Runx1 通过增强软骨生成和骨生成来上调软骨细胞向成骨细胞谱系的分化，并促进骨形成。
Runx1 up-regulates chondrocyte to osteoblast lineage commitment and promotes bone formation by enhancing both chondrogenesis and osteogenesis.
机构信息
Department of Metabolism and Endocrinology, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, U.S.A.
出版信息
Biochem J. 2020 Jul 17;477(13):2421-2438. doi: 10.1042/BCJ20200036.
One of the fundamental questions in bone biology is where osteoblasts originate and how osteoblast differentiation is regulated. The mechanism underlying which factors regulate chondrocyte to osteoblast lineage commitment remains unknown. Our data showed that Runt-related transcription factor 1 (Runx1) is expressed at different stages of both chondrocyte and osteoblast differentiation. Runx1 chondrocyte-specific knockout (Runx1f/fCol2α1-cre) mice exhibited impaired cartilage formation, decreased bone density, and an osteoporotic phenotype. The expressions of chondrocyte differentiation regulation genes, including Sox9, Ihh, CyclinD1, PTH1R, and hypertrophic chondrocyte marker genes including Col2α1, Runx2, MMP13, Col10α1 in the growth plate were significantly decreased in Runx1f/fCol2α1-cre mice chondrocytes. Importantly, the expression of osteoblast differentiation regulation genes including Osx, Runx2, ATF4, and osteoblast marker genes including osteocalcin (OCN) and osteopontin (OPN) were significantly decreased in the osteoblasts of Runx1f/fCol2α1-cre mice. Notably, our data showed that osteoblast differentiation regulation genes and marker genes are also expressed in chondrocytes and the expressions of these marker genes were significantly decreased in the chondrocytes of Runx1f/fCol2α1-cre mice. Our data showed that chromatin immunoprecipitation (ChIP) and promoter mapping analysis revealed that Runx1 directly binds to the Indian hedgehog homolog (Ihh) promoter to regulate its expression, indicating that Runx1 directly regulates the transcriptional expression of chondrocyte genes. Collectively, we revealed that Runx1 signals chondrocyte to osteoblast lineage commitment and promotes endochondral bone formation through enhancing both chondrogenesis and osteogenesis genes expressions, indicating Runx1 may be a therapeutic target to enhance endochondral bone formation and prevent osteoporosis fractures.
骨生物学的一个基本问题是成骨细胞的起源以及成骨细胞分化是如何被调控的。哪些因素调节软骨细胞向成骨细胞谱系的决定仍然未知。我们的数据表明，Runt 相关转录因子 1（Runx1）在软骨细胞和成骨细胞分化的不同阶段都有表达。Runx1 软骨细胞特异性敲除（Runx1f/fCol2α1-cre）小鼠表现出软骨形成受损、骨密度降低和骨质疏松表型。Runx1f/fCol2α1-cre 小鼠软骨细胞中软骨细胞分化调节基因，包括 Sox9、Ihh、CyclinD1、PTH1R 和肥大软骨细胞标记基因，包括 Col2α1、Runx2、MMP13、Col10α1 的表达显著降低。重要的是，Runx1f/fCol2α1-cre 小鼠成骨细胞中骨细胞分化调节基因，包括 Osx、Runx2、ATF4 和骨细胞标记基因，包括骨钙素（OCN）和骨桥蛋白（OPN）的表达显著降低。值得注意的是，我们的数据表明骨细胞分化调节基因和标记基因也在软骨细胞中表达，并且这些标记基因在 Runx1f/fCol2α1-cre 小鼠的软骨细胞中的表达显著降低。我们的数据表明，染色质免疫沉淀（ChIP）和启动子作图分析表明，Runx1 直接结合印度刺猬同源物（Ihh）启动子以调节其表达，表明 Runx1 直接调节软骨细胞基因的转录表达。总的来说，我们揭示了 Runx1 通过增强成软骨和成骨基因的表达来信号转导软骨细胞向成骨细胞谱系的决定，并促进软骨内骨形成，表明 Runx1 可能是增强软骨内骨形成和预防骨质疏松性骨折的治疗靶点。
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