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9‐ cis retinoic acid accelerates calcitriol‐induced osteocalcin production and promotes degradation of both vitamin D receptor and retinoid X receptor in human osteoblastic cells
Author(s) -
Jääskeläinen Tiina,
Ryhänen Sanna,
Mäenpää Pekka H.
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10572
Subject(s) - calcitriol , retinoic acid , calcitriol receptor , retinoid x receptor gamma , osteocalcin , endocrinology , retinoid x receptor beta , retinoid x receptor , medicine , chemistry , retinoid , retinoic acid receptor , retinoid x receptor alpha , receptor , retinoic acid receptor alpha , degradation (telecommunications) , vitamin d and neurology , biology , biochemistry , alkaline phosphatase , nuclear receptor , enzyme , transcription factor , gene , telecommunications , computer science
Abstract vitamin D receptor (VDR) and retinoid X receptor (RXR) heterodimerize to mediate the genomic actions of 1α,25‐dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 , calcitriol), the biologically active form of vitamin D 3 . In this study, we show that 9‐ cis retinoic acid (9‐cisRA), the ligand for RXR, accelerates calcitriol‐induced expression of osteocalcin gene, the marker for mature osteoblasts. Calcitriol and its synthetic analog KH1060 (1 nM) induced osteocalcin secretion after a 96‐h incubation period as detected by radioimmunoassay. When these compounds were used together with 9‐cisRA, osteocalcin protein secretion was, however, detected already after 72 and 48 h, respectively. Detection of osteocalcin mRNA with quantitative PCR revealed elevated mRNA levels already after a 4‐h treatment of the cells with calcitriol, KH1060, or 9‐cisRA compared with untreated cells. In combination treatments, 9‐cisRA rapidly stimulated osteocalcin mRNA synthesis induced by the different vitamin D 3 compounds. In MG‐63 cells treated with calcitriol or KH1060, the stimulation was maximal after the first 4 h and diminished thereafter. In fact, after the 48‐h incubation 9‐cisRA reduced osteocalcin mRNA levels in KH1060‐treated cells, the amount of mRNA being only 44% of the levels obtained with KH1060 alone. The reduction was accompanied by an increased degradation rate of both VDR and RXRβ in the presence of 9‐cisRA. Furthermore, 9‐cisRA increased the formation of RXRβ–VDR–VDRE complex on the osteocalcin gene VDRE. These results suggest that 9‐cisRA accelerates calcitriol‐induced osteocalcin production in human osteoblastic cells through increased formation of transcriptionally active chromatin complexes and, subsequently, promotes degradation of the heterodimeric complex of VDR and RXR. © 2003 Wiley‐Liss, Inc.