The effects of OSM on proliferation an
d differentiation of osteosarcoma an
d nontransforme
d osteoblasts were analyze
d. OSM
downregulates osteoblast markers but in
duces the glial fibrillary aci
dic protein by the combine
d activation of PKC
delta an
d STAT3, offering new lines of therapeutic investigations. INTRODUCTION: Oncostatin M (OSM) is a multifunctional cytokine of the interleukin-6 family implicate
d in embryonic
development,
differentiation, inflammation, an
d regeneration of various tissues, mainly the liver, bone, an
d the central nervous an
d hematopoietic systems. One particularity of OSM relies on its growth inhibitory an
d pro-
differentiating effects on a variety of tumor cell lines such as melanoma, provi
ding arguments for a therapeutic application of OSM. The objective of this stu
dy was to analyze the effects of OSM on osteosarcoma cell lines proliferation an
d differentiation. MATERIALS AND METHODS: Proliferation was analyze
d by 3H thymi
dine incorporation. Differentiation was analyze
d by semiquantitative RT-PCR an
d immunocytochemistry for various markers. Alizarin re
d S staining was use
d to evaluate bone no
dule formation. Morphological changes were stu
die
d by confocal an
d electron microscopy. Western blotting, kinases inhibitors, an
d dominant negative STAT3 were use
d to i
dentifie
d the signaling pathways implicate
d. RESULTS: OSM inhibits the growth of rat osteosarcoma cell lines as well as normal osteoblasts, in correlation with in
duction of the cyclin-
depen
dent kinases inhibitor p21WAF1. However, OSM re
duces osteoblast markers such as alkaline phosphatase, osteocalcin, an
d bone sialoprotein, lea
ding to strong inhibition of mineralize
d no
dule formation. This inhibitory effect is restricte
d to mature osteoblasts an
d differentiate
d osteosarcoma because OSM effectively stimulates osteoblast markers an
d bone no
dule formation in early, but not late, bone marrow mesenchymal stem cell (BMSC) cultures. In osteosarcoma cells or BMSC, OSM in
duces expression of the glial fibrillary aci
dic protein (GFAP) as well as morphological an
d ultrastructural changes, for example, elongate
d shape an
d bun
dles of microfilaments in cell processes. Rottlerin (PKC
delta inhibitor), an
d to a lesser
degree UO126 (MEK/ERK inhibitor), prevents the loss of osteoblastic markers by OSM, whereas
dominant negative STAT3 prevents GFAP in
duction. CONCLUSIONS: These results highlight the particular gene expression profile of OSM-treate
d osteosarcoma cells an
d BMSCs, suggesting either a osteocytic or a glial-like phenotype. Together with the implication of PKC
delta, ERK1/2, an
d STAT3, these results offer new lines of investigations for neural cell transplantation an
d osteosarcoma therapy.
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