Abstract
IntroductionPost-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee.MethodsAnti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid.ResultsIntra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues.ConclusionThese results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA.
Highlights
Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture
To assess the effect of drug delivery, native levels of mouse IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII) were quantified in serum obtained at time of sacrifice in those animals that received either drug using commercially available ELISA kits (IL-1Ra, MRA00; sTNFRII, MRT20; R&D Systems)
Serum quantification of locally delivered drugs demonstrated that local intraarticular injection of either IL-1Ra or sTNFRII into the joint space subsequently migrated to the serum on days 1 and 3 and was cleared fully from the circulation by day 14
Summary
Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee. Following joint injury, elevated synovial fluid levels of pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factoralpha (TNF-α), have been reported with the highest levels observed acutely within the first 24 h after injury [12,13,14,15]. Cartilage-derived biomarkers are significantly increased within the first month following knee injury [13,22,23], which suggests that significant cartilage damage is occurring within weeks of trauma and that early intervention may influence the long-term sequela of joint degeneration [24]
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