Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
Cell Death Dis. 2020 May 11;11(5):344. doi: 10.1038/s41419-020-2562-5.
The CUE domain-containing 2 (CUEDC2) protein plays critical roles in many biological processes, such as the cell cycle, inflammation, and tumorigenesis. However, whether CUEDC2 is involved in osteoblast differentiation and plays a role in bone regeneration remains unknown. This study investigated the role of CUEDC2 in osteogenesis and its underlying molecular mechanisms. We found that CUEDC2 is expressed in bone tissues. The expression of CUEDC2 decreased during bone development and BMP2-induced osteoblast differentiation. The overexpression of CUEDC2 suppressed the osteogenic differentiation of precursor cells, while the knockdown of CUEDC2 showed the opposite effect. In vivo studies showed that the overexpression of CUEDC2 decreased bone parameters (bone volume, bone area, and bone mineral density) during ectopic bone formation, whereas its knockdown increased bone volume and the reconstruction percentage of critical-size calvarial defects. We found that CUEDC2 affects STAT3 activation by regulating SOCS3 protein stability. Treatment with a chemical inhibitor of STAT3 abolished the promoting effect of CUEDC2 silencing on osteoblast differentiation. Together, we suggest that CUEDC2 functions as a key regulator of osteoblast differentiation and bone formation by targeting the SOCS3-STAT3 pathway. CUEDC2 manipulation could serve as a therapeutic strategy for controlling bone disease and regeneration.
CUE 结构域包含蛋白 2（CUEDC2）在许多生物学过程中发挥着关键作用，如细胞周期、炎症和肿瘤发生。然而，CUEDC2 是否参与成骨细胞分化并在骨再生中发挥作用尚不清楚。本研究探讨了 CUEDC2 在成骨中的作用及其潜在的分子机制。我们发现 CUEDC2 在骨组织中表达。CUEDC2 的表达在骨发育和 BMP2 诱导的成骨细胞分化过程中降低。CUEDC2 的过表达抑制前体细胞的成骨分化，而 CUEDC2 的敲低则表现出相反的效果。体内研究表明，在异位骨形成过程中，CUEDC2 的过表达降低了骨参数（骨体积、骨面积和骨密度），而其敲低则增加了骨体积和关键大小颅骨缺损的重建百分比。我们发现 CUEDC2 通过调节 SOCS3 蛋白稳定性来影响 STAT3 的激活。STAT3 的化学抑制剂处理消除了 CUEDC2 沉默对成骨细胞分化的促进作用。综上所述，我们认为 CUEDC2 通过靶向 SOCS3-STAT3 通路作为成骨细胞分化和骨形成的关键调节剂发挥作用。CUEDC2 的操纵可以作为控制骨疾病和再生的治疗策略。
