Lymphoblastoid interferon-alpha downregulates parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor expression in human osteoblastic cells (Saos-2).
Interferon-alpha (IFN-alpha) is a pleiotropic cytokine that modulates the cellular functions of both osteoblastic and osteoclastic lineages. It remains unclear whether IFN-alpha regulates the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor, which is a major target molecule regulating skeletal metabolism. In this study, we examined the effect of IFN-alpha on the expression of PTH/PTHrP receptor in human osteoblastic cells (Saos-2). IFN-alpha inhibited the expression of PTH/PTHrP receptor gene in both a time- and dose-dependent manner. The mRNA level was decreased to 61.1% of that of the untreated control by 48 h treatment with 6000 U/mL of IFN-alpha. IFN-alpha also decreased cAMP response to PTH(1-34) in a dose-dependent manner and significantly depressed expression of the receptor protein. However, IFN-alpha did not exert any effect on other osteoblastic markers, such as alkaline phosphatase (ALP) activity, cAMP response to prostaglandin E2 (PGE2), and secretion of bone gla-protein (BGP) and bone sialoprotein (BSP). Finally, IFN-alpha decreased PTH/PTHrP receptor mRNA to 60.7% that of control in the presence of actinomycin D. These data suggest that IFN-alpha downregulates the expression of PTH/PTHrP receptor and its signaling without affecting other osteoblastic markers, and that IFN-alpha regulates its gene expression mainly by decreasing the stability of its mRNA.
Tsuda-Futami
E
E
Second Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Shioi
A
A
Jono
S
S
Inaba
M
M
Nishizawa
Y
Y
Morii
H
H
D000469:Alkaline Phosphatase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D016898:Interferon-alpha / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000096:biosynthesis* / Q000235:genetics; D012795:Sialoglycoproteins / Q000378:metabolism; D019379:Teriparatide / Q000494:pharmacology
C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D016898:Interferon-alpha; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D012795:Sialoglycoproteins; D015675:Osteocalcin; D019379:Teriparatide; D000242:Cyclic AMP; D000469:Alkaline Phosphatase; D015232:Dinoprostone