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The Pathogenic Potential of RUNX2

  • Lihua Ni1 and
  • Cheng Yuan2,* 
 Author information
Exploratory Research and Hypothesis in Medicine   2021;6(3):87-89

doi: 10.14218/ERHM.2021.00028

Runx2 is a well-known transcription factor for bone development. The current understanding of the other aspects of Runx2 functions is at an early stage. The roles of Runx2 in nonosseous tissues are gradually discovered. Of interest, Xiao et al. showed the value of Runx2 as a novel prognostic biomarker and as a potential therapeutic target for lung cancer through bioinformatic analysis.1 This is an interesting and valuable study.

Lung cancer is one of the most common malignancies, which leads to substantial mortality globally.2 Xiao et al. explored the expression levels, functions, and prognostic values of Runx2 in lung cancer via bioinformatics analysis.1 Bioinformatics is predominantly a discipline that handles genetic information.3,4 Easy access to bioinformatics tools and the efficient analyses of bioinformatics data are of vital importance to integrate distributed studies and to establish new hypotheses. The contribution of the internet to this integration is significant. Some limitations in the study of Xiao et al. should be mentioned.1 First, more analysis of the online data on Runx2 in lung cancer, which excludes confounders, such as age, tumor stage, and recurrence status should be refined. In addition, large scale experiments and multicenter clinical trials are required to confirm the role of Runx2 in lung cancer.

Studies have reported that Runx2 could participate in disorders of bone metabolism, ectopic calcification of the cardiovascular system, the abnormal development of teeth, tumorigenesis, and organ fibrosis. Osteoblast’s proliferation and differentiation are probably regulated by Runx2. Sun et al. defined the functional role of VSMC-derived Runx2 in regulating vascular calcification and promoting infiltration of macrophages into calcified lesions to form osteoclast-like cells.5 Elevated Runx2 could transcriptionally activate genes mediating tumor progression and metastasis, which includes the Runx2 target gene osteopontin (OPN). Studies had shown that Runx2 control OPN levels.6 In addition, the Runx2/OPN axis could regulate the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in the metastasis of osteosarcoma cells to the lung.6 The detailed information on Runx2 in the regulation of pathogenicity are summarized in Table 1.7–25

Table 1

Effects and mechanism of Runx2 in multiple systems

Target sitesEffectsMechanismsReferences
BonePromote bone formation1. Enhance the proliferation of osteoblast progenitors
2. Enhance the proliferation of suture mesenchymal cells and induce their commitment into osteoblast lineage cells
710
CardiovascularInduce vascular and aortic valve calcification1. VSMC-derived Runx2 promote the calfication of VSMC and formation of vascular osteoclasts
2. Promotes osteoblasts differentiation of human aortic valve interstitial cells
5,11
TeethTooth formation and eruption1. Form calcified tooth tissue
2. Regulate proliferation of the dental lamina
3. Regulates the alveolar remodeling process
1214
TumorigenesisOsteosarcoma, none-small cell lung cancer, breast cancer, prostate cancer, and renal cell carcinomas1. Regulate epithelial-mesenchymal transition
2. Affects tumor microenvironment remodeling
3. Regulates tumor growth, invasion, and metastasis
6,1520
Organ fibrosis1. Aortic fibrosis
2. Renal fibrosis
3. Pulmonary fibrosis
4. Myocardial fibrosis
1. Increased TGF-beta signaling pathway
2. Increased ECM expression
3. Contributes to profibrotic cell function
2125

Of interest, some factors could influence the expression of Runx2, which include: (1) microRNAs. The deletion of the microRNA processing enzyme Dicer leads to decreased expression of miRNAs and Runx2, which suggests a critical role for microRNA in the regulation of Runx2. A regulatory effect of Runx2-related microRNAs in the skeleton has been described, such as miR-23a, miR-30a, miR-449a, and miR-22.26 The biogenesis and activity of microRNAs are under sophisticated control at transcriptional and post-transcriptional levels, which restricts miRNA expression to particular tissues or developmental stages; (2) some traditional Chinese medicines have been reported to influence the expression of Runx2.27,28 Icariin, a flavonoid isolated from the herb Epimedium pubescens, could induce osteogenic differentiation in vitro in a Runx2-dependent manner;29 and (3) the changes in the internal environment. Hyperglycemia, hyperphosphate, and oxidative stress could affect the expression of Runx2.30–32 A better understanding of the regulation mechanism of Runx2 contributed to the development of target drugs. The factors that affect Runx2 expression should be studied further.

The term bioinformatics has been established for two decades. With the advancement of bioinformatics concepts, data can be accessed and collected on a global scale. As discussed previously, the role of Runx2 as a transcription factor in skeletal system, ectopic calcification, abnormal development of teeth, tumorigenesis, and organ fibrosis has attracted the attention or researchers (Fig. 1). The mechanism of how Runx2 could regulate these diseases requires further research. Strategies that target Runx2 could be potentials for the treatment of related diseases.

Pathogenic potential of Runx2
Fig. 1  Pathogenic potential of Runx2

The expression of Runx2 is regulated by several factors, such as microRNAs, traditional Chinese medicine, hyperglycemia, hyperphosphate, and oxidative stress. The dysregulated expression of Runx2 contributes to disorders of bone metabolism, ectopic calcification of cardiovascular system, abnormal development of teeth, tumorigenesis, and organ fibrosis.

Abbreviations

ECM: 

extracellular matrix

OPN: 

osteopontin

VSMC: 

vascular smooth muscle cell

Declarations

Acknowledgement

None.

Funding

This work was supported by grants from the Fundamental Research Funds for the Central University (2042021kf0150 and 2042020kf0137), Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund, Project (znpy2020027 and znpy2019036). Excellent Doctor (Post), and Zhongnan Hospital of Wuhan University (ZNYB2020009).

Conflict of interest

The authors have no conflict of interest related to this publication.

Authors’ contributions

Yuan Cheng conceived and designed this study. Ni Lihua and Yuan Cheng wrote the manuscript and approved the submitted version.

References

  1. Xiao D, Liu K, Chen J, Gong Y, Zhou X, Huang J. RUNX2 as a Potential Prognosis Biomarker and New Target for Human Lung Cancer. Explor Res Hypothesis Med 2021 View Article
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424 View Article
  3. Zhou LT, Lv LL, Qiu S, Yin Q, Li ZL, Tang TT, et al. Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease. J Transl Med 2019;17(1):59 View Article
  4. Ni LH, Yuan C, Zhang CJ, Xiang YD, Wu J, Wang XL, et al. Co-Expression Network Analysis Identified LTF in Association with Metastasis Risk and Prognosis in Clear Cell Renal Cell Carcinoma. Onco Targets Ther 2020;13:6975-6986 View Article
  5. Sun Y, Byon CH, Yuan K, Chen J, Mao X, Heath JM, et al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 2012;111(5):543-552 View Article
  6. Villanueva F, Araya H, Briceño P, Varela N, Stevenson A, Jerez S, et al. The cancer-related transcription factor RUNX2 modulates expression and secretion of the matricellular protein osteopontin in osteosarcoma cells to promote adhesion to endothelial pulmonary cells and lung metastasis. J Cell Physiol 2019;234(8):13659-13679 View Article
  7. Garcia J, Smith SS, Karki S, Drissi H, Hrdlicka HH, Youngstrom DW, et al. miR-433-3p suppresses bone formation and mRNAs critical for osteoblast function in mice. J Bone Miner Res 2021 View Article
  8. Yen YT, Chien M, Wu PY, Hung SC. PP2A in LepR+ mesenchymal stem cells contributes to embryonic and postnatal endochondral ossification through Runx2 dephosphorylation. Commun Biol 2021;4(1):658 View Article
  9. Liu Y, Wang L, Yang Y, Xiong J. Silencing Hoxa2 reverses dexamethasone-induced dysfunction of MC3T3-E1 osteoblasts and osteoporosis in rats. Adv Clin Exp Med 2021;30(5):525-534 View Article
  10. Zhou X, Beilter A, Xu Z, Gao R, Xiong S, Paulucci-Holthauzen A, et al. Wnt/ß-catenin-mediated p53 suppression is indispensable for osteogenesis of mesenchymal progenitor cells. Cell Death Dis 2021;12(6):521 View Article
  11. Yu C, Li L, Xie F, Guo S, Liu F, Dong N, et al. LncRNA TUG1 sponges miR-204-5p to promote osteoblast differentiation through upregulating Runx2 in aortic valve calcification. Cardiovasc Res 2018;114(1):168-179 View Article
  12. Camilleri S, McDonald F. Runx2 and dental development. Eur J Oral Sci 2006;114(5):361-373 View Article
  13. Bertonnier-Brouty L, Viriot L, Joly T, Charles C. Gene expression patterns associated with dental replacement in the rabbit, a new model for the mammalian dental replacement mechanisms. Dev Dyn 2021 View Article
  14. Yoon H, Kim HJ, Shin HR, Kim BS, Kim WJ, Cho YD, et al. Nicotinamide Improves Delayed Tooth Eruption in Runx2(+/-) Mice. J Dent Res 2021;100(4):423-431 View Article
  15. Wu CY, Li L, Chen SL, Yang X, Zhang CZ, Cao Y. A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma. Cell Death Dis 2021;12(4):319 View Article
  16. Yang DP, Huang WY, Chen G, Chen SW, Yang J, He RQ, et al. Clinical significance of transcription factor RUNX2 in lung adenocarcinoma and its latent transcriptional regulating mechanism. Comput Biol Chem 2020;89:107383 View Article
  17. Jing GY, Zheng XZ, Ji XX. lncRNA HAND2-AS1 overexpression inhibits cancer cell proliferation in hepatocellular carcinoma by downregulating RUNX2 expression. J Clin Lab Anal 2021;35(4):e23717 View Article
  18. Wu X, Huang J, Yang Z, Zhu Y, Zhang Y, Wang J, et al. MicroRNA-221-3p is related to survival and promotes tumour progression in pancreatic cancer: a comprehensive study on functions and clinicopathological value. Cancer Cell Int 2020;20:443 View Article
  19. Zhang L, Liu L, Xu X, He X, Wang G, Fan C, et al. miR-205/RunX2 axis negatively regulates CD44(+)/CD24(-) breast cancer stem cell activity. Am J Cancer Res 2020;10(6):1871-1887
  20. Ma F, Xie Y, Lei Y, Kuang Z, Liu X. The microRNA-130a-5p/RUNX2/STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer. BMC cancer 2020;20(1):580 View Article
  21. Hsu CK, Lin HH, Harn HI, Ogawa R, Wang YK, Ho YT, et al. Caveolin-1 Controls Hyperresponsiveness to Mechanical Stimuli and Fibrogenesis-Associated RUNX2 Activation in Keloid Fibroblasts. J Invest Dermatol 2018;138(1):208-218 View Article
  22. Chen J, Lin Y, Sun Z. Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPKα-mediated activation of RUNX2. Aging cell 2016;15(5):853-860 View Article
  23. Huang YZ, Zhao L, Zhu Y, Tian SJ, Zhang W, Liu S, et al. Interrupting TGF-β1/CCN2/integrin-α5β1 signaling alleviates high mechanical-stress caused chondrocyte fibrosis. Eur Rev Med Pharmacol Sci 2021;25(3):1233-1241 View Article
  24. Raaz U, Schellinger IN, Chernogubova E, Warnecke C, Kayama Y, Penov K, et al. Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes Mellitus. Circ Res 2015;117(6):513-524 View Article
  25. Lv W, Wu M, Ren Y, Luo X, Hu W, Zhang Q, et al. Treatment of keloids through Runx2 siRNA-induced inhibition of the PI3K/AKT signaling pathway. Mol Med Rep 2021;23(1):55 View Article
  26. Zhao W, Zhang S, Wang B, Huang J, Lu WW, Chen D. Runx2 and microRNA regulation in bone and cartilage diseases. Ann N Y Acad Sci 2016;1383(1):80-87 View Article
  27. Liu L, Wang L, Li L, Wang H, Yuan L, Kang L, et al. Effects of triangle grass decoction on bone metabolism in rats with chronic kidney disease complicated with mineral and bone abnormalities. J Ethnopharmacol 2021;275:114126 View Article
  28. Sun W, Li M, Zhang Y, Huang Y, Zhan Q, Ren Y, et al. Total flavonoids of rhizoma drynariae ameliorates bone formation and mineralization in BMP-Smad signaling pathway induced large tibial defect rats. Biomed Pharmacother 2021;138:111480 View Article
  29. Zhao J, Ohba S, Shinkai M, Chung UI, Nagamune T. Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2-dependent manner. Biochem Biophys Res Commun 2008;369(2):444-448 View Article
  30. Malta FS, Garcia RP, Azarias JS, Ribeiro G, Miranda TS, Shibli JA, et al. Impact of hyperglycemia and treatment with metformin on ligature-induced bone loss, bone repair and expression of bone metabolism transcription factors. PloS one 2020;15(8):e0237660 View Article
  31. Zhao L, Wang S, Liu H, Du X, Bu R, Li B, et al. The Pharmacological Effect and Mechanism of Lanthanum Hydroxide on Vascular Calcification Caused by Chronic Renal Failure Hyperphosphatemia. Front Cell Dev Biol 2021;9:639127 View Article
  32. Lee SH, Kim M, Park MH. Diphlorethohydroxycamalol isolated from Ishige okamurae prevents H(2)O(2)-induced oxidative damage via BMP2/Runx2 signaling in osteoblastic MC3T3-E1 cells. Fitoterapia 2021;152:104921 View Article
  • Exploratory Research and Hypothesis in Medicine
  • pISSN 2993-5113
  • eISSN 2472-0712
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The Pathogenic Potential of RUNX2

Lihua Ni, Cheng Yuan
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