Abstract
Progranulin (PGRN) is a recently identified adipokine that is supposed to have anti-inflammatory actions. The proinflammatory cytokine interleukin-1β (IL1β) stimulates several mediators of cartilage degradation. Toll like receptor-4 (TLR4) can bind to various damage-associated molecular patterns, leading to inflammatory condition. So far, no data exist of PGRN effects in inflammatory conditions induced by IL1β or lipopolysaccharide (LPS). Here, we investigated the anti-inflammatory potential of PGRN in IL1β- or LPS-induced inflammatory responses of chondrocytes. Human osteoarthritic chondrocytes and ATDC-5 cells were treated with PGRN in presence or not of IL1β or LPS. First, we showed that recombinant PGRN had no effects on cell viability. We present evidence that PGRN expression was increased during the differentiation of ATDC-5 cell line. Moreover, PGRN mRNA and protein expression is increased in cartilage, synovial and infrapatellar fat pad tissue samples from OA patients. PGRN mRNA levels are upregulated under TNFα and IL1β stimulation. Our data showed that PGRN is able to significantly counteract the IL1β-induced expression of NOS2, COX2, MMP13 and VCAM-1. LPS-induced expression of NOS2 is also decreased by PGRN. These effects are mediated, at least in part, through TNFR1. Taken together, our results suggest that PGRN has a clear anti-inflammatory function.
Highlights
Osteoarthritis (OA) is a multifactorial joint degenerative disease characterized by progressive destruction of articular cartilage, changes in subchondral bone, osteophyte formation and synovial inflammation
Secreted pro-inflammatory cytokines, such as Interleukin 1β (IL1β ), are critical mediators implicated in OA pathophysiology, which make them primary targets for therapeutic strategies[21]
Treatment with increasing concentrations of PGRN for 48 hours showed no toxic effect on cell vitality
Summary
Osteoarthritis (OA) is a multifactorial joint degenerative disease characterized by progressive destruction of articular cartilage, changes in subchondral bone, osteophyte formation and synovial inflammation. The group of Chuanju Liu reported that PGRN antagonised tumour necrosis factor α (TNF-α ) through binding to TNF receptors (TNFR), and exhibited an anti-inflammatory function, by suppressing the pro-inflammatory action of TNF-α in a arthritis murine models[18,19]. These authors found that deficiency of PGRN led to spontaneous OA-like phenotype in ‘aged’ mice. TLR4 activation by lipopolysaccharide (LPS) involves the production of NO28, several pro-inflammatory cytokines[29] and adipokines[5,30] that may work together boosting cartilage degradation[31]. We investigated the effect of PGRN on the expression of some inflammatory mediators and catabolic factors in IL1β - or LPS-stimulated chondrocytes for a better understanding of the underlying mechanisms implicated
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