Effect of retinoids on the growth, ultrastructure, and cytoskeletal structures of malignant rat osteoblasts (original) (raw)
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Differentiation induction of canine osteosarcoma cell lines by retinoids
Research in veterinary science, 2000
The effect of two retinoids, all- trans and 9- cis retinoic acid, on the differentiation of three canine osteosarcoma cells (OOS, HOS, and POS) was examined using markers specifically expressed by phenotypic osteoblasts. Both retinoids induced morphologic differentiation in all the canine osteosarcoma cells. Retinoids enhanced cell flattening and spreading, as well as reduction in cell overlapping. Alkaline phosphatase (ALP) activity and ALP staining was enhanced in OOS, and HOS cells, but decreased in POS cells. These results may suggest that OOS and HOS cells have immature osteoblastic properties and POS cells have mature osteoblastic properties. Retinoids decreased osteocalcin production in all the osteosarcoma cells. They induced an increase in production of type I collagen in HOS and POS cells, but a decrease in OOS cells. These results indicate that retinoids induce differentiation of canine osteosarcoma cells, resulting in an altered expression of their malignant phenotype.
Biochemical and Biophysical Research Communications, 1996
The effect of Retinoic Acid (RA) on human osteoclast-like cell lines, obtained from Giant Cell tumors (GCT) of bone, has been investigated evaluating its action on bone resorption, cell proliferation, microtubular organization and gelatinases expression and activity. Increasing concentrations of RA significantly dosedependently decreased GCTs bone resorption, while 10 07 M RA promoted an increase of cell proliferation. By immunofluorescence we demonstrated that GCTs express A and B gelatinases and, by zymography, that their activity was enhanced in medium collected from GCTs cultured in the presence of 10 07 M RA. These data indicate that RA increases cell proliferation and modulates metalloproteinases (MMPs) activity, crucial events during the migration of osteoclast precursors toward bone surfaces. ᭧
Retinoic acid modulation of mrna levels in malignant, nontransformed, and immortalized osteoblasts
Journal of Bone and Mineral Research, 1991
Clonal cell lines presumably “arrested” at a particular stage of differentiation are useful models to study the processes of differentiation in osteoblasts. UMR-201 is a presumptive preosteoblastic nontransformed rat clonal cell line with a limited life span in culture. Two immortalized cell lines, UMR-201-10A (10A) and UMR-201-10B (10B), were derived from UMR-201 by stable transfection with simian virus (SV) 40 large T antigen. This study compares the growth and profile of gene expression of the immortalized cell lines with those of UMR-201 and UMR-106-06, a rat clonal cell line with well-defined osteoblast-like phenotypic characteristics. All four cell lines constitutively expressed the mRNA for the γ, α, and β receptors for retinoic acid (RA), the growth hormone receptor, pro-α1(I) collagen, osteonectin, bone proteoglycan I, and bone morphogenetic proteins (BMP) 1 and 2A. Alkaline phosphatase mRNA was absent in the preosteoblast cell lines but was induced by treatment with 10−6 M RA, which also increased the steady-state levels of mRNA for osteopontin and BMP1. mRNA for matrix gla protein was constitutively present and further induced by RA in UMR-201 and 10B only. Messenger RNA for bone sialoprotein and bone morphogenetic protein 3 were constitutively expressed in UMR-106-06 and UMR-201 but absent in the immortalized cell lines. None of the cell lines expressed measurable mRNA for bone gla protein or bone proteoglycan II. 10B grew more rapidly than UMR-201, but unlike UMR-201, it was also able to proliferate in serum-free medium and exhibit anchorage-independent growth. In summary, this study identifies novel retinoic acid effects on gene expression in these cells. Differences noted in the expression of mRNAs between UMR-106-06 and the other cell lines may provide some insight into the sequence of expression of these phenotypic characteristics as osteoblasts differentiate.
Cancer Research
BA-HAN-1C is a clonal rat rhabdomyosarcoma cell line composed of proliferating mononuclear cells, which partly fuse to terminally differ entiated postmitotic myotube-like giant cells. The exposure to retinoic acid in vitro resulted in time-and dose-dependent changes of both cell differentiation and cell growth. The mononuclear cells revealed bundles of newly formed thick and thin myofilaments, never observed in untreated cultures, and exhibited signs of contact inhibition. In addition, there was a statistically significant increase (/' < 0.001 ) in the number of terminally differentiated postmitotic myotube-like giant cells and in the creatine kinase activity (/' < 0.05) which was used as a biochemical differentiation marker. At the same time cell growth was significantly inhibited (/' < 0.001) in vitm and a decrease in plating efficiency, as well as in saturation density, was observed. These data demonstrate that retinoic acid can suppress cell growth and simultaneously initiate differentiation in a malignant mesenchymal tumor cell line. However, despite the clonal nature of BA-HAN-1C, the complete status of terminal differentiation was not achieved by all tumor cells. The reason why not all tumor cells responded to retinoic acid is unknown at the present time and will have to be the subject of further studies.
