Central Role of Semaphorin 3B in a Serum‐Induced Arthritis Model and Reduced Levels in Patients With Rheumatoid Arthritis

Abstract

Objective. Semaphorin 3B (Sema3B) decreases the migratory and invasive capacities of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and suppresses expression of matrix metalloproteinases. We undertook this study to examine the role of Sema3B in a mouse model of arthritis and its expression in RA patients.Methods. Clinical responses, histologic features, and FLS function were examined in wild-type (WT) and Sema3B −/− mice in a K/BxN serum transfer model of arthritis. Protein and messenger RNA expression of Sema3B in mouse joints and murine FLS, as well as in serum and synovial tissue from patients with arthralgia and patients with RA, was determined using enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, and RNA sequencing. FLS migration was determined using a wound closure assay.Results. The clinical severity of serum-induced arthritis was significantly higher in Sema3B −/− mice compared to WT mice. This was associated with increased expression of inflammatory mediators and increased migratory capacity of murine FLS. Administration of recombinant mouse Sema3B reduced the clinical severity of serum-induced arthritis and the expression of inflammatory mediators. Sema3B expression was significantly lower in the synovial tissue and serum of patients with established RA compared to patients with arthralgia. Serum Sema3B levels were elevated in patients with arthralgia that later progressed to RA, but not in those who did not develop RA; however, these levels drastically decreased 1 and 2 years after RA development.Conclusion. Sema3B expression plays a protective role in a mouse model of arthritis. In RA patients, expression levels of Sema3B in the serum depend on the disease stage, suggesting different regulatory roles in disease onset and progression.

Recent developments in the synovial fibroblast pathobiology field in rheumatoid arthritis

“…Therefore, the CD13/B1R axis involving RASF may contribute to the inflammatory activation of RASF. Semaphorin 3B was previously shown to reduce migration and invasion as well as the expression of matrix-degrading enzymes by human RASF, properties that could be confirmed recently in animal models [25]. Here, semaphorin 3B knockout animals showed a significantly higher severity of serum-induced arthritis compared with wildtype controls whereas administration of semaphorin 3b reduced clinical severity in this model.…”

ROCK inhibition with Y-27632 reduces joint inflammation and damage in serum-induced arthritis model and decreases in vitro osteoclastogenesis in patients with early arthritis

“…Histological analysis was performed as previously described ( 28 , 29 ). Right hind limbs were prepared for histological analysis by dissecting the skin and sectioning the ankle joints.…”

Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis

“…Both in K/BxN STIA and in RA patients, delayed progression of joint damage upon administration of recombinant sema3B was observed. These data clearly suggest that K/BxN STIA can be effectively modulated in preclinical studies once the target mechanism has been identified ( 63 ).…”