PI3Kγ regulates cartilage damage in chronic inflammatory arthritis

Abstract

The gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) has been viewed as restricted to leukocytes mediating the regulation of chemokine-induced migration and recruitment of neutrophils, monocytes, and macrophages. In line with the observation that PI3Kgamma-deficient mice display defects in adaptive immunity, inhibition of PI3Kgamma reduces synovial inflammation in the collagen-induced arthritis mouse model of inflammatory arthritis [rheumatoid arthritis (RA)], which has been attributed to reduced influx of inflammatory cells. Challenging the concept of leukocyte-restricted PI3Kgamma function, we report here a novel, nonredundant function of PI3Kgamma as an important regulator of fibroblast-induced cartilage destruction during chronic destructive arthritis. We show that in human tumor necrosis factor transgenic mice, the loss of PI3Kgamma leads to a milder inflammatory arthritis. Interestingly, PI3Kgamma deficiency does not alter the recruitment of inflammatory cells, but significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes. In vitro analyses demonstrate that the decreased invasiveness of fibroblasts is mediated by reduced phosphorylation of Akt and extracellular signal-regulated kinase. Using a PI3Kgamma specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3Kgamma. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3Kgamma is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3Kgamma will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA.

PI3K inhibitors as potential therapeutics for autoimmune disease

“…In a K/BxN-serum transfer model of arthritis, in which neutrophils and LTB4 participate in the effector phase of the inflammatory arthritis, selective inhibition of PI3Kδ diminishes joint erosion to a level comparable to inhibition of its PI3Kγ counterpart. Induction and progression of joint destruction was profoundly reduced in the absence of both PI3K isoforms and is consistent with both isoforms being required for LTB4-mediated neutrophil chemotaxis as described earlier [21] Important differences between PI3Kγ and PI3Kδ have been noted in the mechanisms underpinning joint destruction. For example, in a model of osteoclastogenesis, the PI3Kδ selective inhibitor IC-87114 significantly inhibited the generation of osteoclasts whereas selective inhibition of PI3Kγ with AS-605240 had no effect [23].…”

“…PI3Kγ expression is significantly higher in the synovium of RA patients compared to synovium from osteoarthritis patients. Furthermore, inhibition of PI3Kγ reduced TNFα-induced MMP production in fibroblasts isolated from human RA patients [21]. This study therefore, provides further mechanistic insights into PI3Kγ in RA that extends beyond its established role in immune cell migration.…”

“…Loss of PI3Kγ in human TNFα mice led to reduced arthritis compared to controls [21]. Interestingly, PI3Kγ deficiency does not alter the recruitment of inflammatory cells as observed in the CIA model of RA, but it significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes.…”

Novel Phosphoinositide 3-Kinaseδ,γInhibitor: Potent Anti-Inflammatory Effects and Joint Protection in Models of Rheumatoid Arthritis

“…Among these, the d isoform is especially important in B cell activation, whereas the g isoform is required for chemokine signaling. In light of these activities and their abundant expression in RA synovium and fibroblast-like synoviocytes (FLSs) (Hayer et al, 2009;Bartok et al, 2012), p110g and p110d represent possible therapeutic targets for RA.…”

“…A PI3Kg inhibitor also reduces clinical severity of arthritis and neutrophil accumulation in a collagen-induced arthritis (CIA) model . PI3Kg-deficient mice or administration of PI3Kg inhibitor in antigen-induced arthritis also decreases clinical arthritis and macrophage migration (Hayer et al, 2009;Gruen et al, 2010). In the K/BxN serum transfer model, p110d…”