Haploinsufficiency for either one of the type-II regulatory subunits of protein kinase A improves the bone phenotype of Prkar1a+/- mice.
Haploinsufficiency for either one of the type-II regulatory subunits of protein kinase A improves the bone phenotype of Prkar1a+/- mice.
复制标题
蛋白激酶 A 的任一 II 型调节亚基的单倍体不足可改善 Prkar1a /- 小鼠的骨表型。
DOI：
10.1093/hmg/ddv320
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发表时间：
2015
影响因子：
3.5
通讯作者：
Stratakis,ConstantineA
中科院分区：
文献类型：
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作者：
Liu,Sisi;Saloustros,Emmanouil;Mertz,EdwardL;Tsang,Kitman;Starost,MatthewF;Salpea,Paraskevi;Faucz,FabioR;Szarek,Eva;Nesterova,Maria;Leikin,Sergey;Stratakis,ConstantineA
Carney复合体(CnC)是一种易患多发性肿瘤的人类遗传综合征，与骨软骨黏液瘤(OMX)等骨病变相关。最常见的致病原因是PRKAR1a缺乏症；PrKAR1A型蛋白激酶A调节亚基的编码。Prkar1a+/−小鼠发生骨髓瘤、纤维异型增生样病变和其他肿瘤。这些动物的肿瘤组织中PKA活性增加是由于一个非调控的PKA催化亚基，以及由PRKAR2A和PRKAR2B亚基介导的PKA II型活性增加。为了更好地了解PKA活性改变对骨骼的影响，我们研究了Prkar2a和Prkar2b基因敲除(KO)小鼠和杂合子小鼠；这些小鼠都没有发生骨损伤。当用Prkar2a+/generatePrkar1a+/−Prkar2a+/−andPrkar1a+/−Prkar2b+/−animals，和Prkar2b+/−小鼠进行骨移植时，形成了与Prkar1a+/−小鼠相似的骨损伤。然而，在两个双杂合子组中都发现了更好的整体骨组织和矿化，以及更少的FDL损伤，这表明在Prkar1a+/−小鼠中观察到的未成熟骨结构得到了部分恢复。进一步的研究表明，bothPrkar1a+/−Prkar2a+/−andPrkar1a+/−Prkar2b+/−mice的成骨增加和新骨形成率较高，但它们之间存在一些微小的差异。这些观察结果得到了各种标记和研究的证实。PKA活性测定显示，两个双杂合子组的PKA-II预期降低。因此，PKA-II调节亚基中的任何一个的单倍性不足改善了Prkar1a单倍体不足的小鼠的骨表型，支持了Prka-1a+/−小鼠的骨表型与PrKAR2a和PrKAR2B调节亚基部分相关的假说。
Carney Complex (CNC), a human genetic syndrome predisposing to multiple neoplasias, is associated with bone lesions such as osteochondromyxomas (OMX). The most frequent cause for CNC is PRKAR1A deficiency;PRKAR1Acodes for type-I regulatory subunit of protein kinase A (PKA).Prkar1a+/−mice developed OMX, fibrous dysplasia-like lesions (FDL) and other tumors. Tumor tissues in these animals had increased PKA activity due to an unregulated PKA catalytic subunit and increased PKA type II (PKA-II) activity mediated by the PRKAR2A and PRKAR2B subunits. To better understand the effect of altered PKA activity on bone, we studiedPrkar2aandPrkar2bknock out (KO) and heterozygous mice; none of these mice developed bone lesions. WhenPrkar2a+/−andPrkar2b+/−mice were used to generatePrkar1a+/−Prkar2a+/−andPrkar1a+/−Prkar2b+/−animals, bone lesions formed that looked like those of thePrkar1a+/−mice. However, better overall bone organization and mineralization and fewer FDL lesions were found in both double heterozygote groups, indicating a partial restoration of the immature bone structure observed inPrkar1a+/−mice. Further investigation indicated increased osteogenesis and higher new bone formation rates in bothPrkar1a+/−Prkar2a+/−andPrkar1a+/−Prkar2b+/−mice with some minor differences between them. The observations were confirmed with a variety of markers and studies. PKA activity measurements showed the expected PKA-II decrease in both double heterozygote groups. Thus, haploinsufficiency for either of PKA-II regulatory subunits improved bone phenotype of mice haploinsufficient forPrkar1a, in support of the hypothesis that the PRKAR2A and PRKAR2B regulatory subunits were in part responsible for the bone phenotype ofPrkar1a+/−mice.