The Role Of MYO6 In Bone Destruction Of Arthritis And Its Mechanisms

Background and objectives:Rheumatoid arthritis（RA）is a chronic autoimmune disease charactered by joint inflammation and bone destruction.Osteoclasts,multinucleated cells derived from the monocyte,is the only cell responsible for bone resorption.Osteoclasts frist adhere to bone surface with sealing zone,and secret proton and matrix enzymes（TRAP,MMP9,CtsK）to degrade bone.At last,bone degradation is absorbed into osteoclasts by endocytosis and then metabolized.Myosin Ⅵ（MY06）is an unconditional myosin that travel toward protein end and it plays an importantly role in endocytosis,viscle traffiking,endosome maturation,actin filament assembling.But the role and mechanism of MYO6 in osteoclasts remain unknown.Methods:1.In vivo,collagen-induced arthritis mouse model was established to explore the role of MYO6 in arthritis.Foot swelling score were recorded and IL-1β,TNF-α,IgG2α,CTX-1 were tested by ELISA to measure the degree of inflammation in CIA mice.Besides,micro-CT and HE staining were used to investigate the role of MYO6 in bone destruction.2.In vitro,BMM derived osteoclasts from wildtype and MYO6 knockout were used to investigate the role and mechanism of MYO6 in osteoclasts differentiation and function.Conventional experimental methods were used in this section,such as TRAP staining,cell immunofluorescence,RT-qPCR,western blot and so on.Results:The deficiency of MYO6 impaired osteoclasts differentiation and function,delay the development of arthritis and bone destruction in CIA mice.Further experiment found out the deficiency of MYO6 inhibited sealing zone formation by inhibit the activation of FAK/AKT pathway and down-regulating integrin-β3/c-Src pathway;interfered endocytic pathway by downregulating Rab5 expression and disturbing EEA1 and LAPMP1 location.The interaction between MYO6 and Dab2 may be the reason why MYO6 participates in a series of functions of osteoclasts.Conclusion:MYO6 participates in a series of function of osteoclasts,including osteoclasts differentiation,sealing zone formation and endosome transport by binding to Dab2.MYO6 may be a new target for the treatment of bone erosion in rheumatoid arthritis.