Figure 8
Schematic diagram outlining the potential molecular targets and in vivo effect of WFA leading to bone anabolic effect in osteogenic cells and osteoclast precursors induced by proteasome inhibition. BMP signaling induced by WFA prevents degradation of Smad receptors. The transcription factor Runx2, which is induced by BMP2, is further stabilized by preventing completion of proteasomal degradation by E3 ubiquitin ligase, Smurf2. WFA decreases tumor necrosis factor α (TNFα), induced NF-Kb and Smurf2 expression resulting in increased Smad and Runx2 levels. In vivo proteasome inhibition simultaneously increases osteoblastogenesis by stabilizing RunX2 and reduces osteoclast numbers directly by inhibiting RANKL: OPG ratio. Thus, osteoclast differentiation is suppressed by inability of RANKL to bind with RANK. This results in reduced number of TRAP-positive cells. Simultaneous induction of osteoblastogenesis and suppression of osteoclastogenesis results in increased bone mass. Our in vivo data demonstrate that WFA exerted an osteogenic effect in osteopenic OVx mice and accelerated the bone-healing process after bone marrow injury of long bones (See text for details
