title: Sustained intra-articular delivery of IL-1RA from a thermally-responsive elastin-like polypeptide as a therapy for post-traumatic arthritis.
abstract: Post-traumatic arthritis (PTA) is a rapidly progressive form of arthritis that develops due to joint injury, including articular fracture. Current treatments are limited to surgical restoration and stabilization of the joint; however, evidence suggests that PTA progression is mediated by the upregulation of pro-inflammatory cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α). Although these cytokines provide potential therapeutic targets for PTA, intra-articular injections of anti-cytokine therapies have proven difficult due to rapid clearance from the joint space. In this study, we examined the ability of a cross-linked elastin-like polypeptide (xELP) drug depot to provide sustained intra-articular delivery of IL-1 and TNF-α inhibitors as a beneficial therapy. Mice sustained a closed intra-articular tibial plateau fracture; treatment groups received a single intra-articular injection of drug encapsulated in xELP. Arthritic changes were assessed 4 and 8 weeks after fracture. Inhibition of IL-1 significantly reduced the severity of cartilage degeneration and synovitis. Inhibition of TNF-α alone or with IL-1 led to deleterious effects in bone morphology, articular cartilage degeneration, and synovitis. These findings suggest that IL-1 plays a critical role in the pathogenesis of PTA following articular fracture, and sustained intra-articular cytokine inhibition may provide a therapeutic approach for reducing or preventing joint degeneration following trauma.
authors: Duke University Medical Center, Box 3389, Durham, NC 27710, USA.olson016@mc.duke.edu.
authors: K A
authors: KA
authors: Kimmerling
authors: B D
authors: BD
authors: Furman
authors: D S
authors: DS
authors: Mangiapani
authors: M A
authors: MA
authors: Moverman
authors: S M
authors: SM
authors: Sinclair
authors: J L
authors: JL
authors: Huebner
authors: A
authors: A
authors: Chilkoti
authors: V B
authors: VB
authors: Kraus
authors: L A
authors: LA
authors: Setton
authors: F
authors: F
authors: Guilak
authors: S A
authors: SA
authors: Olson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein / Q000378:metabolism; D002358:Cartilage, Articular / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000293:injuries; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods; D004549:Elastin / Q000737:chemistry; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications; D055114:X-Ray Microtomography
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D003692:Delayed-Action Preparations; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D004549:Elastin; D019278:Matrix Metalloproteinase 3
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