Peripheral corticotropin releasing hormone signaling is mediated by Type 1alpha receptors in early human inflammatory arthritis

Corticotropin Releasing Hormone (CRH) is essential for modulating the effects of the inflammatory response in vivo. Elevated levels of CRH are produced locally in inflamed human synovial tissue and observations indicate a role for CRH in the pathogenesis of inflammatory joint disease. CRH action is initiated by two distinct subtypes of CRH receptors, CRH-R1 and CRH-R2, which are approximately 68% homologous. Each subtype exhibit spliced variants (α and β), displaying pharmacologically and functionally distinct isoforms. To further elucidate the peripheral biological role for CRH we examined the expression of known CRH receptors subtypes in inflamed human synovium (n = 14) and compared the expression patterns to normal synovium. Immunohistochemistry and RT-PCR confirmed enhanced expression of CRH-R1 receptors in rheumatoid (RA) and psoriatic (PsA) arthritis synovial tissue. In all tissues studied CRH R1α mRNA was identified, however, we were unable to detect other CRH R1 or CRH R2 isoforms in the same cohort of patients. Immunoreactive CRH-R1 is abundantly expressed on vascular endothelial cells and discrete perivascular cell populations, positively identified as mast cells. In contrast, in normal synovial tissue, neither CRH receptor subtype is expressed. Selective up-regulation of CRH receptors in inflamed synovial tissue indicates that CRH functions locally, in an autocrine/paracrine receptor-mediated response. Our findings suggest that CRH signaling, via CRH-R1α, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation.