Thymosin β4 in rheumatoid arthritis: Friend or foe

Abstract

Abstract. Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics. IntroductionCytokines control an extensive range of inflammatory progressions that are associated with the pathogenesis of rheumatoid arthritis (RA). In arthritic joints, pro-inflammatory activities lead to the induction of autoimmunity, chronic inflammation, and, ultimately, joint damage (1). A better understanding of these pathogenic mechanisms has enabled the development of therapeutic agents to inhibit cytokine actions, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, which have greatly contributed to the management of RA patients (2,3). Biological therapies have contributed innovative improvements to RA treatment (4). However, despite these improvements, 30-50% of RA patients who are non-responders to disease-modifying antirheumatic drugs (DMARDs) fail to respond to treatment with biologic agents (5). Furthermore, radiographic joint damage can proceed even when clinical disease reduction is achieved by biologic agents (6).These results indicate that the inhibition of cytokine networks may not be satisfactory to suppress RA progression. Thus, there is a need for new therapeutic agents to target new molecules, which encouraged us to redirect our efforts to screen other therapeutic targets from joint synovial fluids of RA patients. Recently, we observed that the level of thymosin β4 (Tβ4), which has many biological roles, was significantly increased in the serum and joint fluids of RA patients (7,8). This review aims to discuss the current understanding of the potential role of Tβ4 in RA pathogenesis while addressing current knowledge regarding the association between Tβ4 and arthritic joints for RA management. Rheumatoid arthritisRA is an autoimmune inflammatory disease whose pathogenic mechanisms remain elusive. RA pathogenesis is attributed to a complex interaction between genetic and environmental factors (7). The class II major histocompatibility complex molecules HLA-DR1 and HLA-DR4 are regarded as major...

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“…Furthermore, it demonstrates anti-inflammatory properties and shields cells from oxidative stress. Studies have also suggested a possible role of Tβ4 in the pathogenesis of rheumatoid arthritis (RA), as significant increases in Tβ4 levels were observed in the synovial fluid and serum of RA patients, which appear to prevent the activation of immune responses associated with RA [35].…”

Jinwujiangu Capsule Treats Fibroblast-Like Synoviocytes of Rheumatoid Arthritis by Inhibiting Pyroptosis via the NLRP3/CAPSES/GSDMD Pathway

“…Currently, the underlying mechanism of RA is not completely understood. However, it has been found that the synovial tissue of RA shows tumor-like growth characteristics accompanied by a high concentration of inflammatory factors related to the development of RA [ 2 ]. Fibroblast-like synoviocytes (FLS) constitute the main part of the synovial tissue and play an important role in the pathogenesis of RA [ 3 ].…”