Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11β-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11β-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11β-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis.
Janko Sattler, Jinwen Tu, Shihani Stoner, Jingbao Li, Frank Buttgereit, Markus J Seibel, Hong Zhou and Mark S Cooper
Tatiana V Novoselova, Peter J King, Leonardo Guasti, Louise A Metherell, Adrian J L Clark and Li F Chan
The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r − / −) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap − / − mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap − / − mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.
W Liu, Y Wang, X Han, X Cai, Y Zhu, M Zhang, S Gong, J Li and L Ji
Type 1 diabetes (T1DM) is associated with a higher risk of premature death, but there are factors in certain patients with T1DM that protect them from complications and premature death. These factors had not been identified in non-Caucasian populations, so we aimed to identify factors that protect against the development of diabetic nephropathy (DN) and diabetic retinopathy (DR) in long-standing T1DM in China.
Ninety-five T1DM patients with >30 years’ duration of diabetes were enrolled in this nationwide study. Differences between groups of patients with and without complications were compared, and multivariable regression analysis was used to evaluate the relationships between candidate protective factors and the development of DN or DR.
Thirty of the participants did not have DN and the same amount did not have DR. 6/52 of participants without DN were from a rural area, whereas 11/28 of participants with DN had been born in a rural area (P = 0.005). Systolic blood pressure (SBP) was higher in participants with DN (135 ± 26 mmHg vs 121 ± 13 mmHg; P = 0.002). In participants without DR, 27/30 were married or cohabitating, and only 3/30 were single, never married, or widowed, but for those with proliferative DR (PDR), 13/26 had been married (P = 0.003). A rural or urban origin and SBP were associated with DN in the multivariable analysis.
we have shown that higher socioeconomic status, indicated by birth in an urban area, and being married or cohabitating, are accompanied by better blood pressure control and a lower risk of microvascular complications in Chinese patients with long-standing T1DM. These findings illustrate the importance of improving care for patients with T1DM in China.