Intercellular Adhesion Molecule 1 Discriminates Functionally Different Populations of Human Osteoblasts: Characteristic Involvement of Cell Cycle Regulators

Tanaka, Yoshiya; Maruo, Akihiko; Fujii, Koichi; Nomi, Masashi; Nakamura, Toshio; Eto, Sumiya; Minami, Yasuhiro

doi:10.1359/jbmr.2000.15.10.1912

Cited by 82 publications

(76 citation statements)

References 44 publications

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“…Possibly, cultured osteoblasts are heterogeneous in their expression of cell adhesion molecules. Such heterogeneity has previously been described for osteoblasts expressing ICAM-1, where ICAM-1-positive osteoblasts were particularly involved in the attachment and subsequent differentiation of osteoclast precursor cells (26). Interestingly, we found that AZD0530 caused an arrest at the prefusion stage of osteoclast precursor cells (i.e., they did attach to osteoblasts).…”

Section: Discussionsupporting

confidence: 77%

“…5 Considering the effect of AZD0530 on the sequence of events in osteoclast formation, it became apparent that AZD0530 did not interfere with the initial binding of PBMCs to osteoblasts, but did so with stages of osteoclast differentiation. In line with the lack of an effect on binding is the unaltered mRNA expression of ICAM-1, a cell-cell adhesion molecule important in osteoclastogenesis (26). An intriguing finding was the difference in binding of PBMCs to osteoblasts.…”

Section: Discussionmentioning

confidence: 94%

“…These time points respectively represent the adhesion stage and the end stage where multinucleated TRACP-positive cells are present in the coculture. Adhesion molecule intercellular adhesion molecule-1 (ICAM-1), which is crucial for osteoblast-osteoclast precursor interaction (26), parathyroid hormone-related protein (PTHrP), which is highly expressed in metastatic clones of the c-Src expressing MDA-MB-231 cell line (28), osteoclastogenesis factor RANKL and its regulator osteoprotegerin (OPG), osteoblast marker tissue nonspecific alkaline phosphatase, and osteoclast (Fig. 4).…”

Section: Effect Of Azd0530 On Osteoclast Activity In Cultures Of Mousmentioning

confidence: 99%

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The Src Inhibitor AZD0530 Reversibly Inhibits the Formation and Activity of Human Osteoclasts

Vries

Mullender

Duin

et al. 2009

Molecular Cancer Research

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Tumor cells in the bone microenvironment are able to initiate a vicious cycle of bone degradation by mobilizing osteoclasts, multinucleated cells specialized in bone degradation. c-Src is highly expressed both in tumors and in osteoclasts. Therefore, drugs like AZD0530, designed to inhibit Src activity, could selectively interfere with both tumor and osteoclast activity. Here we explored the effects of AZD0530 on human osteoclast differentiation and activity. The effect on osteoclasts formed in vivo was assessed in mouse fetal calvarial explants and in isolated rabbit osteoclasts, where it dose-dependently inhibited osteoclast activity. Its effect on formation and activity of human osteoclasts in vitro was determined in cocultures of human osteoblasts and peripheral blood mononuclear cells. AZD0530 was most effective in inhibiting osteoclast-like cell formation when present at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial phase of osteoclast formation. Formation of active phosphorylated c-Src, which was highly present in osteoclast-like cells in cocultures and in peripheral blood mononuclear cell monocultures, was significantly reduced by AZD0530. Furthermore, it reversibly prevented osteoclast precursor migration from the osteoblast layer to the bone surface and subsequent formation of actin rings and resorption pits. These data suggest that Src is pivotal for the formation and activity of human osteoclasts, probably through its effect on the distribution of the actin microfilament system. The reversible effect of AZD0530 on osteoclast formation and activity makes it a promising candidate to temper osteoclastic bone degradation in bone diseases with enhanced osteoclast activity such as osteolytic metastatic bone disease. (Mol Cancer Res 2009;7(4):476-88)

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 94%

Section: Effect Of Azd0530 On Osteoclast Activity In Cultures Of Mousmentioning

confidence: 99%

See 1 more Smart Citation

The Src Inhibitor AZD0530 Reversibly Inhibits the Formation and Activity of Human Osteoclasts

Vries

Mullender

Duin

et al. 2009

Molecular Cancer Research

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“…Mutinuclear osteoclast-like cell formation from osteoblasts is related to the upregulation of p21, with the majority of cells remaining at the G0/G1 phase (Tanaka et al, 2000). The integrity of p21 within centrosomes is related to apoptosis, multinucleation and normal mitotic progression .…”

Section: Discussionmentioning

confidence: 99%

p16 gene transfer increases cell killing with abnormal nucleation after ionising radiation in glioma cells

et al. 2003

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It is well established that cells synchronised at the G1 -S phase are highly radiosensitive. In this study, p16-null human glioma cell lines were induced into G1 cell cycle arrest by adenovirus-mediated p16 gene transfer, and examined for radiation-induced cell killing. Clonogenic analysis and trypan blue extraction test showed that the p16 gene transfer enhanced radiation-induced cell killing in p16-null glioma cell lines. TUNEL assays and pulse-field gel electrophoresis confirmed that the radiation-induced cell killing of p16-transfected cells could be caused by a nonapoptotic mechanism. Gimsa staining demonstrated that irradiation alone or Ax-mock infection plus irradiation results in a slight increase in the frequency of cells with abnormal nucleus, compared to unirradiated uninfected or Ax-mock infected cells. However, Ax-hp16 or Ax-hp21 infection alone modestly increased the frequency of cells with abnormal nucleus (especially bi-and multinucleation), and 4-Gy irradiation of Ax-hp16 or Ax-hp21 infected cells substantially enhanced this frequency. These results suggest that there exists some unknown interaction between radiation and p16 in cytoplasm/ membranes, which decreases cytokinesis and promotes abnormal nucleation. Thus, p16 expression prevented radiation-induced apoptosis by promoting abnormal nucleation, thereby leading to another mode of cell death.

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“…These data indicate that although SC express early osteogenic markers, their differentiation to a classic fully osteoblastic phenotype cannot be achieved even after appropriate induction. To verify if SC might be considered similar to another cell type, the socalled ''bone lining cell'' [12], expressing very low levels of Type I collagen and osteocalcin and known to contribute to bone collagen degradation, we analyzed the mRNA for ICAM-1, the expression of which is increased in this osteoblast subtype [12,43]. Interestingly, ICAM-1 plays a pivotal role in osteoclastogenesis, because osteoblasts expressing ICAM-1 support bone resorption activity [44,45].…”

Section: Cell Culturesmentioning

confidence: 99%

Histogenetic Characterization of Giant Cell Tumor of Bone

Salerno

Avnet

Alberghini

et al. 2008

Clin Orthop Relat Res

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The unpredictable behavior of giant cell tumor (GCT) parallels its controversial histogenesis. Multinucleated giant cells, stromal cells, and CD68 + monocytes/ macrophages are the three elements that interact in GCT. We compared the ability of stromal cells and normal mesenchymal stromal cells to differentiate into osteoblasts. Stromal cells and mesenchymal cells had similar proliferation rates and lifespans. Although stromal cells expressed early osteogenic markers, they were unable to differentiate into osteoblasts but they did express intracellular adhesion molecule-1, a marker of bone-lining cells. They were unable to form clones in a semisolid medium and unable to promote osteoclast differentiation, although they exerted a strong chemotactic effect on osteoclast precursors. Stromal cells may be either immature proliferating osteogenic elements or specialized osteoblast-like cells that fail to show neoplastic features but can induce the differentiation of osteoclast precursors. They might be secondarily induced to proliferate by a paracrine effect induced by monocytemacrophages and/or giant cells. The increased number of giant cells in GCT may be secondary to an autocrine circuit mediated by the receptor activator of nuclear factor kB.

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Intercellular Adhesion Molecule 1 Discriminates Functionally Different Populations of Human Osteoblasts: Characteristic Involvement of Cell Cycle Regulators

Cited by 82 publications

References 44 publications

The Src Inhibitor AZD0530 Reversibly Inhibits the Formation and Activity of Human Osteoclasts

The Src Inhibitor AZD0530 Reversibly Inhibits the Formation and Activity of Human Osteoclasts

p16 gene transfer increases cell killing with abnormal nucleation after ionising radiation in glioma cells

Histogenetic Characterization of Giant Cell Tumor of Bone

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