Hepatocyte growth factor-regulated genes in differentiated RAW 264.7 osteoclast and undifferentiated cells

Gaasch, Julie A.; Bolwahnn, Alanna B.; Lindsey, J. Suzanne

doi:10.1016/j.gene.2005.10.036

Cited by 13 publications

(6 citation statements)

References 62 publications

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“…In the bone, OBs represent the major source of hepatocyte growth factor (HGF), the only known ligand of the receptor tyrosine kinase MET. HGF is a cytokine with pleiotropic functions, including the stimulation of cell proliferation and migration [ 17 – 20 ]. Physiologically, it regulates OC differentiation and supports survival and proliferation of hematopoietic progenitor cells in the bone microenvironment, thereby contributing to bone and hematopoietic homeostasis [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

et al. 2016

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IntroductionThe occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown.Methods and ResultsPre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration.ConclusionsOur data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.

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Section: Introductionmentioning

confidence: 99%

Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

et al. 2016

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“…RAW264.7 cells have been extensively used as osteoclast precursors because they can be induced to stably differentiate into osteoclast-like cells by using RANKL with or without M-CSF, and RAW264.7 cell-derived osteoclasts perform similarly to primary osteoclasts isolated from bones in conventional assays for osteoclast function (28). In addition, ephrin B2 mRNA was reported to be expressed in RAW264.7 cells (29). We proposed that RAW264.7 cells may be a suitable model for this research.…”

Section: Discussionmentioning

confidence: 99%

Preliminary identification of potential PDZ-domain proteins downstream of ephrin B2 during osteoclast differentiation of RAW264.7 cells

Mao

Huang²,

Zhao³

et al. 2011

Int J Mol Med

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Abstract. The EphB4 receptor and ephrin B2 ligand were recently reported to influence the coupling between osteoclasts and osteoblasts in bone biology, but their downstream signaling pathways remain unclear. This study focuses on the preliminary identification of downstream PDZ-domain proteins involved in EphB4/ephrin B2 reverse signaling in osteoclasts. Similarly to primary osteoclast precursors isolated from the bone, we observed that the RAW264.7 cell line, a mouse monocyte/macrophage cell line that is used in conventional assays for osteoclast function, expressed ephrin B2 during RANKL-induced osteoclast differentiation, and that preclustered EphB4 inhibited this osteoclast differentiation. The results demonstrate that RAW264.7 cells provide a good model for further research of EphB4/ ephrin B2 signaling in osteoclasts. Immunofluorescence staining and Western blot analysis revealed that all of the eight PDZ-domain proteins previously reported to interact with ephrin B ligands were expressed in the differentiated RAW264.7 osteoclasts. However, in a co-immunoprecipitation assay, only Dishevelled 2 (Dvl2) among eight PDZ-domain proteins tested co-precipitated with ephrin B2 and vice versa, suggesting an endogenous interaction between Dvl2 and ephrin B2 in RANKL-induced osteoclasts. Furthermore, preclustered EphB4 reduced the expression level of Dvl2. Collectively, our results indicate that Dvl2 could be the potential PDZ-domain protein that acts downstream of ephrin B2 in RANKL-induced osteoclast differentiation of RAW264.7 cells, providing a potential novel therapeutic target for bone diseases.

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“…Moreover, the absence of modulation of Dlx5 and Dlx6 expression during osteoclastogenesis suggests that these homeoproteins have limited, if any, function in this specific differentiation process. Interestingly, the hepatocyte growth factor (HGF) was shown to modulate Dlx5 and Dlx6 expression in undifferentiated RAW264.7 cells and RAW264.7‐derived osteoclasts (Gaasch et al, 2006). This growth factor is known to modulate different osteoclast processes excluding differentiation (Fuller et al, 1995), to be able to substitute for M‐CSF function onto both osteoclast precursors and mature osteoclasts (Knowles and Athanasou, 2009) and to participate in the coupling between osteoblasts and osteoclasts (Grano et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Dlx homeobox gene family expression in osteoclasts

Lezot¹,

Thomas²,

Blin-Wakkach³

et al. 2010

Journal Cellular Physiology

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Skeletal growth and homeostasis require the finely orchestrated secretion of mineralized tissue matrices by highly specialized cells, balanced with their degradation by osteoclasts. Time- and site-specific expression of Dlx and Msx homeobox genes in the cells secreting these matrices have been identified as important elements in the regulation of skeletal morphology. Such specific expression patterns have also been reported in osteoclasts for Msx genes. The aim of the present study was to establish the expression patterns of Dlx genes in osteoclasts and identify their function in regulating skeletal morphology. The expression patterns of all Dlx genes were examined during the whole osteoclastogenesis using different in vitro models. The results revealed that Dlx1 and Dlx2 are the only Dlx family members with a possible function in osteoclastogenesis as well as in mature osteoclasts. Dlx5 and Dlx6 were detected in the cultures but appear to be markers of monocytes and their derivatives. In vivo, Dlx2 expression in osteoclasts was examined using a Dlx2/LacZ transgenic mouse. Dlx2 is expressed in a subpopulation of osteoclasts in association with tooth, brain, nerve, and bone marrow volumetric growths. Altogether the present data suggest a role for Dlx2 in regulation of skeletal morphogenesis via functions within osteoclasts.

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Hepatocyte growth factor-regulated genes in differentiated RAW 264.7 osteoclast and undifferentiated cells

Cited by 13 publications

References 62 publications

Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

Preliminary identification of potential PDZ-domain proteins downstream of ephrin B2 during osteoclast differentiation of RAW264.7 cells

Dlx homeobox gene family expression in osteoclasts

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