Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis

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.

RETRACTED ARTICLE: Comparison of double-bundle anterior cruciate ligament reconstruction with and without autologous conditioned serum application

“…Inflammation is one key factor in bone wasting, and IL-1, TNFa, and other cytokines have been implicated in its aetiology [3,22,44,52]. After joint surgery and in general, it is important to control synovitis [11,12,19,36] in order to resolve (post-traumatic) joint inflammation rapidly. Treatment of inflammation with common NSAIDs does not specifically address the underlying pathways, and excessive NSAID use may interfere with the healing process.…”

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

“…Before drawing conclusions regarding the role of these proteases in the development of posttraumatic OA, these patients will need to be followed over time to evaluate if these MMPs and aggrecan degradation are more strongly correlated with the ultimate development of posttraumatic OA. Prior studies have suggested various cell-signaling mechanisms that may play a role in the development of posttraumatic OA including transforming growth factor-b, endothelin-1, interleukin-1b, and NF-jB [12,15,22,33,37,38]. Our current study should draw attention to the postinjury presence of MMPs and aggrecan degradation as potentially playing a role in progression to OA as well.…”

IL-1β, in contrast to TNFα, is pivotal in blood-induced cartilage damage and is a potential target for therapy

“…Also in murine models of inflammatory arthritis and posttraumatic osteoarthritis, no effect on cartilage destruction upon TNFa blockade has been found, corroborating this hypothesis. [36][37][38] Nevertheless, this study does not exclude a role for TNFa in inducing the reversible (short-term) changes to cartilage.…”

“…35 In experimental arthritis, blocking IL-1 prevents cartilage damage upon inflammation 36,37 as is also observed in a posttraumatic osteoarthritis model. 38 Therapeutic efficacy of IL-1RA is demonstrated in hand osteoarthritis 39 and in 2 cases suffering from another form of ironinduced arthropathy in case of hemochromatosis. 40 Opposing IL-1 was most effective when performed within 8 hours after blood exposure, but benefit was still achieved when performed until 24 hours after exposure to blood.…”