RUNX2 regulates osteoblast differentiation

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R-HSA-8940973
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Pathway
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Homo sapiens
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The complex of RUNX2 and CBFB regulates transcription of genes involved in differentiation of osteoblasts.
RUNX2 stimulates transcription of the BGLAP gene, encoding osteocalcin (Ducy and Karsenty 1995, Ducy et al. 1997). Binding of the RUNX2:CBFB complex to the BGLAP gene promoter is increased when RUNX2 is phosphorylated on serine residue S451 (Wee et al. 2002). Osteocalcin, a bone-derived hormone, is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). Association of the activated androgen receptor (AR) with RUNX2 prevents binding of RUNX2 to the BGLAP promoter (Baniwal et al. 2009). When YAP1, tyrosine phosphorylated by SRC and/or YES1, binds to RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited (Zaidi et al. 2004). Signaling by SRC is known to inhibit osteoblast differentiation (Marzia et al. 2000).
Simultaneous binding of RUNX2 and SP7 (Osterix, also known as OSX) to adjacent RUNX2 and SP7 binding sites, respectively, in the UCMA promoter, synergistically activates UCMA transcription. UCMA stimulates osteoblast differentiation and formation of mineralized nodules (Lee et al. 2015).
The SCF(SKP2) E3 ubiquitin ligase complex inhibits differentiation of osteoblasts by polyubiquitinating RUNX2 and targeting it for proteasome-mediated degradation (Thacker et al. 2016). This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015).

Literature References
PubMed ID Title Journal Year
7891679 Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene

Ducy, P, Karsenty, G

Mol. Cell. Biol. 1995
26091038 Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation

Wei, J, Shimazu, J, Makinistoglu, MP, Maurizi, A, Kajimura, D, Zong, H, Takarada, T, Lezaki, T, Pessin, JE, Hinoi, E, Karsenty, G

Cell 2015
14765127 Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription

Zaidi, SK, Sullivan, AJ, Medina, R, Ito, Y, van Wijnen, AJ, Stein, JL, Lian, JB, Stein, GS

EMBO J. 2004
19389811 Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA

Baniwal, SK, Khalid, O, Sir, D, Buchanan, G, Coetzee, GA, Frenkel, B

Mol. Endocrinol. 2009
26778333 Skp2 inhibits osteogenesis by promoting ubiquitin-proteasome degradation of Runx2

Thacker, G, Kumar, Y, Khan, MP, Shukla, N, Kapoor, I, Kanaujiya, JK, Lochab, S, Ahmed, S, Sanyal, S, Chattopadhyay, N, Trivedi, AK

Biochim. Biophys. Acta 2016
9182762 Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation

Ducy, P, Zhang, R, Geoffroy, V, Ridall, AL, Karsenty, G

Cell 1997
11038178 Decreased c-Src expression enhances osteoblast differentiation and bone formation

Marzia, M, Sims, NA, Voit, S, Migliaccio, S, Taranta, A, Bernardini, S, Faraggiana, T, Yoneda, T, Mundy, GR, Boyce, BF, Baron, R, Teti, A

J. Cell Biol. 2000
26967290 Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication

Karsenty, G, Olson, EN

Cell 2016
25865393 Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation

Lee, YJ, Park, SY, Lee, SJ, Boo, YC, Choi, JY, Kim, JE

Osteoarthr. Cartil. 2015
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