osteoclastogenesis in inflammatory arthritis

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