Abstract
This paper investigates the protective effect of interleukin-1 receptor antagonist (IL-1Ra) released from hyaluronic acid chitosan (HA-CS) microspheres in a controlled manner on IL-1β-induced inflammation and apoptosis in chondrocytes. The IL-1Ra release kinetics was characterized by an initial burst release, which was reduced to a linear release over eight days. Chondrocytes were stimulated with 10 ng/ml IL-1β and subsequently incubated with HA-CS-IL-1Ra microspheres. The cell viability was decreased by IL-1β, which was attenuated by HA-CS-IL-1Ra microspheres as indicated by an MTT assay. ELISA showed that HA-CS-IL-1Ra microspheres inhibited IL-1β-induced inflammation by attenuating increases in NO2 − and prostaglandin E2 levels as well as increase in glycosaminoglycan release. A terminal deoxyribonucleotide transferase deoxyuridine triphosphate nick-end labeling assay revealed that the IL-1β-induced chondrocyte apoptosis was decreased by HA-CS-IL-1Ra microspheres. Moreover, HA-CS-IL-1Ra microspheres blocked IL-1β-induced chondrocyte apoptosis by increasing B-cell lymphoma 2 (Bcl-2) and decreasing Bcl-2-associated X protein and caspase-3 expressions at mRNA and protein levels, as indicated by reverse-transcription quantitative polymerase chain reaction and western blot analysis, respectively. The results of the present study indicated that HA-CS-IL-1Ra microspheres as a controlled release system of IL-1Ra possess potential anti-inflammatory and antiapoptotic properties in rat chondrocytes due to their ability to regulate inflammatory factors and apoptosis associated genes.
Highlights
Osteoarthritis (OA) is an age-related degenerative disease of the joints leading to progressive cartilage damage [1]
With regard to the variation in composition and structure, a slight increase in the microsphere size was observed from CS-interleukin1 receptor antagonist (IL-1Ra) (Figure 1(c)) to hyaluronic acid chitosan (HA-CS)-IL-1Ra microspheres (Figure 1(d))
It is widely accepted that increases in IL-1β levels can lead to the production and accumulation of high levels of proinflammatory cytokines and trigger apoptosis in chondrocytes [26]
Summary
Osteoarthritis (OA) is an age-related degenerative disease of the joints leading to progressive cartilage damage [1]. Interleukin-1β (IL-1β) is one of the most important inflammatory cytokines and has a central role in the pathogenesis of OA [3]. IL-1β has been reported to accelerate the aging and increase the chondrocyte apoptosis which is thought to be important in OA [4,5,6]. The inhibition of the IL-1β pathway presents a promising means of preventing inflammation and apoptosis in chondrocytes in the pathogenesis of OA. One of the major endogenous inhibitors of the IL-1 pathway is the anti-inflammatory cytokine interleukin receptor antagonist (IL-1Ra) which binds the IL-1RI with similar specificity and affinity to that of IL-1, while it does not activate any downstream signals [7, 8]. IL-1Ra has been demonstrated to inhibit the progression of OA, suggesting that IL-1Ra is a suitable target for the treatment of OA [9, 10]
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