Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice.

Joint trauma resulting in post-traumatic arthritis (PTA) is estimated to account for 12% of the 27 million Americans with symptomatic osteoarthritis (OA) (1–3). Even with optimal treatment, displaced articular fractures in the lower extremity have a 10–20% incidence of PTA (4). Despite the impact of PTA, the sequence of events leading to arthritis following an articular fracture is not fully understood. An articular fracture is a complex event with several injurious aspects, including mechanical insult to the joint tissues, release of blood and marrow contents into the joint space, and potentially systemic polytrauma (5). The inflammatory response resulting from articular fracture may be a significant factor in the progression of PTA, but its effect remains incompletely characterized (6). Pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and degenerative joints and may play an important role in the pathogenesis of PTA similar to their role in primary OA of joints in patients without antecedent injury (7, 8). The manner in which these cytokines and mediators influence sustained joint tissue inflammation and cartilage degeneration following articular trauma, however, remains unclear. In order to further characterize these mechanisms, we developed a murine model of articular fracture of the tibial plateau that results in progressive arthritic changes in the bone, articular cartilage, and other joint tissues in the C57BL/6 mouse (9). However, the inbred MRL/MpJ strain, known as the “superhealer”, is protected from PTA and does not develop degenerative joint changes following articular fracture (10). The MRL/MpJ strain is of particular interest due to its demonstrated ability to regenerate a wide array of tissues ranging from fibrocartilage in the ear to myocardium to articular cartilage (11–14). While the exact genetic differences responsible for the enhanced regenerative capability of this strain are not known, the MRL/MpJ mouse exhibits decreased levels of inducible pro-inflammatory cytokines such as IL-1 and TNF-α in response to lipopolysaccharide (LPS) stimulation (15). We hypothesized that the 'superhealer' MRL/MpJ strain of mice responds to closed articular fracture with a reduced inflammatory response compared to C57BL/6 mice. We measured synovial gene expression of inflammatory cytokines and chemokines, synovial fluid and serum levels of inflammatory cytokines, and the extent of infiltrating inflammatory cells in the synovium, at a variety of early and late time points in MRL/MpJ mice compared to C57BL/6 mice following closed articular fracture.