PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate.
PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate.
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PTHRP靶向盐诱导的激酶HDAC4和HDAC5，以抑制生长板中的软骨细胞肥大。
DOI：
10.1016/j.bone.2020.115709
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发表时间：
2021-01
期刊：
影响因子：
4.1
通讯作者：
Kronenberg HM
中科院分区：
文献类型：
--
作者：
Nishimori S;Wein MN;Kronenberg HM
软骨细胞肥大是软骨内成骨过程中的关键步骤，软骨内成骨过程驱动骨的延长和向软骨内成骨的过渡。甲状旁腺激素相关蛋白(PTHrP)和组蛋白脱乙酰酶4(HDAC4)均可抑制软骨细胞肥大。多个小鼠遗传学模型的使用揭示了PTHrP和HDAC4如何参与调节软骨细胞肥大的途径。PTHrP/cAMP/蛋白激酶A(PKA)信号通路使盐诱导蛋白激酶3(Sik3)上的PKA靶点磷酸化，从而抑制Sik3的活性。抑制Sik3激酶活性可减少14-3-3结合部位上Sik3对HDAC4的磷酸化；较低水平的HDAC4磷酸化则允许HDAC4核易位。在细胞核中，转录因子肌细胞增强因子2(Mef2)激活Runx2相关转录因子(Runx2)，这两个转录因子共同驱动肥大过程。HDAC4结合Mef2和Runx2并阻止它们的活动。在这条途径中存在基因冗余。当SIK3活性较低时，SIK1和SIK2也介导PTHrP/cAMP/PKA信号转导。当HDAC4低表达时，HDAC5也介导PTHrP信号。因此，PTHrP触发了一系列的激酶级联反应，从而抑制了促进软骨细胞肥大的关键转录因子(Mef2和Runx2)。
Hypertrophy of chondrocytes is a crucial step in the endochondral bone formation process that drives bone lengthening and the transition to endochondral bone formation. Both Parathyroid hormone-related protein (PTHrP) and Histone deacetylase 4 (HDAC4) inhibit chondrocyte hypertrophy. Use of multiple mouse genetics models reveals how PTHrP and HDAC4 participate in a pathway that regulates chondrocyte hypertrophy. PTHrP/cAMP/Protein Kinase A (PKA) signaling pathway phosphorylates the PKA-target sites on salt-inducible kinase 3 (Sik3), which leads to inhibition of Sik3 kinase activity. Inhibition of Sik3 kinase activity decreases phosphorylation of HDAC4 by Sik3 at binding sites for 14-3-3; lower levels of HDAC4 phosphorylation then allow HDAC4 nuclear translocation. In the nucleus, the transcription factor, Myocyte Enhancer Factor 2 (Mef2), activates Runt-related transcription factor 2 (Runx2), and together these two transcription factors drive the hypertrophic process. HDAC4 binds both Mef2 and Runx2 and blocks their activities. There are genetic redundancies in this pathway. Sik1 and Sik2 also mediate PTHrP/cAMP/PKA signaling when Sik3 activity is low. HDAC5 also mediates PTHrP signaling when HDAC4 expression is low. Thus, PTHrP triggers a kinase cascade that leads to inhibition of the key transcription factors (Mef2 and Runx2) that promote chondrocyte hypertrophy.
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影响因子：
11.8
作者：
Arnold, Michael A.;Kim, Yuri;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
64.5
作者：
Chang, Shurong;Young, Bryan D.;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
5.3
作者：
Chang, SR;McKinsey, TA;Olson, EN
通讯作者：
Olson, EN
影响因子：
158.5
作者：
POWELL, D;SINGER, FR;POTTS, JT
通讯作者：
POTTS, JT
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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