RUNX2 regulates osteoblast differentiation

RUNX2 stimulates transcription of the BGLAP gene, encoding osteocalcin. Binding of the RUNX2:CBFB complex to the BGLAP gene promoter is increased when RUNX2 is phosphorylated on serine residue S451. 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. When YAP1, tyrosine phosphorylated by SRC and/or YES1, binds to RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited. Signaling by SRC is known to inhibit osteoblast differentiation.

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.

The SCF(SKP2) E3 ubiquitin ligase complex inhibits differentiation of osteoblasts by polyubiquitinating RUNX2 and targeting it for proteasome-mediated degradation. This process is inhibited by glucose uptake in osteoblasts.