Bone-protective Property And Mechanisms Of Metformin On UHMWPE Particle-induced Osteolysis Via Mature Osteocytes

Metformin,an anti-hyperglycemic agents used for type 2 diabetes,has recently been found to have more effects apart from glucose regulation.We found that in ultra-high molecular weight polyethylene(UHMWPE)particle-induced osteolysis mouse models,metformin had bone protect property and reduced the negative regulator of bone formation Sclerostin(SOST)and Dickkopf-related protein 1(DKK1),and increased osteoprotegerin(OPG)secretion and rised ratio of OPG/ Receptor Activator for Nuclear Factor-? B Ligand(RANKL).In vitro we established a 3D co-culture system in which metformin affects osteoblasts and osteoclasts through mature osteocytes secretion.Metformin(50 ?M)significantly decreased Sclerostin and DKK1 mRNA expression,promoting alkaline phosphatase activity and proliferation of osteoblast,and increasing OPG secretion and ratio of OPG/RANKL,thus inhibiting osteoclastogenesis.Moreover,the effect on OPG was reversed by Adenosine 5‘-monophosphate(AMP)-activated protein kinase(AMPK)inhibitor,Compound C.Our finding suggests that metformin induces differentiation and mineralization of osteoblasts,while inhibits osteoclastogenesis via mature osteocytes secretion.Therefore,the drug might be beneficial for not only diabetes but also in other bone disorders by acting on mature osteocytes.