Reactome | RUNX2 regulates osteoblast differentiation

RUNX2 regulates osteoblast differentiation

Stable Identifier

R-HSA-8940973

Type

Pathway

Species

Homo sapiens

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RUNX2 regulates osteoblast differentiation

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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