IL-1ra delivered from polylactic-co-glycolic acid microspheres attenuates IL-1β-mediated degradation of nucleus pulposus in vitroReportar como inadecuado




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Arthritis Research and Therapy

, 14:R179

First Online: 03 August 2012Received: 30 April 2012Revised: 13 July 2012Accepted: 03 August 2012

Abstract

IntroductionInflammation plays a key role in the progression of intervertebral disc degeneration, a condition strongly implicated as a cause of lower back pain. The objective of this study was to investigate the therapeutic potential of polylactic-co-glycolic acid PLGA microspheres loaded with interleukin-1 receptor antagonist IL-1ra for sustained attenuation of interleukin-1 beta IL-1β mediated degradative changes in the nucleus pulposus NP, using an in vitro model.

MethodsIL-1ra was encapsulated in PLGA microspheres and release kinetics were determined over 35 days. NP agarose constructs were cultured to functional maturity and treated with combinations of IL-1β and media conditioned with IL-1ra released from microspheres at intervals for up to 20 days. Construct mechanical properties, glycosaminoglycan content, nitrite production and mRNA expression of catabolic mediators were compared to properties for untreated constructs using unpaired Student-s t-tests.

ResultsIL-1ra release kinetics were characterized by an initial burst release reducing to a linear release over the first 10 days. IL-1ra released from microspheres attenuated the degradative effects of IL-1β as defined by mechanical properties, glycosaminoglycans GAG content, nitric oxide production and mRNA expression of inflammatory mediators for 7 days, and continued to limit functional degradation for up to 20 days.

ConclusionsIn this study, we successfully demonstrated that IL-1ra microspheres can attenuate the degradative effects of IL-1β on the NP for extended periods. This therapeutic strategy may be appropriate for treating early-stage, cytokine-mediated disc degeneration. Ongoing studies are focusing on testing IL-1ra microspheres in an in vivo model of disc degeneration, as a prelude to clinical translation.

Abbreviations3Dthree-dimensional

ADAMTS-4a disintegrin and metalloproteinase with thrombospondin motifs 4

CMchemically defined medium

DMEMDulbecco-s modified Eagle-s medium

FBSfetal bovine serum

GAGglycosaminoglycan

GAPDHglyceraldehyde 3-phosphate dehydrogenase

IL-1βinterleukin-1 beta

IL-1rainterleukin-1 receptor antagonist

IL-6interleukin-6

INOSinducible nitric oxide synthase

MMPmatrix metalloproteinase

NPnucleus pulposus

PBSphosphate-buffered saline

PLGApolylactic-co-glycolic acid

PSFpenicillin-streptomycin-fungizone

PVApolyvinyl alcohol

rhIL-1rarecombinant human interleukin-1 receptor antagonist

rpmrevolutions per minute

SEMscanning electron microscopy

TGF-β3transforming growth factor-beta 3

TLR-4Toll-like receptor 4

TNF-αtumor necrosis factor-alpha.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3932 contains supplementary material, which is available to authorized users.

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Autor: Deborah J Gorth - Robert L Mauck - Joseph A Chiaro - Bhavana Mohanraj - Nader M Hebela - George R Dodge - Dawn M Elli

Fuente: https://link.springer.com/







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