Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway.
Biphasic regulation of osteoblast development via the ERK MAPK-mTOR pathway.
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通过ERK MAPK-mTOR通路对成骨细胞发育的双相调节。
DOI：
10.7554/elife.78069
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发表时间：
2022-08-17
期刊：
影响因子：
7.7
通讯作者：
Shim, Jae-Hyuck
中科院分区：
文献类型：
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作者：
Kim, Jung-Min;Yang, Yeon-Suk;Hong, Jaehyoung;Chaugule, Sachin;Chun, Hyonho;van Der Meulen, Marjolein C. H.;Xu, Ren;Greenblatt, Matthew B.;Shim, Jae-Hyuck
新出现的证据支持骨祖细胞的成骨分化是整体骨形成和骨量的关键决定因素。尽管大量研究显示有丝分裂原活化蛋白激酶（MAPKs）在成骨细胞分化中的功能，但这些研究都没有在体内证明MAPKs在谱系承诺后的成骨细胞成熟中所起的作用。在这里，我们描述了成骨细胞中的细胞外信号调节激酶（ERK）途径如何通过抑制雷帕霉素（mTOR）途径的机制靶点来控制骨形成。我们还表明，虽然ERK抑制在早期启动时会阻止成骨前体的分化，但ERK抑制令人惊讶地促进成骨细胞分化的后期阶段。因此，在成熟成骨细胞和骨细胞中，使用小复合抑制剂抑制ERK通路或条件缺失MAP2Ks Map2k1 （MEK1）和Map2k2 (MEK2)，由于成骨细胞分化增强，显着增加骨形成。成熟成骨细胞中诱导缺失ERK通路的小鼠也表现出类似的表型，表明这种表型反映了出生后对晚期成骨细胞成熟的持续抑制。从机制上讲，ERK抑制通过mTOR2激活增加线粒体功能和SGK1磷酸化，导致成骨细胞分化和血管生成和成骨因子的产生，促进骨形成。这种表型通过抑制mTOR而部分逆转。我们的研究揭示了成骨细胞中ERK通路功能的惊人二分法，即ERK激活促进成骨细胞前体的早期分化，但通过mtor介导的线粒体功能和SGK1调节抑制成骨细胞的后续分化。
Emerging evidence supports that osteogenic differentiation of skeletal progenitors is a key determinant of overall bone formation and bone mass. Despite extensive studies showing the function of mitogen-activated protein kinases (MAPKs) in osteoblast differentiation, none of these studies show in vivo evidence of a role for MAPKs in osteoblast maturation subsequent to lineage commitment. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks Map2k1 (MEK1) and Map2k2 (MEK2), in mature osteoblasts and osteocytes, markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partially reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.