Cyclin D1/CDK4 induces Runx2 and Runx3 phosphorylation, ubiquitination, and proteasome degradation. PTHrP prevents chondrocyte differentiation by down-regulation of Runx2 and Runx3 protein levels through a cyclin D1-dependent manner.

PTHrP prevents chondrocyte premature hypertrophy through down-regulation of the steady-state protein levels of Runx2 and Runx3 in proliferating and pre-hypertrophic chondrocytes. In addition to promoting chondrocyte differentiation, Runx2 also stimulates Fgf18 expression in the perichondrium, which, in turn, inhibits chondrocyte proliferation.

Schematic illustration of the full-length human type I Runx2 isoform, beginning with the N-terminal sequence MRIPV (NP_004339). The structural and functional protein domains of Runx2 are shown, along with the relative positions of the residues demonstrated to undergo post-translational modification. Runx2 has 10 lysine residues that are potential sites of ubiquitination and acetylation. Also shown, between residues 409 and 412, is the PY motif (PPXY) necessary for interaction of Runx2 with ubiquitin E3 ligase Smurf1. Serine residues modified by phosphorylation are also shown. In red are those residues where phosphorylation has a negative affect on Runx2 transcriptional activity, and in green are those residues where phosphorylation has a positive effect on Runx2 transcriptional activity. All residues are conserved between human and mouse type I and type II isoforms. Q/A, glutamine/alanine-rich domain; RHD, Runt homology domain; NLS, nuclear localization signal; PST, proline/serine/threonine-rich domain; NMTS, nuclear matrix-targeting signal; VWRPY, last 5 amino acids constituting a conserved repression domain. Noted beneath are the relative functions of these domains.