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.

Objective To examine the relationship between inflammation and post-traumatic arthritis in a murine intra-articular fracture model. Methods Male C57BL/6 and MRL/MpJ “superhealer” mice received tibial plateau fractures using a previously established method. Mice were sacrificed at 0 (within 4 hours), 1, 3, 5, 7, 28 and 56 days after fracture. Synovial tissue samples were taken prior to fracture and at 0, 1, 3, 5 and 7 days to examine gene expression of pro-inflammatory cytokines using RT-PCR. Synovial fluid and serum samples were collected to measure cytokine concentrations using ELISA. Histologic analysis was used to evaluate whole joint synovitis and cartilage degradation, and immunohistochemistry to evaluate the distribution of interleukin-1 in the joint tissues from all time points. Results Compared to the C57BL/6 mice, the MRL/MpJ mice had lower intra-articular and systemic inflammation following joint injury, as evidenced by lower gene expression of TNF-α and IL-1β in synovial tissue, and lower protein levels of IL-1α and IL-1β in the synovial fluid, serum, and joint tissues. Furthermore, MRL/MpJ mice had lower gene expression of macrophage inflammatory proteins (MIPs) and macrophage derived chemokine (MDC/CCL22) in synovial tissue, and reduced acute and late-stage infiltration of synovial macrophages after joint injury. Conclusion C57BL/6 mice exhibited higher levels of inflammation than MRL/MpJ mice, which are protected from post-traumatic arthritis in this model. These data thus suggest an association between joint tissue inflammation and post-traumatic arthritis in mice.

Accumulating evidence underscores the large role played by the environment in the health of communities and individuals. We review the currently known contribution of environmental exposures and pollutants on kidney disease and its associated morbidity. We review air pollutants, such as particulate matter; water pollutants such as trace elements, per- and polyfluorooakyl substances, and pesticides; and extreme weather events and natural disasters. We also discuss gaps in the evidence which at present relies heavily on observational studies and animal models, and propose using recently developed quantitative methods to help bridge the gaps. With the expected increase in the intensity and frequency of many environmental exposures in the decades to come, an improved understanding of their potential effect on kidney disease is crucial to mitigate potential morbidity and mortality.

Obesity is a risk factor for kidney disease. The role of diet in this association is difficult to study in humans. In this study, zebrafish fed a high-calorie diet, regardless of fat macronutrient composition, developed glomerulomegaly, foot process effacement, and filtration barrier dysfunction, recapitulating the changes seen in humans with obesity. Calorie restriction reversed the changes. This work suggests that macronutrient composition may be less important than total calories in the development of obesity-related kidney disease.

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