Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Republic of Korea.
Medical Convergence Research Center, Wonkwang University Hospital, Iksan, Republic of Korea.
Exp Mol Med. 2018 Apr 27;50(4):1-18. doi: 10.1038/s12276-018-0076-3.
Claudins (Cldns) are well-established components of tight junctions (TJs) that play a pivotal role in the modulation of paracellular permeability. Several studies have explored the physiologic aspects of Cldn family members in bone metabolism. However, the effect of Cldn11, a major component of central nervous system myelin, on bone homeostasis has not been reported. In this study, we demonstrate that Cldn11 is a potential target for bone disease therapeutics as a dual modulator of osteogenesis enhancement and osteoclastogenesis inhibition. We found that Cldn11 played a negative role in the receptor activator of nuclear factor kappa B ligand-induced osteoclast (OC) differentiation and function by downregulating the phosphorylated form of extracellular signal-regulated kinase (ERK), Bruton's tyrosine kinase, and phospholipase C gamma 2, in turn impeding c-Fos and nuclear factor in activated T cell c1 expression. The enhancement of osteoblast (OB) differentiation by positive feedback of Cldn11 was achieved through the phosphorylation of Smad1/5/8, ERK, and c-Jun amino-terminal kinase. Importantly, this Cldn11-dependent dual event in bone metabolism arose from targeting EphrinB2 ligand reverse signaling in OC and EphB4 receptor forward signaling in OB. In agreement with these in vitro effects, subcutaneous injection of Cldn11 recombinant protein exerted anti-resorbing effects in a lipopolysaccharide-induced calvarial bone loss mouse model and increased osteogenic activity in a calvarial bone formation model. These findings suggest that Cldn11 is a novel regulator in bone homeostasis.
紧密连接（TJs）中的紧密连接蛋白（Claudins，Cldns）是调节细胞旁通透性的重要组成部分。有几项研究探讨了 Cldn 家族成员在骨代谢中的生理作用。然而，中枢神经系统髓鞘的主要成分 Cldn11 对骨稳态的影响尚未见报道。在这项研究中，我们证明 Cldn11 是骨疾病治疗的潜在靶点，它可以作为骨生成增强和破骨细胞生成抑制的双重调节剂。我们发现 Cldn11 通过下调核因子 κB 受体激活剂配体诱导的破骨细胞（OC）分化和功能的细胞外信号调节激酶（ERK）、布鲁顿酪氨酸激酶和磷脂酶 C 伽马 2 的磷酸化形式，负调控 OC 的分化和功能，从而抑制 c-Fos 和活化 T 细胞核因子 c1 的表达。Cldn11 通过对 Smad1/5/8、ERK 和 c-Jun 氨基末端激酶的磷酸化，实现了对成骨细胞（OB）分化的正向反馈增强。重要的是，这种骨代谢中的 Cldn11 依赖性双重事件源于 OC 中 EphrinB2 配体反向信号和 OB 中 EphB4 受体正向信号的靶向。与这些体外效应一致，Cldn11 重组蛋白的皮下注射在脂多糖诱导的颅骨骨丢失小鼠模型中发挥了抗吸收作用，并在颅骨骨形成模型中增加了成骨活性。这些发现表明 Cldn11 是骨稳态的一种新型调节因子。
