Vitamin D3 differentially regulates parathyroid hormone parathyroid hormone-related peptide receptor expression in bone and cartilage
Vitamin D3 differentially regulates parathyroid hormone parathyroid hormone-related peptide receptor expression in bone and cartilage
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DOI：
10.1172/jci3265
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发表时间：
1999-02-01
影响因子：
15.9
通讯作者：
White, JH
中科院分区：
文献类型：
--
作者：
Amizuka, N;Kwan, MY;White, JH
小鼠甲状旁腺激素(PTH)/甲状旁腺激素相关肽(PTHrP)受体(PTHR)基因转录受启动子P1和P2调控。我们进行了转录特异的原位杂交，发现P2是控制PTHR基因在骨和软骨中表达的主要启动子。体内用1α，25-二羟基维生素D3(D3)治疗，在促进骨吸收的条件下，特异性地下调成骨细胞中P2特异性转录，但不下调软骨细胞中的P2特异性转录。成骨细胞系MC3T3-E1体外用D3处理后，P2特异性转录本和PTHR蛋白的表达均降低。这一作用不能被放线菌酮阻断，表明D3通过下调P2启动子的转录来抑制PTHR的表达。D3在软骨细胞系CFK2中未观察到类似的抑制作用。基因转移实验表明，P2在MC3T3-E1和CFK2细胞中都是活性的，而P1不是；D3特异性地抑制了MC3T3-E1中P2启动子的活性，而不是CFK2细胞中的P2启动活性。D3对P2活性的抑制需要位于P2转录起始点上游1.6kb以上的启动子序列。因此，P2启动子控制着PTHR基因在成骨细胞和软骨细胞中的表达。D3通过抑制成骨细胞中P2启动子的活性，以细胞特异性的方式下调PTHR基因的转录，但在软骨细胞中不起作用。
Transcription of the mouse parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR) gene is controlled by promoters P1 and P2. We performed transcript-specific in situ hybridization and found that P2 is the predominant promoter controlling PTHR gene expression in bone and cartilage. Treatment with 1 alpha,25-dihydroxyvitamin D3 (D3) in vivo specifically downregulated P2-specific transcripts in osteoblasts, but not in chondrocytes, under conditions where it enhanced bone resorption. Treatment of the osteoblastic cell Line MC3T3-E1 with D3 in vitro reduced expression of both P2-specific transcripts and PTHR protein. This effect was not blocked by cycloheximide, indicating that D3 inhibits PTHR expression by downregulating transcription of the P2 promoter. A similar inhibitory effect of D3 was not observed in the chondrocytic cell line CFK2. Gene-transfer experiments showed that P2, but not P1, is active in both MC3T3-E1 and CFK2 cells, and that D3 specifically inhibited P2 promoter activity in MC3T3-E1, but not in CFK2 cells. Inhibition of P2 activity by D3 required promoter sequences lying more that 1.6 kb upstream of the P2 transcription start site. Thus, the P2 promoter controls PTHR gene expression in both osteoblasts and chondrocytes. D3 downregulates PTHR gene transcription in a cell-specific manner by inhibiting P2 promoter activity in osteoblasts, but not in chondrocytes.