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Nuclear αNAC Influences Bone Matrix Mineralization and Osteoblast Maturation In Vivo

机译:核αNAC影响体内的骨基质矿化和成骨细胞成熟。

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摘要

Nascent-polypeptide-associated complex and coactivator alpha (αNAC) is a protein shuttling between the nucleus and the cytoplasm. Upon phosphorylation at residue serine 43 by integrin-linked kinase, αNAC is translocated to the nuclei of osteoblasts, where it acts as an AP-1 coactivator to increase osteocalcin gene transcription. To determine the physiological role of nuclear αNAC, we engineered a knock-in mouse model with a serine-to-alanine mutation at position 43 (S43A). The S43A mutation resulted in a decrease in the amount of nuclear αNAC with reduced osteocalcin gene promoter occupancy, leading to a significant decrease in osteocalcin gene transcription. The S43A mutant bones also expressed decreased levels of α1(I) collagen mRNA and as a consequence had significantly less osteoid tissue. Transient transfection assays and chromatin immunoprecipitation confirmed the α1(I) collagen gene as a novel αNAC target. The reduced quantity of bone matrix in S43A mutant bones was mineralized faster, as demonstrated by the significantly reduced mineralization lag time, producing a lower volume of immature, woven-type bone characterized by poor lamellation and an increase in the number of osteocytes. Accordingly, the expression of the osteocyte differentiation marker genes DMP-1 (dentin matrix protein 1), E11, and SOST (sclerostin) was increased. The accelerated mineralization phenotype was cell autonomous, as osteoblasts isolated from the calvaria of S43A mutant mice mineralized their matrix faster than did wild-type cells. Thus, inhibition of αNAC nuclear translocation results in an osteopenic phenotype caused by reduced expression of osteocalcin and type I collagen, accelerated mineralization, and immature woven-bone formation.
机译:新生多肽相关复合物和共激活因子α(αNAC)是一种在细胞核和细胞质之间穿梭的蛋白质。整联蛋白连接的激酶在残基丝氨酸43处进行磷酸化后,αNAC易位到成骨细胞核中,在那里它充当AP-1辅助激活剂以增加骨钙蛋白基因的转录。为了确定核αNAC的生理作用,我们设计了一种在第43位(S43A)具有丝氨酸至丙氨酸突变的敲入小鼠模型。 S43A突变导致减少的骨钙素基因启动子占用的核αNAC数量减少,从而导致骨钙素基因转录的显着减少。 S43A突变体骨骼还表达了降低的α1(I)胶原mRNA水平,因此,类骨组织明显减少。瞬时转染测定法和染色质免疫沉淀法证实α1(I)胶原蛋白基因是新型的αNAC靶标。 S43A突变体骨骼中减少的骨基质数量更快地被矿化,这可通过明显减少矿化滞后时间来证明,从而产生较低体积的未成熟,编织型骨骼,其特征为薄层化不良和骨细胞数量增加。因此,骨细胞分化标记基因DMP-1(牙本质基质蛋白1),E11和SOST(硬化蛋白)的表达增加。加速矿化表型是细胞自主的,因为从S43A突变小鼠的颅盖中分离的成骨细胞比野生型细胞更快地矿化其基质。因此,抑制αNAC核移位会导致骨质减少的表型,这是由于骨钙素和I型胶原蛋白的表达降低,矿化加速和编织骨形成不成熟引起的。

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