Basic Research Lab for "Epigenetic Regeneration of Aged Skeleto-Muscular System (ERASMUS)", Department of Molecular Genetics and Dental Pharmacology, School of Dentistry, Dental Research Institute, Seoul National University, Seoul, South Korea.
Exp Mol Med. 2020 Aug;52(8):1178-1184. doi: 10.1038/s12276-020-0471-4. Epub 2020 Aug 13.
RUNX2 is a master transcription factor of osteoblast differentiation. RUNX2 expression in the bone and osteogenic front of a suture is crucial for cranial suture closure and membranous bone morphogenesis. In this manner, the regulation of RUNX2 is precisely controlled by multiple posttranslational modifications (PTMs) mediated by the stepwise recruitment of multiple enzymes. Genetic defects in RUNX2 itself or in its PTM regulatory pathways result in craniofacial malformations. Haploinsufficiency in RUNX2 causes cleidocranial dysplasia (CCD), which is characterized by open fontanelle and hypoplastic clavicles. In contrast, gain-of-function mutations in FGFRs, which are known upstream stimulating signals of RUNX2 activity, cause craniosynostosis (CS) characterized by premature suture obliteration. The identification of these PTM cascades could suggest suitable drug targets for RUNX2 regulation. In this review, we will focus on the mechanism of RUNX2 regulation mediated by PTMs, such as phosphorylation, prolyl isomerization, acetylation, and ubiquitination, and we will summarize the therapeutics associated with each PTM enzyme for the treatment of congenital cranial suture anomalies.
RUNX2 是成骨细胞分化的主转录因子。RUNX2 在骨和缝的成骨前缘的表达对于颅缝闭合和膜状骨形态发生至关重要。以这种方式，RUNX2 的调节受到通过逐步募集多种酶介导的多种翻译后修饰（PTM）的精确控制。RUNX2 本身或其 PTM 调节途径中的遗传缺陷导致颅面畸形。RUNX2 的单倍不足导致颅锁骨发育不全（CCD），其特征为囟门未闭和锁骨发育不全。相比之下，已知 RUNX2 活性的上游刺激信号 FGFRs 的功能获得性突变导致颅缝早闭（CS），其特征为缝过早闭合。这些 PTM 级联的鉴定可以为 RUNX2 调节提供合适的药物靶点。在这篇综述中，我们将重点介绍 PTM（如磷酸化、脯氨酰异构化、乙酰化和泛素化）介导的 RUNX2 调节机制，并总结与每种 PTM 酶相关的治疗方法，以治疗先天性颅缝畸形。
