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P&F Grant Awards

Year 4

Grant # 7

ASXL Proteins Regulate Bone Resorption

PI: Wei Zou, MD, Ph.D.,


Specific Aims

Rosiglitizone (BRL) is an insulin-sensitizing drug which exerts its effect by activating the transcription factor PPARγ. While BRL is probably the most effective oral treatment of type II diabetes mellitus (DM II) it carries complications including increased fracture risk. This predisposition to fracture is consistent with the fact that PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Surprisingly however, BRLactivated PPARγ also stimulates osteoclast formation. We have discovered that the nuclear protein ASXL2 is essential for PPARγ -stimulated osteoclast formation. Specifically, osteoclastogenesis is arrested in the absence of ASXL2, in vitro, and mice lacking the protein have osteoclast-autonomous osteopetrosis. We have also established that like PPARγ, ASXL2 accelerates osteoclast formation by promoting mitochondrial biogenesis and increasing RANKL-induced c-Fos expression which in turn stimulates NFATc1. Importantly, BRL-enhanced osteoclastogenesis is completely arrested absent ASXL2. Given that in other cells, ASXL2 interacts with PPARγ, BRL-induced bone loss, in the context of DM II, may entail ASXL2 regulation of the nuclear receptor’s transcriptional activity. ASXL1 is a paralog of ASXL2 which also recognizes PPARγ in fat cells. However, whereas ASXL2 promotes BRL-stimulated PPARγ activation, in adipocytes, ASXL1 inhibits it. As BRL exerts its osteoclastogenic properties via PPARγ we hypothesize, that similar to adipogenesis, the effects of ASXL1 deletion on osteoclast formation and function, in vitro and in vivo, are opposite those of ASXL2. Thus, our specific aim is to determine the effects of ASXL1 deletion on basal and PPARγ -mediated osteoclast formation and function in vitro and in vivo.