Mechanism of Pdia3-dependent 1α,25-dihydroxy vitamin D3 signaling in musculoskeletal cells
Mechanism of Pdia3-dependent 1α,25-dihydroxy vitamin D3 signaling in musculoskeletal cells
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DOI：
10.1016/j.steroids.2012.04.018
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发表时间：
2012-08-01
期刊：
影响因子：
2.7
通讯作者：
Schwartz, Zvi
中科院分区：
文献类型：
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作者：
Boyan, Barbara D.;Chen, Jiaxuan;Schwartz, Zvi
1 α，25-二羟基维生素D3 [1,25(OH)2D3]通过传统的类固醇激素受体介导的基因转录和启动快速的膜相关信号通路作用于细胞。有两种受体参与了1,25(OH)2D3的快速信号传导，即经典的核维生素D受体（VDR）和最近发现的蛋白二硫异构酶，A家族，成员3 （Pdia3）。我们的实验室和其他团队已经建立了各种工具来研究这两种受体的作用，包括基因敲除、条件敲除、沉默和在各种模型系统（生长板软骨细胞、成骨细胞、鸡肠上皮细胞、小鼠胚状体、细胞外基质囊泡和分离细胞膜）中的过表达。这些数据表明Pdia3在1,25(OH)2D3诱导的磷脂酶A2 （PLA2）和蛋白激酶C （PKC）激活和下游反应中是必需的。Pdia3+/-杂合子小鼠也表现出软骨和骨缺陷。VDR存在于质膜上，一个VDR-/-小鼠品系缺乏经鳞，尽管在另一个VDR-/-小鼠品系中，125 (OH)2D3诱导PKC激活和经鳞不受影响。在成骨细胞分化的背景下，这两种受体在胚胎样体的成骨过程中都有表达，而在MC3T3-E1前成骨细胞中，这两种受体的沉默会导致更成熟的成骨细胞表型。Pdia3存在于小泡中，与PLA2激活蛋白（PLAA）和caveolin-1相互作用，通过PLA2、磷脂酶C （PLC）、PKC，最终通过有丝分裂原激活蛋白激酶ERK1/2家族（MAPK）启动快速信号传导。利用生长板软骨细胞和基质囊泡模型，我们已经证明了pdia3依赖性信号响应1,25(OH)2D3调节生长板生理。(c) 2012 Elsevier Inc.版权所有。
1 alpha,25-Dihydroxy vitamin D3 [1,25(OH)2D3] acts on cells through traditional steroid hormone receptor-mediated gene transcription and by initiating rapid membrane-associated signaling pathways. Two receptors have been implicated in rapid signaling by 1,25(OH)2D3, the classical nuclear vitamin D receptor (VDR) and the more recently identified protein disulfide isomerase, family A, member 3 (Pdia3). Our lab along with other groups has established various tools to investigate the role of these two receptors, including gene knock-out, conditional knock-out, silencing, and over-expression in various model systems (growth plate chondrocytes, osteoblastic cells, chick intestinal epithelial cells, mouse embryoid bodies, extracellular matrix vesicles and isolated cell membranes). The data demonstrate the requirement for Pdia3 in 1,25(OH)2D3 induced phospholipase A2 (PLA2) and protein kinase C (PKC) activation and downstream responses. Pdia3+/- heterozygote mice also exhibit both cartilage and bone defects. VDR is present on the plasma membrane and one VDR-/- mouse strain lacks transcaltachia, although 1,25(OH)2D3 induced PKC activation and transcaltachia are not affected in another VDR-/- mouse strain. In the context of osteoblast differentiation, both receptors are expressed during osteogenic commitment of embryoid bodies and silencing of each causes a more mature osteoblast phenotype in MC3T3-E1 pre-osteoblasts. Pdia3 exists in caveolae, where it interacts with PLA2 activating protein (PLAA) and caveolin-1 to initiate rapid signaling via PLA2, phospholipase C (PLC), PKC, and ultimately the ERK1/2 family of mitogen activated protein kinases (MAPK). Using the growth plate chondrocyte and matrix vesicle models, we have demonstrated that Pdia3-dependent signaling in response to 1,25(OH)2D3 regulates growth plate physiology. (c) 2012 Elsevier Inc. All rights reserved.