Increased Serum GP88 (Progranulin) Concentrations in Rheumatoid Arthritis

Abstract

GP88 (Progranulin; PGRN) is a secreted glycosylated protein with important functions in several processes, including immune response and cancer growth. Recent reports have shown that PGRN is a therapeutic target for rheumatoid arthritis (RA) because of its capability to bind with tumor necrosis factor receptor (TNFR). However, the serum PGRN level in RA patients has not been investigated. We used enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of PGRN in 417 healthy subjects, 56 patients with RA and 31 patients with osteoarthritis (OA). In RA patients, we also measured the serum TNF-α and sTNFR concentration. Immunohistochemical staining of PGRN was performed using synovectomy tissue of RA patients. The serum PGRN normal range was established as 40.1 ± 8.7 ng/ml. PGRN levels were not influenced by sex or age. A significant increase in serum PGRN levels was observed in RA (50.2 ± 11.1 ng/ml) and OA (45.4 ± 6.6 ng/ml) groups compared to those in age-matched healthy controls (40.4 ± 9.9 ng/ml) (p<0.05, Tukey). Further, PGRN levels in the synovial fluid of RA patients (68.4 ± 3.4 ng/ml) were found to be significantly higher than those in OA patients (35.9 ± 16.8 ng/ml). Immunohistochemical staining of PGRN revealed that the highest positive signal was detected in macrophages. Circulating PGRN in RA patients was weakly associated with TNF-α and sTNFR 2 concentration. Furthermore, PGRN/TNF-α ratio was correlated the stage of the disease in RA patients. The concentrations of serum PGRN in RA were found to be significantly higher than those in age-matched healthy controls, although it remains to be clarified how blood PGRN is related to the pathogenesis of RA. Our results showed that the serum PGRN may be a useful approach to monitor the disease activity in RA patients.

PGRN Suppresses Inflammation and Promotes Autophagy in Keratinocytes Through the Wnt/β-Catenin Signaling Pathway

“…PGRN is expressed in a broad range of tissues and cell types including epithelial cells, neurons, macrophages, skeletal muscle, chondrocytes, adipose tissue, hematopoietic cells, and immune cells, including T cells and DCs [22,23]. The levels of PGRN were found to be elevated in cancers, rheumatoid arthritis, activated microglia in many neurodegenerative diseases, and neutrophils that promoted antibody diversity in B cells [24][25][26][27][28]. It was previously demonstrated that the expression of PGRN in intact skin is low, but in injured skin, it raises significantly [29].…”

The role of progranulin in arthritis

“…PGRN has been reported to show a therapeutic effect in vivo through its interaction with TNFRs in multiple murine models of inflammatory arthritis . Moreover, the PGRN/TNFR interaction has been confirmed and extended in multiple disease models …”

“…RA is a chronic autoimmune disease characterized by typical synovial and articular cartilage damage, finally leading to joint dysfunction with varied clinical presentations . PGRN level is elevated in both serum and synovial fluid in patients with RA, and this increased level of PGRN correlates with disease activity . Given that TNF‐α acts as a chief mediator of proinflammatory cascade responses in RA and that PGRN disturbs TNF‐α/TNFR signaling, Tang et al .…”

“…36,49 Moreover, the PGRN/TNFR interaction has been confirmed and extended in multiple disease models. 15,28,29,31,36,48,49,52,53,[56][57][58][59][60][61][62][63][64][65][66][67][68] More specifically, it has been reported that the PGRN-TNFR interaction plays an important role in the endoplasmic reticulum (ER) stress response. 60 Deletion of PGRN leads to increased susceptibility to ER stress-induced apoptosis; however, the administration of rPGRN successfully protects against ER stress-induced cell death.…”

“…74 PGRN level is elevated in both serum and synovial fluid in patients with RA, and this increased level of PGRN correlates with disease activity. 62,70,75,76 Given that TNF-␣ acts as a chief mediator of proinflammatory cascade responses in RA and that PGRN disturbs TNF-␣/ TNFR signaling, Tang et al 36 applied multiple murine models to investigate the role of PGRN in the pathogenesis of inflammatory arthritis in vivo. Under the collagen-induced arthritis model of RA, PGRN-deficient (Pgrn −/− ) mice exhibited accelerated disease onset, significantly increased arthritis severity score, and increased arthritis incidence, relative to control littermates.…”