Nobiletin promotes fracture healing in osteoporosis rats by inhibiting STING/NF-κB signal pathway / 免疫学杂志

ABSTRACT

This study was performed to investigate the impact of nobiletin(NOB)on fracture healing in osteoporosis(OP)rats through the stimulator of interferon gene(STING)/nuclear transcription factor kappa B(NF-κB)signal pathway.A rat model of OP fracture was established by ovariectomy and right femoral shaft fracture intramedullary fixation;the rats after modeling were randomly grouped into model group,high dose(NOB-H,30 mg/kg NOB),medium dose(NOB-M,20 mg/kg NOB),low dose(NOB-L,10 mg/kg NOB)NOB group and NOB-H+ STING activator(DMXAA)group(30 mg/kg NOB+25 mg/kg DMXAA),and 18 rats experienced only ovaries expose were used as sham operation group.After the intervention,the fracture healing status of rats were measured;Micro-CT was used to detect the changes of bone trabecular microstructure in rats;commercial kits were used to detect the serum levels of bone metabolism related indicators(alkaline phosphatase(ALP),calcium,phosphorus)and inflammatory factors(tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β));HE was used to detect the morphological changes and trabecular area of femur,while Western blot was applied to detect the expression of STING/NF-κB pathway related proteins.Compared with the control group,the fracture line in the model group was clear,the trabecular structure was disordered and the gap was large,furthermore,the levels of TNF-α and IL-1β,the expression of STING and p-NF-κB p65/NF-κB p65 were significantly increased,the trabecular area,the levels of ALP,calcium,phosphorus,and bone mineral density(BMD),bone volume fraction(BV/TV),bone trabecular number(Tb.N)and bone trabecular thickness(Tb.Th)were significantly decreased(P<0.05);compared with the model group,the fracture line of NOB-L group,NOB-M group and NOB-H group gradually blurred,the trabecular structure arranged orderly,and the gap gradually decreased,and the trend of the index changes mentioned above were opposite to that of the model group(P<0.05).STING activators attenuated the promotion of fracture healing by NOB in OP rats and increased the inflammatory responses.In conclusion,NOB can reduce inflammatory reaction and promote fracture healing in OP rats,which may be related to the inhibition of STING/NF-κB signal pathway.