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

Abstract

Introduction: 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.

Methods: Anti-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.

Results: Intra-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.

Conclusion: These 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.

Figure 1

The effect of local intra-articular and systemic administration of IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor II (sTNFRII) on degenerative changes in joint tissues following articular fracture. Histologic images of knee joints stained with Safranin-O (red) and fast green (green) following fracture (F = femur, T = tibia, M = meniscus, white arrow = articular fracture, yellow arrow = fibrocartilage), and total joint Mankin score of arthritic degenerative changes in joint tissues for contralateral control and fractured limbs following local intra-articular (IA) administration of saline, IL-1Ra and sTNFRII (A-B) and systemic administration of saline, IL-1Ra and sTNFRII (C-D). Data presented as mean + standard deviation (*significant difference between limbs, ^#significant differences between treatment groups).

Figure 2

The effect of local intra-articular and systemic administration of IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor II (sTNFRII) on synovial inflammation of the knee joint following articular fracture. Synovitis scores of lateral and medial sides of knee joints for contralateral control and fractured limbs and histologic images of synovium stained with H&E on the medial side of joint with femur (F), tibia (T), and synovial lining near medial meniscus (M) identified by black arrows following local intra-articular (IA) administration of saline, IL-1Ra and sTNFRII (A-B) and systemic administration of saline, IL-1Ra and sTNFRII (C-D). Data presented as mean + standard deviation (*significant difference between limbs, ^#significant difference between treatment groups).

Figure 3

The effect of local intra-articular and systemic administration of IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor II (sTNFRII) on bone morphology of the tibial plateau following articular fracture. (A) Bone fraction and (B) bone density of the fractured limb as normalized to the contralateral control limb of each mouse for the tibial. Data presented as mean ± standard deviation (*difference between paired limbs is significantly different to zero, ^#significant difference between means in treatment groups). Representative axial micro computed tomography (microCT) images of the tibial plateau following (C) local intra-articular and (D) systemic administration of IL-1Ra and sTNFRII at 8 weeks following articular fracture. Bar, 1 mm.

Figure 4

Synovial fluid levels of Cartilage oligomeric matrix protein (COMP) were elevated with fracture. Synovial fluid levels following fracture for contralateral control and fractured limbs with (A) Local intra-articular (IA) and (B) systemic administration of saline, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor II (sTNFRII) (*significant difference between limbs).