Corticotropin-releasing hormone signaling in synovial tissue from patientswith early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor

Objective. Elevated levels of corticotropin-releasing hormone (CRH) are pro duced locally in inflamed human synovial tissue, and previous observations indicate a role for CRH in the pathogenesis of inflammatory joint disease. To further elucidate the biologic role of CRH at peripheral sites, we exami ned the expression of known CRH receptor subtypes in inflamed human synoviu m and compared the expression patterns in normal synovium. Methods. Immunohistochemical analysis was used to confirm enhanced expressi on of specific CRH receptor subtypes in rheumatoid arthritis (RA) and psori atic arthritis (PsA) synovium. Immunofluorescence double-labeling was used to further characterize CRH receptor-expressing cells. Reverse transcriptas e-polymerase chain reaction analysis was performed to examine CRH receptor subtype messenger RNA (mRNA) expression in RA, PsA, and normal synovial tis sue. In addition, CRH receptor expression was examined in isolated synovial endothelial cells and synoviocytes. Results. Selective up-regulation of CRH receptors in inflamed synovial tiss ue indicated that CRH functions locally, in an autocrine/paracrine receptor -mediated manner. Immunoreactive CRH receptor type 1 (CRH-R1) was expressed abundantly on vascular endothelial cells and discrete perivascular cell po pulations, identified as mast cells. In all samples of inflamed synovium. s tudied, CRH-R1 alpha mRNA was detected; however, we were unable to identify CRH-R1 beta or any CRH-R2 isoforms in samples from the same cohort of pati ents. CRH receptor subtype expression in separated synovial cell population s revealed a pattern of staining similar to that seen in vivo. In contrast, neither CRH receptor subtype was expressed in normal synovial tissue. Conclusion. Our findings suggest that CRH signaling, via CRH-R1 alpha, may play a role in both the vascular changes and the pathologic mechanisms asso ciated with joint inflammation in human arthritis.