Runt-related transcription factor 2 (RUNX2), also known as CBFA1, AML-3, PEBP-2alphaA, and OSF-2, is a transcription factor that places a critical role in osteoblast differentiation and bone development (1-3). RUNX2 is a DNA-binding protein that belongs to the RUNX family which share a common runt domain (3). RUNX2 has two main isoforms which vary based on the two promoter regions (3). The main canonical isoform (P1) has MASN/DS at its N-terminus while the other (P2) isoform includes a MRIPV pentapeptide at its N-terminus (3). The RUNX2 P1 isoform has a theoretical molecular weight of 56 kDa and is synthesized as a 521 amino acid (aa) protein containing multiple domains. Specifically, RUNX2 contains transactivation domains (AD1, 2 and 3), a glutamine/alanine (Q/A)-rich domain, a runt homology domain (RHD), a nuclear localization signal (NLS), a proline/serine/threonine (PST)-rich domain, a nuclear matrix targeting signal (NMTS), a repression domain (RD), and a VWRPY region (3). RUNX2 is a heterodimer of an alpha and beta subunit where the alpha subunit binds DNA through the runt domain and the binding affinity is increased through heterodimerization (4).
Functionally, RUNX2 promotes the expression of osteoblast-specific genes vital for the osteoblast differentiation and proliferation process including type I collagen, osteocalcin (OCN), and alkaline phosphatase (APC) (1, 3). Further evidence for the role of RUNX2 is highlighted by a study of Runx2-/-mice which completely lack osteoblasts (4). Additionally, RUNX2 is also required for chondrocyte maturation, which are the cells responsible for cartilage formation (1, 3, 5). Given the role of RUNX2 in bone and cartilage maturation and formation, it is clear that defects or mutations in RUNX2 cause various bone and bone-related diseases (3, 6, 7). For instance, cleidocranial dysplasia (CCD), which presents with delayed cranial suture closure phenotypes, hypoplastic clavicles, extra teeth, and short stature, is caused by haploinsufficiency in RUNX2 (2, 3, 6). Furthermore, metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is a bone dysplasia disorder with a phenotype of abnormalities in the long bones, an underdeveloped jawbone, and short fingers that is caused by a duplication in RUNX2 (6). Finally, RUNX2 has been shown to be upregulated in mouse models of the joint disorder osteoarthritis (OA) and may be a potential molecular target for disease treatment (7).
Alternative names for RUNX2 include Acute myeloid leukemia 3 protein CBFA1, CBF-alpha-1, CCD1, CCDAML3, CLCD, Core-binding factor subunit alpha-1, MGC120023, ML3, oncogene AML-3, OSF2, osteoblast-specific transcription factor 2, PEA2aA, PEA2-alpha A, PEBP2A, polyomavirus enhancer-binding protein 2 alpha A subunit, runt related transcription factor 2, SL3/AKV core-binding factor alpha A subunit, and SL3-3 enhancer factor 1 alpha A subunit.
1. Ferreira, L. B., Gimba, E., Vinagre, J., Sobrinho-Simoes, M., & Soares, P. (2020). Molecular Aspects of Thyroid Calcification. International journal of molecular sciences. https://doi.org/10.3390/ijms21207718
2. Kim, W. J., Shin, H. L., Kim, B. S., Kim, H. J., & Ryoo, H. M. (2020). RUNX2-modifying enzymes: therapeutic targets for bone diseases. Experimental & molecular medicine. https://doi.org/10.1038/s12276-020-0471-4
3. Vimalraj, S., Arumugam, B., Miranda, P. J., & Selvamurugan, N. (2015). Runx2: Structure, function, and phosphorylation in osteoblast differentiation. International journal of biological macromolecules. https://doi.org/10.1016/j.ijbiomac.2015.04.008
4. Uniprot (Q13950)
5. Komori T. (2017). Roles of Runx2 in Skeletal Development. Advances in experimental medicine and biology. https://doi.org/10.1007/978-981-10-3233-2_6
6. Moffatt, P., Ben Amor, M., Glorieux, F. H., Roschger, P., Klaushofer, K., Schwartzentruber, J. A., Paterson, A. D., Hu, P., Marshall, C., FORGE Canada Consortium, Fahiminiya, S., Majewski, J., Beaulieu, C. L., Boycott, K. M., & Rauch, F. (2013). Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2. American journal of human genetics. https://doi.org/10.1016/j.ajhg.2012.12.001
7. Chen, D., Kim, D. J., Shen, J., Zou, Z., & O'Keefe, R. J. (2019). Runx2 plays a central role in Osteoarthritis development. Journal of orthopaedic translation. https://doi.org/10.1016/j.jot.2019.11.008