The PPAR-γ Inhibitor T0070907 Inhibits Osteoclastogenesis And Counteracts OVX-induced Bone Loss In Mice

Objective : Bone homeostasis is actively maintained in equilibrium by osteoclast resorption and osteoblastogenesis.Osteoclasts are key determinant cellular components implicated in the development and progression of disorders driven by bone damage.Herein,we studied the upshot of T0070907,an antagonist of peroxisome proliferator-activated receptor-gamma(PPAR-γ),on osteoclastogenesis using cell and animal models.Methods:We detected the expression levels of related m RNA and protein by using Quantitative-PCR and western blotting.The effects of T0070907 on cells were observed by staining,absorption of bovine bone slices,immunofluorescence and other experiments;The target gene was over-expressed and silenced in vitro by a DNA plasmid and si RNA,and its effect was observed;Using the model of osteoporosis induced by ovariectomy in mice,the therapeutic effect of T0070907 was evaluated.Results:These assays revealed that T007 hindered the osteoclastogenesis caused by the treatment with the receptor activator of nuclear factor-κB ligand(RANKL)through inhibiting the levels of PPAR-γ in cells.The expression of c-fos,nuclear factor of activated T cells C1(NFATc1),cathepsin K(CTSK)and TRAP are decreased.With the raises of T0070907 dosage and the prolongation of treatment time,the inhibition effect is more obvious.The PPAR-γ si RNA partially reproduced the inhibitory action of T0070907.The opposite findings were produced after PPAR-γ overexpression.Furthermore,T0070907 prevented from bone loss in a mouse model of osteoporosis induced by ovariectomy(OVX).These findings implied that T0070907 is a potential efficient drug for the prophylaxis and cure of osteoclast-related disorders.Conclusion : Taken together,our findings demonstrated that T0070907 impedes osteoclastogenesis and promote osteoblastogenesis by inhibiting PPAR-γ expression and will be useful for the therapy of bone related diseases,essentially osteoporosis.