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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Autophagy and 3-Phosphoinositide-Dependent Kinase 1 (PDK1)-Related Kinome in Pagetic Osteoclasts
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Autophagy and 3-Phosphoinositide-Dependent Kinase 1 (PDK1)-Related Kinome in Pagetic Osteoclasts

机译：在疏松疏松骨质体中的自噬和3-磷酸肌酐依赖性激酶1（PDK1） - 相关的Kinome

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In Paget's disease of bone (PDB), a major contributory factor are osteoclasts (OCs) that are larger, more numerous, resistant to apoptosis, and hyperactive. The aim of this human in vitro study was to identify kinase cascades involved in the OC phenotype and to determine their impact on downstream processes. Basal phosphorylation levels of Akt and ERK were found to be elevated in PDB OCs. Given our previous findings that 3-phosphoinositide-dependent protein kinase 1 (PDK1) associates with the crucial adaptor p62 in OCs, we hypothesized that PDK1 may play an important role in OC-related kinome regulation. The increased phosphorylation of Akt and its substrate GSK3 beta observed in PDB OCs was reduced significantly upon PDK1 inhibition, as well as that of 4EBP1 and Raptor. This suggests a PDK1/Akt-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) in PDB OCs. The resistance to apoptosis and the bone resorption were also overcome upon PDK1 inhibition. Studying autophagy by LC3B expression, we found a less inducible autophagy compared with control cells, which was reversed by PDK1 inhibition. In addition, PBD OCs exhibited higher LC3B-II/LC3B-I ratios and numbers of p62 and LC3B puncta per OC area, which did not further increase in the presence of lysosomal protease inhibitors, suggesting an accumulation of non-degradative autophagosomes. Together these results indicate a strong potential regulatory role for PDK1 in OC stimulatory pathways (Akt, ERK) and autophagy induction (via mTORC1), which may contribute to the OC phenotype in PDB. We also identified defects in late autophagosome maturation in these cells, the mechanism of which remains to be determined. (C) 2016 American Society for Bone and Mineral Research.
机译：在Paget的骨骼疾病（PDB）中，主要的贡献因素是骨壳（OC等），较大，抗细胞凋亡，抗细胞凋亡和过度活跃。这种人体外研究的目的是鉴定癌症型的激酶梯级，并确定它们对下游过程的影响。发现AKT和ERK的基础磷酸化水平在PDB OC中升高。鉴于我们以前的发现，3-磷酸阳性依赖性蛋白激酶1（PDK1）与OC的关键衔接子P62相关联，我们假设PDK1可能在oc相关的Kinome调节中发挥重要作用。在PDK1抑制下，在PDB OCS中观察到的AKT及其衬底GSK3β的增加和其基质GSK3β的增加，以及4EBP1和猛禽。这表明PDB OCS中雷帕霉素络合物1（MTORC1）的哺乳动物靶标的PDK1 / akt依赖性激活。在PDK1抑制时还克服了对细胞凋亡和骨吸收的抗性。通过LC3B表达研究自噬，我们发现与对照细胞相比的诱导型自噬，由PDK1抑制逆转。此外，PBD OCs显示出较高的LC3B-II / LC3B-I比和P62和LC3B点的数量，每个OC面积，这在存在溶酶体蛋白酶抑制剂的情况下没有进一步增加，表明非降解自血管体的积累。这些结果在一起表明对OC刺激途径（AKT，ERK）和自噬诱导（通过MTORC1）的PDK1强的潜在调节作用，这可能有助于PDB中的OC表型。我们还确定了这些细胞中的晚期自噬成熟中的缺陷，其机制仍有待确定。 （c）2016年美国骨骼和矿物学学会。

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