Acute inflammation is commonly associated with activation of the HPA axis leading to higher levels of circulating glucocorticoids. However, studies have indicated that some persistent inflammatory conditions, including rheumatoid arthritis, are associated with abnormal HPA responses. What causes this abnormal HPA axis response is not currently understood. A recent paper by Sattler et al. focused on the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) an activator of glucocorticoids which is believed to play a key role in regulating basal levels of circulating glucocorticoids by mediating the interconversion between the hormonally active and inactive forms. They theorized that increased expression of 11β-HSD1 within the CNS could be responsible for increasing the amount of negative feedback generated by circulating glucocorticoids, and thereby decreasing the overall HPA axis response to inflammation.
To test this they looked at two separate mouse models of immune-mediated arthritis. In the first, KRN mice transgenic for a T cell receptor that recognizes an epitope of bovine RNase were bred onto an NOD background resulting in K/BxN offspring that spontaneously develop severe arthritis. In the second model, serum from the arthritic K/BxN mice was transferred to normal mice resulting in the induction of arthritis. Both models share some features with human immune-mediated arthritis; but the spontaneous version develops as the rats age (beginning 25-35 days after birth) and remains sustained thereafter, while the serum transfer model resolves about 14 days after transfer representing a fairly short period of exposure.
Experimental and control mice from each group were sacrificed at 12 pm, age 60 days for the spontaneous K/BxN and 7 days after serum transfer for the serum induced mice, and assigned to overlapping groups for assessment of clinical scoring of joint inflammation, serum hormone levels for corticosterone (DetectX Corticosterone EIA Kit, K014-H) and ACTH, gene expression studies of 11b-HSD1 mRNA, and immunohistochemcial staining for both 11β-HSD1 and glucocorticoid receptor (GR). Clinical assessment of joint inflammation indicated that arthritis developed in both models. However, no significant difference was found in levels of Corticosterone and ACTH between mice with either type of arthritis and their corresponding controls. Suggesting that although rheumatoid arthritis in humans is associated changes in circulating glucocorticoids, these particular mouse models of arthritis may not. It is also important to note that glucocorticoid levels have well known circadian patterns, with 12pm representing the low point based on the light/dark cycle for these mice. It is possible that different results may have been observed if the mice had been sacrificed at a different time of day. Unlike the glucocorticoids, differences in 11β-HSD1 gene expression were observed between the two models. The K/BxN mice showed no change in 11β-HSD1 gene expression between arthritic and control mice in the hippocampus, hypothamalus, cerebral cortex or cerebellum. However, expression was increased by 29% in the arthritic mice. For the serum transfer mice, 11β-HSD1 was decreased by 24% in the hippocampus, and increased by 50% in the pituitary. What these changes mean and why corresponding changes in serum glucocorticoids were not observed is not entirely understood at this point. Little is really known about the exact pathways that mediate normal HPA axis activity, it is possible enzymes that breakdown corticosterone and ACTH were also activated by these immune-mediated arthritis models, or that some other feedback mechanism is preventing additional expression of the glucocorticoids.
The scope of this experiment was fairly narrow, and additional work needs to be done to further understand the results. However, understanding how the HPA axis effects arthritis may open the way for new potential treatments which could greatly improve quality of life for many people.