Constitutive protein kinase A activity in osteocytes and late osteoblasts produces an anabolic effect on bone.
Constitutive protein kinase A activity in osteocytes and late osteoblasts produces an anabolic effect on bone.
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构成蛋白激酶A在骨细胞和晚成骨细胞中的活性会对骨骼产生合成代谢作用。
DOI：
10.1016/j.bone.2013.04.001
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发表时间：
2013-08
期刊：
影响因子：
4.1
通讯作者：
Nissenson, Robert
中科院分区：
文献类型：
--
作者：
Kao, Richard S.;Abbott, Marcia J.;Louie, Alyssa;O'Carroll, Dylan;Lu, Weidar;Nissenson, Robert
骨细胞参与骨形成的控制。然而，调控骨细胞生物学功能的信号转导途径却不清楚。有限的证据表明Gs/cAMP通路在骨细胞功能中的重要作用。在本研究中，我们探讨了这一假设，cAMP依赖性激酶A（PKA）的激活在骨细胞中起着关键作用，在控制骨骼稳态。为了验证这一假设，我们将携带Cre条件突变PKA催化亚基等位基因（编码PKA组成型活性形式（CαR））的小鼠与在骨细胞特异性启动子DMP 1控制下表达Cre的小鼠交配。这使我们能够指导CαR在双转基因后代的骨细胞中表达。Cre表达检测表明，CαR在晚期成骨细胞中也有表达。通过μCT测定12周龄小鼠的皮质骨和松质骨参数。CαR在骨细胞和晚期成骨细胞中的表达改变了胫腓骨交界处（TFJ）近端皮质骨的形状，并使其大小显著增加。在股骨远端的骨小梁中，骨体积分数、骨小梁数量和骨小梁厚度增加。这些增加部分是由于TFJ近端皮质骨的骨内膜表面上的骨形成率（BFR）增加以及股骨远端小梁骨表面上的BFR增加。表达CαR的小鼠显示成骨细胞标志物如osterix、runx 2、胶原1α1和碱性磷酸酶（ALP）的表达显著增加。有趣的是，骨细胞标记基因DMP 1的表达显著上调，但单位骨面积的骨细胞数量没有改变。SOST（骨细胞中PKA信号传导的假定靶点）的表达在雌性中显著下调。重要的是，未检测到骨吸收的变化。总之，骨细胞和晚期成骨细胞中的组成性PKA信号传导导致雌性小鼠TFJ近端皮质骨尺寸的小幅扩张和骨小梁的增加。这与SOST的下调和几个成骨细胞标志物基因的上调有关。PKA通路在骨细胞和晚期成骨细胞中的激活足以启动合成代谢骨骼反应。
Osteocytes have been implicated in the control of bone formation. However, the signal transduction pathways that regulate the biological function of osteocytes are poorly defined. Limited evidence suggests an important role for the Gs/cAMP pathway in osteocyte function. In the present study, we explored the hypothesis that cAMP-dependent kinase A (PKA) activation in osteocytes plays a key role in controlling skeletal homeostasis. To test this hypothesis, we mated mice harboring a Cre-conditional, mutated PKA catalytic subunit allele that encodes a constitutively active form of PKA (CαR) with mice expressing Cre under the control of the osteocyte-specific promoter, DMP1. This allowed us to direct the expression of CαR to osteocytes in double transgenic progeny. Examination of Cre expression indicated that CαR was also expressed in late osteoblasts. Cortical and trabecular bone parameters from 12-week old mice were determined by μCT. Expression of CαR in osteocytes and late osteoblasts altered the shape of cortical bone proximal to the tibia-fibular junction (TFJ) and produced a significant increase in its size. In trabecular bone of the distal femur, fractional bone volume, trabecular number, and trabecular thickness were increased. These increases were partially the results of increased bone formation rates (BFRs) on the endosteal surface of the cortical bone proximal to the TFJ as well as increased BFR on the trabecular bone surface of the distal femur. Mice expressing CαR displayed a marked increase in the expression of osteoblast markers such as osterix, runx2, collagen 1α1, and alkaline phosphatase (ALP). Interestingly, expression of osteocyte marker gene, DMP1, was significantly up-regulated but the osteocyte number per bone area was not altered. Expression of SOST, a presumed target for PKA signaling in osteocytes, was significantly down-regulated in females. Importantly, no changes in bone resorption were detected. In summary, constitutive PKA signaling in osteocytes and late osteoblasts led to a small expansion of the size of the cortical bone proximal to the TFJ and an increase in trabecular bone in female mice. This was associated with down-regulation of SOST and up-regulation of several osteoblast marker genes. Activation of the PKA pathway in osteocytes and late osteoblasts is sufficient for the initiation of an anabolic skeletal response.
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DOI：
10.1083/jcb.201105063
发表时间：
2011-10-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Backs J;Worst BC;Lehmann LH;Patrick DM;Jebessa Z;Kreusser MM;Sun Q;Chen L;Heft C;Katus HA;Olson EN
通讯作者：
Olson EN
DOI：
10.1083/jcb.200610046
发表时间：
2007-02-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ge C;Xiao G;Jiang D;Franceschi RT
通讯作者：
Franceschi RT
影响因子：
4.1
作者：
Akhter, MP;Wells, DJ;Recker, RR
通讯作者：
Recker, RR
影响因子：
3.3
作者：
Cherian, PP;Siller-Jackson, AJ;Jiang, JX
通讯作者：
Jiang, JX
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML