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RUNX2
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<h2 id="function">Function</h2> <h3>Osteoblast differentiation</h3> <p>This protein is a member of the RUNX family of transcription factors and has a <a href="/facts/Runt_domain/N7t0wL2r">Runt DNA-binding domain</a>. It is essential for osteoblastic differentiation and skeletal <a href="/facts/Morphogenesis/zHJh8Eae">morphogenesis</a>. It acts as a <a href="/facts/Scaffold_protein/uKnJq24r">scaffold</a> for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a <a href="/facts/Heterodimer/c8LwFJPG">heterodimeric</a> complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as <a href="/facts/Alternative_splicing/nNRwPVNK">alternate splicing</a>. </p><p>The cellular dynamics of Runx2 protein are also important for proper osteoblast differentiation. Runx2 protein is detected in <a href="/facts/Preosteoblast/N6mMDQvR">preosteoblasts</a> and the expression is upregulated in immature osteoblasts and downregulated in mature osteoblasts. It is the first transcription factor required for determination of osteoblast commitment, followed by <a href="/facts/Sp7_transcription_factor/Wv5PEfAH">Sp7</a> and <a href="/facts/Wnt_signaling_pathway/7wxpKrjy">Wnt-signaling</a>. Runx2 is responsible for inducing the differentiation of multipotent <a href="/facts/Mesenchymal_stem_cell/W0jeK2a3">mesenchymal cells</a> into immature osteoblasts, as well as activating expression of several key downstream proteins that maintain osteoblast differentiation and <a href="/facts/Bone_matrix/fTFx9XDA">bone matrix</a> genes. </p><p><a href="/facts/Knockout_mouse/Aw50cobf">Knock-out</a> of the DNA-binding activity results in inhibition of osteoblastic differentiation. Because of this, Runx2 is often referred to as the master regulator of bone.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h3>Cell cycle regulation</h3> <p>In addition to being the master regulator of osteoblast differentiation, Runx2 has also been shown to play several roles in cell cycle regulation. This is due, in part, to the fact that Runx2 interacts with many cellular proliferation genes on a <a href="/facts/Transcription_(biology)/bDgp9HDN">transcription</a> level, such as <a href="/facts/Myc/7FGlAtFk">c-Myb</a> and <a href="/facts/C/EBP/c3d9l7F8">C/EBP</a>,<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> as well as <a href="/facts/TP53/YEGULLgM">p53</a>/<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> These functions are critical for osteoblast proliferation and maintenance. This is often controlled via oscillating levels of Runx2 within throughout cell cycle due to regulated degradation and transcriptional activity. </p><p>Oscillating levels of Runx2 within the cell contribute to cell cycle dynamics. In the <a href="/facts/MC3T3-E1/kEkwB5I0">MC3T3-E1</a> osteoblast cell line, Runx2 levels are a maximum during G1 and a minimum during G2, S, and mitosis.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> In addition, the oscillations in Runx2 contribute to G1-related anti-proliferative function.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> It has also been proposed that decreasing levels of Runx2 leads to cell cycle exit for proliferating and differentiating osteoblasts, and that Runx2 plays a role in mediating the final stages of osteoblast via this mechanism.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> Current research posits that the levels of Runx2 serve various functions. </p><p>In addition, Runx2 has been shown to interact with several <a href="/facts/Kinase/dhlHpjnD">kinases</a> that contribute to facilitate cell-cycle dependent dynamics via direct protein phosphorylation. Furthermore, Runx2 controls the <a href="/facts/Gene_expression/alCPohLR">gene expression</a> of <a href="/facts/Cyclin_D2/lvMtYhJW">cyclin D2</a>, <a href="/facts/Cyclin_D3/eWasw7CL">D3</a>, and the <a href="/facts/P21/gb0VLtY8">CDK inhibitor p21(cip1)</a> in hematopoietic cells. It has been shown that on a molecular level, Runx associates with the cdc2 partner <a href="/facts/Cyclin_B1/opvj6nJb">cyclin B1</a> during mitosis.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The phosphorylation state of Runx2 also mediates its DNA-binding activity. The Runx2 <a href="/facts/DNA-binding_protein/HEMm9eDX">DNA-binding</a> activity is correlated with cellular proliferation, which suggests Runx2 phosphorylation may also be related to Runx2-mediated cellular proliferation and cell cycle control. To support this, it has been noted that Runx is phosphorylated at Ser451 by cdc2 kinase, which facilitates cell cycle progression through the regulation of G2 and M phases.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="pathology">Pathology</h2> <h3>Cleidocranial dysplasia</h3> <p>Mutations in Runx2 are associated with the disease <a href="/facts/Cleidocranial_dysostosis/qj4m1eFa">Cleidocranial dysostosis</a>. One study proposes that this phenotype arises partly due to the Runx2 dosage insufficiencies. Because Runx2 promotes exit from the cell cycle, insufficient amounts of Runx2 are related to increased proliferation of osteoblasts observed in patients with cleidocranial disostosis.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h3>Osteosarcoma</h3> <p>Variants of Runx2 have been associated with the osteosarcoma phenotype.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> Current research suggests that this is partly due to the role of Runx2 in mitigating the cell cycle.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Runx2 plays a role as a tumor suppressor of osteoblasts by halting cell cycle progression at G1.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Compared to normal osteoblast cell line MC3T3-E1, the oscillations of Runx2 in osteosarcoma ROS and SaOS cell lines are aberrant when compared to the oscillations of Runx2 levels in normal osteoblasts, suggesting that deregulation of Runx2 levels may contribute to abnormal cell proliferation by an inability to escape the cell cycle. Molecularly, It has been proposed that proteasome inhibition by <a href="/facts/MG132/NG8aW6dD">MG132</a> can stabilize Runx2 protein levels in late G1 and S in MC3T3 cells, but not in osteosarcoma cells which consequently leads to a cancerous phenotype.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="regulation-and-co-factors">Regulation and co-factors</h2> <p>Due to its role as a master transcription factor of osteoblast differentiation, the regulation of Runx2 is intricately connected to other processes within the cell. </p><p><a href="/facts/Twist_transcription_factor/lTIjHaUq">Twist</a>, <a href="/facts/Msh_homeobox_2/HuUcNdXa">Msh homeobox 2</a> (Msx2), and promyeloctic leukemia zinc-finger protein (PLZF) act upstream of Runx2. <a href="/facts/Sp7_transcription_factor/Wv5PEfAH">Osterix (Osx)</a> acts downstream of Runx2 and serves as a marker for normal osteoblast differentiation. <a href="/facts/Zinc_finger_protein_521/24cyqgcW">Zinc finger protein 521</a> (ZFP521) and <a href="/facts/ATF4/5SHtKwa7">activating transcription factor 4</a> (ATF4) are <a href="/facts/Cofactors_and_coenzymes/DSI1Fh7y">cofactors</a> of Runx2.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Binding of the transcriptional coregulator, <a href="/facts/WWTR1/5HCuCMe8">WWTR1 (TAZ)</a> to Runx2 promotes transcription. </p><p>Furthermore, in proliferating <a href="/facts/Chondrocyte/wVM93CGh">chondrocytes</a>, Runx2 is inhibited by <a href="/facts/Cyclin_D/Cdk4/XActvlPL">CyclinD1/CDK4</a> as part of the cell cycle.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>RUNX2 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/Androgen_receptor/NBPRszqm">AR</a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></li> <li><a href="/facts/Estrogen_receptor_alpha/PXU6tYY3">ER-α</a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a></li> <li><a href="/facts/C-Fos/SHKzGqYX">C-Fos</a>,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a></li> <li><a href="/facts/C-jun/Cbvb15yT">C-jun</a>,<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li><a href="/facts/HDAC3/lewe7kpB">HDAC3</a>,<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></li> <li><a href="/facts/MYST4/EBpzr0Mo">MYST4</a>,<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></li> <li><a href="/facts/Mothers_against_decapentaplegic_homolog_1/cYgoEr7r">SMAD1</a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></li> <li><a href="/facts/Mothers_against_decapentaplegic_homolog_3/6j6Go6va">SMAD3</a>,<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> and</li> <li><a href="/facts/STUB1/T2kmytP1">STUB1</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></li></ul> <p>and </p> <ul><li>SMOC1.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></li></ul> <p><a href="/facts/Mir-133_microRNA_precursor_family/n2QYzosV">miR-133</a> and <a href="/facts/Cyclin_D/Cdk4/XActvlPL">CyclinD1/CDK4</a> directly inhibits Runx2.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/RUNX1/GAgvmcQl">RUNX1</a></li> <li><a href="/facts/RUNX3/YBrqFq80">RUNX3</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Otto F, Kanegane H, Mundlos S (March 2002). <a href="https://doi.org/10.1002%2Fhumu.10043">"Mutations in the RUNX2 gene in patients with cleidocranial dysplasia"</a>. <i>Human Mutation</i>. 19 (3): 209–16. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fhumu.10043">10.1002/humu.10043</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11857736">11857736</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:2578591">2578591</a>.</li> <li>Komori T (March 2002). "[Cbfa1/Runx2, an essential transcription factor for the regulation of osteoblast differentiation]". <i>Nihon Rinsho. Japanese Journal of Clinical Medicine</i>. 60 (Suppl 3): 91–7. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11979975">11979975</a>.</li> <li>Stock M, Otto F (June 2005). "Control of RUNX2 isoform expression: the role of promoters and enhancers". <i>Journal of Cellular Biochemistry</i>. 95 (3): 506–17. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fjcb.20471">10.1002/jcb.20471</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15838892">15838892</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:29657025">29657025</a>.</li> <li>Blyth K, Cameron ER, Neil JC (May 2005). "The RUNX genes: gain or loss of function in cancer". <i>Nature Reviews. Cancer</i>. 5 (5): 376–87. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fnrc1607">10.1038/nrc1607</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15864279">15864279</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:335980">335980</a>.</li> <li>Schroeder TM, Jensen ED, Westendorf JJ (September 2005). <a href="https://doi.org/10.1002%2Fbdrc.20043">"Runx2: a master organizer of gene transcription in developing and maturing osteoblasts"</a>. <i>Birth Defects Research. Part C, Embryo Today</i>. 75 (3): 213–25. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fbdrc.20043">10.1002/bdrc.20043</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16187316">16187316</a>.</li> <li>Frenkel B, Hong A, Baniwal SK, Coetzee GA, Ohlsson C, Khalid O, Gabet Y (August 2010). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770230">"Regulation of adult bone turnover by sex steroids"</a>. <i>Journal of Cellular Physiology</i>. 224 (2): 305–10. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fjcp.22159">10.1002/jcp.22159</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770230">5770230</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/20432458">20432458</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://www.ncbi.nlm.nih.gov/books/NBK1513/">GeneReviews/NCBI/NIH/UW entry on Cleidocranial Dysplasia</a></li> <li><a href="https://meshb.nlm.nih.gov/record/ui?name=Runx2+protein">Runx2+protein</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA (April 2013). "The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines". Journal of Cellular Physiology. 228 (4): 714–23. doi:10.1002/jcp.24218. PMC 3593672. PMID 22949168. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC 3066433. PMID 19739101. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Wysokinski D, Pawlowska E, Blasiak J (May 2015). "RUNX2: A Master Bone Growth Regulator That May Be Involved in the DNA Damage Response". DNA and Cell Biology. 34 (5): 305–15. doi:10.1089/dna.2014.2688. PMID 25555110. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC 3066433. PMID 19739101. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Wysokinski D, Pawlowska E, Blasiak J (May 2015). "RUNX2: A Master Bone Growth Regulator That May Be Involved in the DNA Damage Response". DNA and Cell Biology. 34 (5): 305–15. doi:10.1089/dna.2014.2688. PMID 25555110. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC 3066433. PMID 19739101. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS, van Wijnen AJ (May 2005). "The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts". The Journal of Biological Chemistry. 280 (21): 20274–85. doi:10.1074/jbc.M413665200. PMC 2895256. PMID 15781466. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895256" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895256</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Pratap J, Galindo M, Zaidi SK, Vradii D, Bhat BM, Robinson JA, Choi JY, Komori T, Stein JL, Lian JB, Stein GS, van Wijnen AJ (September 2003). "Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts". Cancer Research. 63 (17): 5357–62. PMID 14500368. <a href="/wiki/PMID_(identifier)" target="_blank">/wiki/PMID_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A (March 2006). "Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation". The Journal of Biological Chemistry. 281 (11): 7118–28. doi:10.1074/jbc.M508162200. PMID 16407259. <a href="https://doi.org/10.1074%2Fjbc.M508162200" target="_blank">https://doi.org/10.1074%2Fjbc.M508162200</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A (March 2006). "Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation". The Journal of Biological Chemistry. 281 (11): 7118–28. doi:10.1074/jbc.M508162200. PMID 16407259. <a href="https://doi.org/10.1074%2Fjbc.M508162200" target="_blank">https://doi.org/10.1074%2Fjbc.M508162200</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Lou Y, Javed A, Hussain S, Colby J, Frederick D, Pratap J, Xie R, Gaur T, van Wijnen AJ, Jones SN, Stein GS, Lian JB, Stein JL (February 2009). "A Runx2 threshold for the cleidocranial dysplasia phenotype". Human Molecular Genetics. 18 (3): 556–68. doi:10.1093/hmg/ddn383. PMC 2638795. PMID 19028669. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638795" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638795</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC 3066433. PMID 19739101. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA (April 2013). "The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines". Journal of Cellular Physiology. 228 (4): 714–23. doi:10.1002/jcp.24218. PMC 3593672. PMID 22949168. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). "Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells". Journal of Cellular Physiology. 221 (3): 560–71. doi:10.1002/jcp.21894. PMC 3066433. PMID 19739101. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066433</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA (April 2013). "The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines". Journal of Cellular Physiology. 228 (4): 714–23. doi:10.1002/jcp.24218. PMC 3593672. PMID 22949168. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593672</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>San Martin IA, Varela N, Gaete M, Villegas K, Osorio M, Tapia JC, Antonelli M, Mancilla EE, Pereira BP, Nathan SS, Lian JB, Stein JL, Stein GS, van Wijnen AJ, Galindo M (December 2009). 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