Establishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis

Abstract

Progranulin (PGRN) was found to play an anti-inflammatory and protective role in both inflammatory and degenerative arthritis (Tang et al., Science 332:478-484, 2011; Zhao et al., Ann Rheum Dis 74:2244-2253, 2015). We recently published a visualized protocol to demonstrate a surgically-induced mouse model for examining the protective role of PGRN in degenerative osteoarthritis (Zhao et al., J Vis Exp:e50924, 2014). Herein we describe a modified collagen-induced arthritis (CIA) mouse model to investigate the anti-inflammatory activity of PGRN in inflammatory arthritis. CIA model is the most commonly used autoimmune model of inflammatory arthritis which shares both immunological and pathological features with human rheumatoid arthritis. Autoimmune inflammatory arthritis is induced by immunization with an emulsion of complete Freund's adjuvant and chicken type II collagen (CII) using a modified procedure in PGRN deficient mice and control littermates. Using the protocol described here, the investigator should be able to reproducibly induce a high incidence of CIA in PGRN deficient mice and also learn how to critically evaluate the severity and incidence of this disease model.

Deficiency of Pdk1 contributes to primordial follicle activation via the upregulation of YAP expression and the pro‑inflammatory response

“…The suppression of YAP in Pdk1 knockout mice may maintain the number of primordial follicles compared with the vehicle control, indicating that YAP plays an essential role in regulating POF. The expression of the core components of Hippo pathway was altered with follicle development, and the trend of this alteration was consistent with that in follicles cultured in vitro in a recent study (19). Primordial follicle activation was accompanied by the attenuation of the Hippo pathway, therefore suggesting a close association of the Hippo pathway and primordial-to-primary transition.…”

“…A mixture of 0.75 ml ketamine (150 mg/kg) and 0.25 ml xylazine (10 mg/kg) was prepared and diluted to 5 ml with sterile 1X PBS (19). Mice (20 g) were administered a 0.125 ml mixture for anesthesia via i.p.…”

Progranulin: A conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases

“…Tang et al demonstrated that rPGRN and Atsttrin, an engineered PGRN derivative containing the minimal TNFR binding motifs, significantly alleviated the disease severity in collagen antibody-induced, collagen-induced and TNF-α transgenic inflammatory arthritis mouse models [7,48,49,81]. Both agents effectively inhibited the progression of inflammatory arthritis, and inflammatory phenotypes returned following the cessation of Atsttrin treatment [7].…”

Atsttrin Promotes Cartilage Repair Primarily Through TNFR2-Akt Pathway

“…Additionally, PGRN is important for chondrocyte proliferation and differentiation, which are functions recapitulated in animal models of cartilage defect (Feng et al, 2010;Kong et al, 2016). Recent studies reported that PGRN and its engineered derivative Atsttrin demonstrated a therapeutic effect in inflammatory and degenerative arthritis murine models through binding to tumor necrosis factor receptors (TNFRs) (Tang et al, 2011;Wei et al, 2017;Wei and Liu, 2018). Atsttrin, comprising half-units of granulins A, C, and F plus linkers P3, P4, and P5, lacks the oncogenic activity of PGRN.…”