Figure 1.

Alterations in transforming growth factor beta signaling cause changes in chondrocyte differentiation and osteoarthritis development. Transforming growth factor beta (TGFβ) can either signal by the Smad2/3 route (canonical) or the Smad1/5/8 route. Smad2/3 and Smad1/5/8 form a complex with Smad4 that enters the nucleus and modulates gene expression and Runx2 function. The signaling by Smad2/3 and Smad1/5/8 is differentially modified by a number of intracellular molecules. Both Smad routes are blocked by Smad7, while Smad6 blocks preferentially the Smad1/5/8 pathway [100,101]. wnt signaling modifies these pathways by stabilization of Smad1/5/8 [102]. Smurf1 and Smurf2 are E3 ubiquitin ligases that inhibit Smad signaling. Smurf1 triggers the degradation of Smad1/5/8 while Smurf2 stimulates mainly the degradation of Smad2/3 [103]. Mitogen-activated protein kinases (MAPKs) modulate the stability and degradation of the Smads by phosphorylation of these molecules [102].