2ND MESSENGER SIGNALING OF C-FOS GENE INDUCTION BY PARATHYROID-HORMONE (PTH) AND PTH-RELATED PEPTIDE IN OSTEOBLASTIC OSTEOSARCOMA CELLS - ITS ROLE IN OSTEOBLAST PROLIFERATION AND OSTEOCLAST-LIKE CELL-FORMATION

被引:32
作者
KANO, J
SUGIMOTO, T
KANATANI, M
KUROKI, Y
TSUKAMOTO, T
FUKASE, M
CHIHARA, K
机构
[1] Department of Medicine, Kobe University School of Medicine, Kobe
关键词
D O I
10.1002/jcp.1041610221
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The present study was performed to clarify second messenger signaling in parathyroid hormone (PTH)-induced c-fos gene expression, to characterize the participation of the c-fos gene in the regulation of osteoblast proliferation and function as well as osteoclast-like cell formation by PTH and to compare these effects of PTH with those of PTH-related peptide (PTHrP). Both human (h) PTH-(1-34) and hPTHrP-(1-34) at 10(-8) M induced a transient c-fos gene expression to a similar degree in osteoblastic osteosarcoma cells, UMR-106. N-6, O-2'-dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) as well as Sp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Sp-cAMPS), an activator of cAMP-dependent protein kinase (PKA), induced a weak c-fos gene expression. Although Rp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS), an inhibitor of PKA, almost completely antagonized dbcAMP- and Sp-cAMPS-induced expression of c-fos gene, it did not cause an obvious inhibition of PTH- or PTHrP-induced expression. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), induced an intense expression of the c-fos gene, while 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD), incapable of activating PKC, and calcium ionophores (A23187 and ionomycin) did not. Protein kinase C inhibitor (H-7, 50 mu M) completely blocked the expression of the c-fos gene by PTH as well as by PTHrP. Antisense oligodeoxynucleotides (as-ODN) complementary to c-fos mRNA, which have been shown to inhibit its mRNA translation, at 1 mu M significantly antagonized PTH- and PTHrP-induced inhibition of [H-3] thymidine incorporation and stimulation of osteoclast-like cell formation in the presence of osteoblasts, but not an increase in alkaline phosphatase activity, compared to control oligodeoxynucleolides with same nucleotides as as-ODN but with a random sequence. The present study indicates the involvement of PKC system in c-fos gene expression by PTH as well as PTHrP and also indicates the involvement of the c-fos gene in the regulation of bone cell physiology by PTH and PTHrP. (C) 1994 Wiley-Liss, Inc.
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页码:358 / 366
页数:9
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