National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, China.
Jiangxi Provincial Children's Hospital, Nanchang, 330006, China.
Biochem Biophys Res Commun. 2022 Jan 22;589:41-47. doi: 10.1016/j.bbrc.2021.12.008. Epub 2021 Dec 3.
FoxO transcription factors (FoxOs) have recently been shown to protect against chondrocyte dysfunction and modulate cartilage homeostasis in osteoarthritis. The mechanism underlying of FoxOs regulate chondrocyte differentiation remains unknown. Runt related transcription factor 1 (RUNX1) mediated both chondrocyte and osteoblast differentiation. Our data showed that FoxO3a and RUNX1 are co-expressed in ATDC5 cells and undifferentiated mesenchyme cells and have similar high levels in chondrocytes undergoing transition from proliferation to hypertrophy. Overexpression of FoxO3a in ATDC5 cells or mouse mesenchymal cells resulted in a potent induction of the chondrocyte differentiation markers. Knockdown FoxO3a or RUNX1 potently inhibits the expressions of chondrocyte differentiation markers, including Sox9, Aggrecan, Col2, and hypertrophic chondrocyte markers including RUNX2, ColX, MMP13 and ADAMTs-5 in ATDC5 cells. Co-immunoprecipitation showed that FoxO3a binds the transcriptional regulator RUNX1. Immunohistochemistry showed that FoxO3a and RUNX1 are highly co-expressed in the proliferative chondrocytes of the growth plates in the hind limbs of newborn mice. Collectively, we revealed that FoxO3a cooperated with RUNX1 promoted chondrocyte differentiation through enhancing both early chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells, indicating FoxO3a interacting with RUNX1 may be a therapeutic target for the treatment of osteoarthritis and other bone diseases.
FoxO 转录因子（FoxOs）最近被证明可以防止软骨细胞功能障碍，并调节骨关节炎中的软骨稳态。FoxOs 调节软骨细胞分化的机制尚不清楚。 Runt 相关转录因子 1（RUNX1）介导软骨细胞和成骨细胞的分化。我们的数据表明，FoxO3a 和 RUNX1 在 ATDC5 细胞和未分化的间充质细胞中共同表达，并且在从增殖向肥大过渡的软骨细胞中具有相似的高水平。在 ATDC5 细胞或小鼠间充质细胞中过表达 FoxO3a 会强烈诱导软骨细胞分化标志物的表达。敲低 FoxO3a 或 RUNX1 会强烈抑制软骨细胞分化标志物的表达，包括 Sox9、Aggrecan、Col2，以及 ATDC5 细胞中的肥大软骨细胞标志物包括 RUNX2、ColX、MMP13 和 ADAMTs-5。共免疫沉淀表明 FoxO3a 与转录调节剂 RUNX1 结合。免疫组织化学显示，FoxO3a 和 RUNX1 在新生小鼠后肢生长板的增殖软骨细胞中高度共表达。总之，我们揭示了 FoxO3a 与 RUNX1 合作通过增强软骨细胞前体细胞的早期软骨形成和终末肥大来促进软骨细胞分化，表明 FoxO3a 与 RUNX1 的相互作用可能是治疗骨关节炎和其他骨骼疾病的治疗靶点。
