通过生物信息学分析和细胞实验鉴定与17-β-雌二醇靶向MKX相关的异位骨化的发生及潜在机制。
Identification of the occurrence and potential mechanisms of heterotopic ossification associated with 17-beta-estradiol targeting MKX by bioinformatics analysis and cellular experiments.
作者信息
Zhang Yunpeng, Zhang Jingwei, Sun Chenyu, Wu Fan
机构信息
Department of surgery, Shanghai Fengxian District Central Hospital, Shanghai, China.
Department of Orthopedics, Shanghai Fengxian District Central Hospital, Shanghai, China.
出版信息
PeerJ. 2022 Jan 3;9:e12696. doi: 10.7717/peerj.12696. eCollection 2022.
BACKGROUND
Tendon heterotopic ossification (HO) is a common condition occurring secondary to tendon injury or surgical trauma that significantly affects the patient's quality of life. The treatment of tendon HO remains challenging due to a lack of clarity regarding the pathological mechanism. Mohawk (MKX) is a key factor in preventing tendon HO; however, its upstream regulatory mechanism remains to be understood. This study aimed to identify potential compounds that target and regulate MKX and explore their functional mechanisms.
METHODS
Bioinformatics analysis of MKX-related compounds and proteins was performed based on data from the STITCH and OncoBinder databases. Subsequently, the SymMap database was used to study MKX-related traditional Chinese medicine drugs and symptoms. Next, the OncoBinder genomic and proteomic discovery model was applied to identify potential regulators of MKX. The analytical tool Expert Protein Analysis System for proteomics was used to predict the three-dimensional structure of MKX, and the AutoDockTools software was used to identify pockets of activity at potential sites for molecular docking. Furthermore, we evaluated the effect of different doses of 17-beta-estradiol on bone marrow-derived mesenchymal stem cells (BM-MSCs).
RESULTS
By predicting the three-dimensional structure of MKX and simulating molecular docking, Pro-Tyr and 17-beta-Estradiol were found to target and bind to MKX. Analysis of the STITCH and OncoBinder databases showed that MKX had a significant regulatory correlation with suppressor interacting 3 A/histone deacetylase 1 (SIN3A/HDAC1). The GO and KEGG pathway enrichment analysis revealed that the functions of MKX and its associated proteins were mainly enriched in osteogenic-related pathways. Assessment of the proliferation of BM-MSCs revealed that 17-beta-estradiol possibly upregulated the mRNA expression of the HDAC1-SIN3A/BMP pathway-related RUNX2, thereby promoting the proliferation of BM-MSCs.
CONCLUSIONS
The compounds Pro-Tyr and 17-beta-Estradiol may bind to MKX and thus affect the interaction of MKX with SIN3A/HDAC1.
背景
肌腱异位骨化（HO）是肌腱损伤或手术创伤后常见的并发症，严重影响患者生活质量。由于病理机制尚不明确，肌腱HO的治疗仍然具有挑战性。莫霍克蛋白（MKX）是预防肌腱HO的关键因素；然而，其上游调控机制仍有待明确。本研究旨在鉴定靶向并调控MKX的潜在化合物，并探究其作用机制。
方法
基于STITCH和OncoBinder数据库的数据，对与MKX相关的化合物和蛋白质进行生物信息学分析。随后，利用SymMap数据库研究与MKX相关的中药药物和症状。接着，应用OncoBinder基因组和蛋白质组发现模型来鉴定MKX的潜在调节因子。使用蛋白质组学分析工具Expert Protein Analysis System预测MKX的三维结构，并使用AutoDockTools软件确定分子对接潜在位点的活性口袋。此外，我们评估了不同剂量的17-β-雌二醇对骨髓间充质干细胞（BM-MSCs）的影响。
结果
通过预测MKX的三维结构并模拟分子对接，发现脯氨酸-酪氨酸和17-β-雌二醇可靶向并结合MKX。对STITCH和OncoBinder数据库的分析表明，MKX与抑制因子相互作用3A/组蛋白去乙酰化酶1（SIN3A/HDAC1）具有显著的调控相关性。基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析显示，MKX及其相关蛋白的功能主要富集在成骨相关通路中。对BM-MSCs增殖的评估表明，17-β-雌二醇可能上调HDAC1-SIN3A/骨形态发生蛋白（BMP）通路相关的RUNX2的mRNA表达，从而促进BM-MSCs的增殖。
结论
化合物脯氨酸-酪氨酸和17-β-雌二醇可能与MKX结合，从而影响MKX与SIN3A/HDAC1的相互作用。
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