Background: Corticosteroid-binding globulin (CBG) plays a critical role in regulating glucocorticoid bioavailability. During inflammation, plasma CBG behaves as an acute phase negative protein due to the down-regulation of hepatic SerpinA6 (Cbg) expression and proteolytic cleavage of CBG. CBG contains a protease-cleavage domain (RCL) that promotes the release of CBG-bound steroids at sites of inflammation. Using an established adjuvant induced arthritis (AA) model of rheumatoid arthritis, we have previously demonstrated that on day 16 post injection the peak of inflammation CBG levels decrease to ~50% of baseline values in Sprague Dawley (SD) rats that develop severe arthritis.
Objective: Characterise plasma CBG levels in a rat AA model, determining (a) when changes in CBG levels occur and (b) what causes these changes.
Methods and results: Charles River SD rats were administered complete Freuds adjuvant (0.6 mg/animal) or saline intradermally at the tail base, separated into two groups (n=12 each) and alternatively sampled (plasma) every other day until day 16 post injection. Overall, the magnitude of decline in CBG matched the severity of inflammation. In severely inflamed rats, significant decreases in CBG levels occurred 2-3 days preceding any clinical manifestation of inflammation. Decreases in CBG levels coincided with the appearance of a proteolytic product in plasma that is consistent with RCL cleavage. Moreover, in severely arthritic rats, separation of the intact CBG from the RCL-cleaved CBG demonstrated that the cleaved CBG had no steroid-binding activity.
Conclusions: In rats that become severely arthritic, decreases in CBG levels occur prior to clinical signs of arthritis, suggesting CBG may be a useful biomarker of arthritis onset and severity. In addition, the RCL-cleaved CBG in plasma lacks high-affinity steroid-binding activity. Dynamic changes in the levels and function of plasma CBG during inflammation likely modulates the tissue availability of corticosterone, effecting the inflammatory reaction and healing process.