Characterization of the action of retinoids on mouse fibroblast cell lines
Experimental Cell Research, 1979
Retinoic acid affects 3T6 and 3T3 cells by inhibiting growth, causing a morphological change and increasing cell-to-substratum adhesiveness. Retinoic acid does not exert such effects on virus-transformed 3T3SV cells. Retinoic acid treatment of 3T6 cells causes a concentration-dependent increase in generation time and a reduction in saturation density. Analysis of cell surface proteins shows that a high molecular weight band of 230 000 D, corresponding to the position of the LETS glycoprotein, is more intensely labeled by iodination of cells treated with retinoic acid compared to control cells. Retinoic acid substantially stimulates the incorporation of "SO, into cell-associated glycosaminoglycans and causes a less dramatic increase in glycosaminoglycans excreted into the medium. The relationship between the increase in these cell surface components and the enhanced adhesiveness is discussed. A retinoic acid binding protein is detectable in the cytosol of 3T6 and 3T3 cells but not in 3T3SV cells, suggesting that the action of retinoids on these cells is mediated via this protein
Biology of the Cell, 1994
The clonal rat rhabdomyosarcoma cell line BA-HAN-1C is composed of proliferating mononuclear cells, some of which spontaneously fuse to terminally differentiated myotube-like giant cells. This cell line has been shown to be susceptible to differentiation induction with all-trans retinoic acid (RA). Since it is still unknown whether exclusively all-trans RA itself or also its metabolites can act as inductive compounds in our cell line, we exposed BA-HAN-IC cells to the metabolites 4-hydroxy RA, 4-oxo RA and 5,6epoxy RA. Exposure to these RA metabolites-resulted in a significant inhibition of proliferation (P < 0.001) and induction of cellular differentiation, as evidenced by a significant increase in the number of myotube-like giant cells (P < 0.05) and a significant increase in creatine kinase activity (P < 0.05). However, differences in the inductive potency of these RA metabolites became apparent. Furthermore, RA metabolites exhibited a significantly weaker (P < 0.05) inductive activity when compared to all-trans RA. Summarizing our results we could demonstrate that the endogenous metabolites 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA are not merely deactivated cellular excretion products of all-trans RA, but potent inducers of differentiation and inhibitors of proliferation, possibly contributing to the complex physiological actions of retinoic acid.
Cancer, 1980
The effects of various retinoids on the proliferative capacities and on the synthesis of DNA, RNA, and protein have been investigated in MCF-7 mammary carcinoma cells in culture. Of the various retinoids tested, retinoic acid revealed maximum activity in inhibiting cell proliferation and thymidine incorporation. The degree of inhibition of cell proliferation by the various retinoids paralleled their capacity to inhibit thymidine incorporation, suggesting suppression of DNA synthesis as a primary cause of restriction of cell growth by these compounds. Two nonepithelial human cell lines were tested for sensitivity to retinoids, and showed diminished responses compared with MCF-7 cells. This suggests a correlation between the ability of retinoids to exert control of differentiation and cell proliferation for a given cell type. Reversibility of the effect of retinoid treatment, high cell viability, and lack of retinoidinduced lysosomal enzyme release, as shown in our studies, indicate that cytotoxicity may be excluded as a cause of decreased cell proliferation and inhibition of thymidine incorporation by retinoids. Cancer 46:2203-2209, 1980. ETINOIDS ARE KNOWN to regulate the differ-R entiation of normal epithelial tissue.'.""."' There have been numerous studies of the prophylactic effects of retinoids on epithelial tumors such as chemically induced tumors of mammary glands,12 skin,' urinary bladder,:'2 and prostate. l 5 Retinoids have also been shown to enhance the antitumor effects of x-rays and chemotherapeutic agents.'.".' The effects of retinoids on cultured tumor cells have been investigated. Dion et u/.$I showed that retinoic acid restored density-dependent inhibition of growth in mouse L-929 cells. Various investigators have examined the inhibitory effects of retinoic acid and retinyl acetate on untransformed and transformed cells in
Cancer research, 1985
Pretreatment with 10(-8) M retinoic acid for 4 days caused changes in three distinct components of the parathyroid hormone (PTH)-stimulated cyclic adenosine 3':5'-monophosphate response in a clonal rat osteogenic sarcoma cell line, UMR 106-06: the amplitude of the cyclic adenosine 3':5'-monophosphate response to PTH was moderately increased after pretreatment with retinoic acid; while the cellular content of the two isoenzymes of the cyclic adenosine 3':5'-monophosphate-dependent protein kinase was approximately equal in control cells, retinoic acid pretreatment was associated with a marked increase in the ratio of type II to type I holoenzyme activity. This change might be due to a decrease in the type I holoenzyme as suggested by immunofluorescence detection of decreased type I regulatory subunit in fixed cells together with the relative decrease in type I holoenzyme determined biochemically; there was a marked alteration of the pattern of PTH-stimulated pr...
British journal of cancer, 1996
Epithelioid sarcoma is a highly malignant soft tissue tumour that is refractory to conventional chemotherapy and irradiation. Since permanent cell lines of this tumour are extremely rare, in vitro data on compounds with significant antiproliferative effects are still lacking. Therefore, we investigated the effects of retinoic acid (RA) and tumour necrosis factor alpha (TNF-alpha) on tumour cell proliferation of three different clonal subpopulations (GRU-1A, GRU-1B, GRU-1C) derived from the same human epithelioid sarcoma cell line, GRU-1. In GRU-1A both RA (P=0.01) and TNF-alpha (P=0.002) exhibited highly significant and dose-dependent growth inhibitory effects, which could further be increased by a combined application of both compounds (P<0.006). GRU-1B proved to be sensitive to RA (P=0.006), whereas no response to TNF-alpha was observed. GRU-1C was resistant to both RA and TNF-alpha. The antiproliferative effect of TNF-alpha was mediated by TNF receptor 1(TNF-R1) and correlated...