Integrin-Linked Kinase Regulates Bone Formation by Controlling Cytoskeletal Organization and Modulating BMP and Wnt Signaling in Osteoprogenitors
Integrin-Linked Kinase Regulates Bone Formation by Controlling Cytoskeletal Organization and Modulating BMP and Wnt Signaling in Osteoprogenitors
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DOI：
10.1002/jbmr.3190
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发表时间：
2017-10-01
影响因子：
6.2
通讯作者：
Maes, Christa
中科院分区：
文献类型：
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作者：
Dejaeger, Marian;Bohm, Anna-Marei;Maes, Christa
细胞-基质相互作用是骨骼细胞生物学的一个基本方面，在骨骼稳态中起着重要作用。这些相互作用主要由跨膜整合素受体介导，整合素受体介导细胞粘附，并通过包括整合素连接激酶（ILK）在内的各种下游效应物将细胞外基质的信号传递到细胞内反应。ILK在局灶黏附位点起衔接蛋白的作用，将整合素与肌动蛋白细胞骨架连接起来，并被报道作为激酶磷酸化信号分子，如GSK-3和Akt。因此，ILK在细胞附着、运动、增殖和存活中起着重要作用。为了评估ILK信号在成骨细胞及其下行成骨细胞谱系中的体内作用，我们使用Osx-Cre:GFP驱动菌株产生了条件敲除小鼠。在osterix表达细胞及其衍生物中缺乏功能性ILK的小鼠没有明显的发育或生长表型，但在5周龄时，它们表现出显著减少的骨小梁骨量，这种情况在雄性小鼠中持续到成年。组织形态学和血清分析显示，破骨细胞的形成和活性没有改变，但有证据表明，成骨细胞功能受损，导致骨矿化减少，未矿化的类骨细胞积累增加。体外分析进一步证实，成骨细胞中ILK的缺失与胶原基质生成和矿化受损有关。在机制上，我们发现缺乏ILK的成骨细胞存在细胞骨架功能受损和信号转导减少的证据。事实上，原代成骨细胞中ILK的缺失损害了f -肌动蛋白的组织、细胞粘附、扩散和迁移，表明细胞-基质相互作用与细胞骨架的耦合存在缺陷。此外，在缺乏ILK的情况下，BMP/Smad和Wnt/-catenin信号传导减少。综上所述，这些数据证明了整合素介导的细胞-基质相互作用和成骨细胞中ILK信号在控制成骨细胞功能中的重要性，这些功能在青少年骨量获取和成人骨重塑和体内平衡过程中发挥着重要作用。(C) 2017年美国骨与矿物研究学会。
Cell-matrix interactions constitute a fundamental aspect of skeletal cell biology and play essential roles in bone homeostasis. These interactions are primarily mediated by transmembrane integrin receptors, which mediate cell adhesion and transduce signals from the extracellular matrix to intracellular responses via various downstream effectors, including integrin-linked kinase (ILK). ILK functions as adaptor protein at focal adhesion sites, linking integrins to the actin cytoskeleton, and has been reported to act as a kinase phosphorylating signaling molecules such as GSK-3 and Akt. Thereby, ILK plays important roles in cellular attachment, motility, proliferation and survival. To assess the in vivo role of ILK signaling in osteoprogenitors and the osteoblast lineage cells descending thereof, we generated conditional knockout mice using the Osx-Cre:GFP driver strain. Mice lacking functional ILK in osterix-expressing cells and their derivatives showed no apparent developmental or growth phenotype, but by 5 weeks of age they displayed a significantly reduced trabecular bone mass, which persisted into adulthood in male mice. Histomorphometry and serum analysis indicated no alterations in osteoclast formation and activity, but provided evidence that osteoblast function was impaired, resulting in reduced bone mineralization and increased accumulation of unmineralized osteoid. In vitro analyses further substantiated that absence of ILK in osteogenic cells was associated with compromised collagen matrix production and mineralization. Mechanistically, we found evidence for both impaired cytoskeletal functioning and reduced signal transduction in osteoblasts lacking ILK. Indeed, loss of ILK in primary osteogenic cells impaired F-actin organization, cellular adhesion, spreading, and migration, indicative of defective coupling of cell-matrix interactions to the cytoskeleton. In addition, BMP/Smad and Wnt/-catenin signaling was reduced in the absence of ILK. Taken together, these data demonstrate the importance of integrin-mediated cell-matrix interactions and ILK signaling in osteoprogenitors in the control of osteoblast functioning during juvenile bone mass acquisition and adult bone remodeling and homeostasis. (C) 2017 American Society for Bone and Mineral Research.