Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1β-induced inflammation in human osteoarthritic chondrocytes

Abstract

Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1β (IL-1β)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-α (TNF-α) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-кB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1β caused a significant up-regulation of PARP-1 and IL-1R, resulting in NF-кB p65 nuclear translocation and phosphorylation associated with an increase of TNF-α secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP-1 inhibition suppressed IL-1β-induced reduction of cell viability and up-regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1β-induced inflammatory response through inhibiting the IL-1R/NF-кB pathway. These data suggested that PARP-1 inhibition prevents IL-1β-induced inflammation response at least partly by inhibiting the IL-1R/NF-кB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA.

The Role of Inflammation in the Pathogenesis of Osteoarthritis

“…Similarly, MMP-13, MMP-3, MMP-2, and MMP-9 increased in the cell line model of osteoarthritis [26,28]. Furthermore, several studies have investigated the MMP-13 level in osteoarthritis patients, and consistent observation is obtained, whereby the MMP-13 level increased significantly in patients with osteoarthritis [30,48,59,[73][74][75][76][77][78]. MMP-13, as a collagenase, is responsible for the degradation of type II collagen [79], which is the main collagen type in articular cartilage [80].…”

“…Other than the cytokines aforementioned, several other cytokines are involved in the pathogenesis of osteoarthritis. Some of the cytokines shown to increase in osteoarthritis are IL-18, TGFβ1 [14], IL-1 receptor (IL-1R) [59], and IL-1 alpha (IL-1α) [23]. Shan et al showed enhanced serum IL-21, IL-17A, and IFN-γ levels in patients with osteoarthritis compared to controls [15].…”

“…MMP-1 is another known collagenase frequently found to be elevated in osteoarthritis [46,53,59,82]. MMP-3, also known as stromelysin-1, cleaves type II collagen and aggrecan.…”

Sex differences in stroke therapies

“…Poly(ADP-ribose) polymerase-1. Poly(ADPribose) polymerase-1 (PARP-1) activation is a major cytotoxic mechanism and plays a key role in the pathogenesis of cardiovascular and inflammatory diseases (Beneke, 2008;Peng et al, 2012;Song et al, 2013;Sun et al, 2015). Emerging data suggest that cell death pathways in ischemic stroke are sexually dimorphic (Reeves et al, 2008;Yuan et al, 2009;Liu et al, 2011;Gibson, 2013).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…PARP inhibitors were tissue-protective in animal models of multiple sclerosis, meningitis, arthritis, stroke, and traumatic brain injury (241,(554)(555)(556)(557)(558)(559)(560). PARP inhibitors reduced neuroinflammation, edema, leukocyte infiltration, and the expression of adhesion proteins (242).…”