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.