Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP)
Runx2 expression and action in chondrocytes are regulated by retinoid signaling and parathyroid hormone-related peptide (PTHrP)
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DOI：
10.1053/joca.2002.0860
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发表时间：
2003-01-01
影响因子：
7
通讯作者：
Enomoto-Iwamoto, M
中科院分区：
文献类型：
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作者：
Iwamoto, M;Kitagaki, J;Enomoto-Iwamoto, M
目的：Runx2（也称为Cbfa1）是软骨细胞成熟和成骨细胞分化所需的转录因子。虽然有关于其在成骨过程中的表达调控的信息，但对其在软骨成熟过程中的表达知之甚少。在这里，我们询问Runx2的表达和功能是否受到视黄酸（RA）和甲状旁腺激素相关肽（PTHrP）的影响，它们分别是软骨细胞成熟的重要刺激物和抑制剂。设计：我们首先克隆并鉴定了鸡软骨细胞表达的Runx2 （cRunx2）。然后，我们构建了cRunx2和显性阴性形式（DN-cRunx2）的表达载体，并测定了它们在类维甲酸和PTHrP治疗前和期间对培养软骨细胞成熟的影响。结果：尽管cRunx2具有非常短的QA结构域，并且缺少一小部分PST结构域，但其转录活性与哺乳动物相似。cRunx2过表达刺激软骨细胞成熟，表现为碱性磷酸酶活性（APase）、矿化、X型胶原蛋白和MMP-13表达的增加，以及印度刺猬蛋白（Ihh）表达的维持。RA治疗刺激cRunx2基因表达，增强其促成熟作用。PTHrP处理可阻断Runx2的表达及其促成熟作用。DN-cRunx2过表达抑制RA成熟，甚至阻止RA发挥促成熟作用。结论：正如之前哺乳动物研究表明的那样，cRunx2具有促软骨细胞成熟活性。它的表达和作用受到类视黄醛信号的有利调节，但被PTHrP完全抑制。提出了一种将cRunx2与PTHrP、Ihh和类视黄醇信号结合并在骨骼形成过程中运作的模型。(C) 2003国际骨关节炎研究学会。Elsevier Science Ltd.出版。版权所有。
Objective: Runx2 (also known as Cbfa1) is a transcription factor required for chondrocyte maturation and osteoblast differentiation. While there is information on the regulation of its expression during osteogenesis, much less is known about it during cartilage maturation. Here we asked whether Runx2 expression and function are affected by retinoic acid (RA) and parathyroid hormone-related peptide (PTHrP), which represent an important stimulator and inhibitor of chondrocyte maturation, respectively.Design: We first cloned and characterized Runx2 expressed by chick chondrocytes (cRunx2). We then constructed expression vectors of cRunx2 and a dominant-negative form (DN-cRunx2) and determined their effects on chondrocyte maturation in culture before and during retinoid and PTHrP treatment.Results: cRunx2 showed similar transactivation activity to that of its mammalian counterparts although it has a very short QA domain and lacks a small portion of the PST domain. cRunx2 over-expression stimulated chondrocyte maturation, as indicated by increases in alkaline phosphatase activity (APase), mineralization, and type X collagen and MMP-13 expression, and by maintenance of Indian hedgehog (Ihh) expression. RA treatment stimulated cRunx2 gene expression and boosted its pro-maturation effects. PTHrP treatment blocked Runx2 expression and its pro-maturation effects. Over-expression of DN-cRunx2 inhibited maturation and even prevented RA from exerting its pro-maturation role.Conclusions: As previously indicated by mammalian studies, cRunx2 has chondrocyte pro-maturation activity. Its expression and roles are favorably modulated by retinoid signaling but are completely inhibited by PTHrP. A model integrating cRunx2 with PTHrP, Ihh and retinoid signaling and operating during skeletogenesis is proposed. (C) 2003 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.