Fri., 10/5/12 Basic Science, PAPER #49, 1:00 pm OTA-2012
Intra-Articular Inhibition of Interleukin-1 Prevents Posttraumatic Arthritis Following Articular Fracture in the Mouse Knee
Daniel S. Mangiapani, MD; Evan M. Zeitler, BA; Bridgett D. Furman, BS;
Janet L. Huebner, MS; Virginia B. Kraus, MD, PhD; Farshid Guilak, PhD; Steven A. Olson, MD;
Duke University Medical Center, Durham, North Carolina, USA
Purpose: Posttraumatic arthritis (PTA) is an accelerated form of osteoarthritis that commonly follows joint trauma, such as articular fracture. While the mechanisms underlying joint degeneration are not fully understood, we have developed a mouse model that predictably induces PTA and suggests that proinflammatory cytokines such as interleukin-1 (IL-1) play a role in its pathogenesis. We hypothesized that exogenous inhibition of systemic or local IL-1 acutely following articular fracture will reduce arthritic changes in the joint.
Methods: Male C57BL/6 mice (n = 48) were subjected to a closed intra-articular fracture (fx) of the tibial plateau using an established protocol. Immediately following fracture, IL-1 receptor antagonist (IL-1Ra) was administered using a continuous systemic infusion of either IL-1Ra (n = 12) or saline (n = 11) for 4 weeks. A second group received a single intra-articular injection of either IL-1Ra (n = 9) or saline (n = 8) immediately following fracture. A group with fracture only and no treatment was also included (n = 8), as well as nonfracture controls (n = 3).
Results: Mice who received a single intra-articular injection of IL-1Ra demonstrated significantly reduced cartilage degeneration in the fractured knee compared to all other treatment groups except nonfracture controls (Figure 1, A). Furthermore, the local IL-1Ra group qualitatively displayed preserved articular cartilage compared to the other treatment groups (Figure 1, B). Mice receiving local IL-1Ra demonstrated reduced synovial inflammation in the medial femur and medial tibia with no statistical difference from the contralateral nonfractured knee (Figure 2, A). Furthermore, the local IL-1Ra group qualitatively displayed reduced inflammatory changes in the synovium compared with other treatment groups receiving fractures (Figure 2, B).
Conclusion: The observation that local administration of IL-1Ra immediately following fracture prevented arthritic changes suggests a critical role of intra-articular and synovial inflammation in the development of PTA. Furthermore, our results are consistent with observations of the MRL/MpJ strain that is protected from PTA. This study may provide evidence for conducting larger clinical trials of anticytokine therapy for acute joint trauma.
Figure 1 A Total Mankin score, all treatment groups. *P <0.05 compared to local IL-1Ra. #P <0.05 compared to right (non-fx) limb. **Left limb not fractured in non-fx controls. B, Safranin O/fast green staining of left (fx) limb.
Figure 2 A Synovitis score; #P <0.05 compared to right limb; **Left limb not fractured in non-fx controls.
Acknowledgements: Arthritis Foundation; NIH AR50245, AG15768, AR48852, AR48182.
Alphabetical Disclosure Listing (808K PDF)
• The FDA has not cleared this drug and/or medical device for the use described in this presentation (i.e., the drug or medical device is being discussed for an “off label” use). ◆FDA information not available at time of printing. Δ OTA Grant.