TSH receptor inhibitory antibody(TBAb) promotes extracellular accumulation of hyaluronic acid in pretibial myxedema primary fibroblasts via PI3K-AKT pathway / 中华内分泌代谢杂志

ABSTRACT

Objective:Pretibial myxedema (PTM) is a localized myxedema characterized by excessive dermal hya-luronan (HA) deposition and elevated serum TSH receptor antibody (TRAb). In this study, we investigated the effects of TRAb and its subtypes, stimulating antibody [TSAb (M22)] and inhibitory antibody[TBAb (K1-70)], on the synthesis of hyaluronic acid produced by PTM primary dermal fibroblasts.Methods:Normal and PTM dermal fibroblasts were isolated and stimulated with M22, K1-70, and IgG from patients respectively. HA concentration in the supernatant before and after stimulation was tested by ELISA. The protein level and phosphorylation variation of CEMIP, HAS2 and PI3K-AKT pathway were detected by Western blot.Results:IgG from patients (TRAb 8.4 IU/L) significantly stimulated the extracellular accumulation of HA in PTM primary fibroblasts. Similarly, both M22 and K1-70 also upregulated HA level in the supernatant, though K1-70 seemed much more effecitve. After treatment with IgG, M22, and K1-70, the expression of HAS2 increased and the expression of CEMIP decreased; meanwhile, p-PI3K and p-AkT increased. Among them, further study on K1-70, promoting HA production by regulating PI3K-AkT signal pathway could be inhibited by PI3K inhibitor (LY294002).Conclusion:TSAb (M22) and TBAb (K1-70), especially TBAb, increase HAS2 and inhibit CEMIP expression by activating PI3-AKT signaling pathway in PTM fibroblasts, leading to increased extracellular HA level.