Abstract: Objective: :To investigate the change of OC differentiation in T2DM mice and effect of different mechanical stimulation on OC differentiation by GPR48- RANKL pathway in T2DM mice.Methods: Forty four-week old C57BL/6 male mice were randomly divided into normal control group (ZC) and T2DM group. Use the method of high-fat diet and STZ to build the model of T2DM mice, and the T2DM mice were randomly divided into T2DM control group (TC), T2DM swimming group (TS) and T2DM downhill run group (TD). And use the swimming and downhill running to train the T2DM mice for eight weeks. After this, use the RT-PCR to test the mRNA expression in the left tibia. Use the WB to test the protein expression in right femur. Take the BMM and induced it differentiation into osteoclast, use the TRAP solution to dye the osteoclasts. Use the vernier caliper to test the shape size of right tibia.Results: Compared to ZC group, the mRNA expression of GPR48、OPG、RANKL、RANK, NFATc2, CTSK and protein expression of GPR48、RANKL、RANK of TC group were all significantly changed (P<0.05 or P<0.01), the number of OC was significantly increased, the width of distal coronary surface and the surface of the proximal coronary was significantly reduced(P<0.05). Compared to TC group, the mRNA expression of GPR48, OPG, RANKL, NFATc2, CTSK and the protein expression of GPR48 and RANKLof TS group were significantly changed(P<0.05 or P<0.01). The number of osteoclast was significantly reduced. The mRNA expression of GPR48, OPG, RANKL, RANK, NFATc2, CTSK and the protein expression of GPR48, RANKL, RANK were all significantly changed(P<0.05 or P<0.01). The number of osteoclast was significantly reduced, the length of tibia and width of the middle sagittal axis were significantly increased(P<0.05). Compared to TS group, the mRNA expression of OPG, CTSK and the protein expression of GPR48, RANK, RANKL of TD group were significantly changed(P<0.05 or P<0.01), OC number were drastically reduced.Conclusion: The osteoclast differentiation of type 2 diabetic mice was significantly increased. The direct mechanical stimulation activited the GPR48-RANKL pathway, which inhibited the RANK and their target gene expression, and then inhibited the osteoclast differentiation of type 2 diabetic mice. The effect of direct mechanical stimulation was better than that of indirect one.

Key words: G Protein Coupled Receptor 48, Receptor Activator for Nuclear Factor-κ B Ligand, Different Mechanical Stimulation, Type 2 Diabetes Mellitus, Osteoclast