Semaphorins: From Angiogenesis to Inflammation in Rheumatoid Arthritis

Abstract

Objective To study the potential implication of semaphorins in the pathogenesis of rheumatoid arthritis (RA). Patient and methods microarray experiments were performed on Affymetrix GeneChip® Human Exon 1.0 ST Arrays in RA and control endothelial cell (ECs) derived from circulating progenitors. Expression of class 3 and 4 Semaphorins (SEMA) and their receptors was assessed by immunohistochemistry in the synovial tissue and by ELISA in the serum of RA patients and controls. Results micro‐array analysis revealed differential expression of class 3/4 semaphorins and their receptors in RA ECs. SEMA4A, Plexin‐D1 and neuropillin‐1 mRNA levels were markedly increased in RA ECs by 1.75, 2.21 and 1.68 fold, respectively. TNFα stimulation led to a 2‐fold increase of SEMA4A mRNA levels in RA ECs, and deficient SEMA4A expression modified RA EC angiogenic properties. Class 3/4 semaphorins as well as their receptors were overexpressed in RA synovial tissue. A respective 1.30 and 1.54‐fold increase of SEMA4A and SEMA3E, as well as a 24% decrease of SEMA3A was detected in the serum of RA patients. SEMA4A, SEMA4D and SEMA3A serum levels correlated with inflammation and proangiogenic markers. In 2 independent cohorts of patients in low disease activity or remission, SEMA4A identified patients with residual disease activity. Conclusion Gene expression profiling of ECs identified class 3/4 semaphorins as potential biomarkers and therapeutic candidates in RA, with confirmed overexpression in ECs, synovial vessels and serum, and correlation with validated markers of inflammation and angiogenesis. Thus, semaphorins might be novel and appealing EC‐derived inflammatory and proangiogenic targets in RA.