Wnt5a/Ror2 promotes Nrf2-mediated tissue protective function of astrocytes after brain injury.

Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase-induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up-regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1-mediated transcription of a gene encoding the Ror-family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage.

Functional knee phenotypes: A helpful classification tool for visualizing potential femoral varus in restricted kinematic alignment total knee arthroplasty in Japan.

PURPOSE: Restricted kinematic alignment (rKA) is a modified technique of kinematically aligned total knee arthroplasty (TKA) within a safe alignment range for long-term implant survivorship. The purpose of this study was to clarify (1) the distribution of functional knee phenotypes in patients who underwent TKA in Japan and (2) whether the application of this classification results in anatomically neutral alignment after rKA TKA. METHODS: Overall, 114 TKA surgeries (mechanical alignment [MA]: 49; rKA: 65) were performed. The joint line orientation angle (JLOA), hip-knee-ankle angle (HKA), femoral mechanical angle (FMA) and tibial mechanical angle (TMA) were obtained. The knees were categorized using a functional knee phenotype classification. Clinical evaluations, including the Knee Injury and Osteoarthritis Outcome, 12-question Forgotten Joint and Oxford Knee Scores, were performed 3 years postoperatively. Between-group comparisons were made. RESULTS: The most common preoperative functional knee phenotype was VARHKA 3° + NEUFMA 0° + VARTMA 3° (11.4%). In the preoperative population, 51 knees (44.7%) had VARFMA ≥ 3°. Postoperatively, the most common functional knee phenotype was NEUHKA 0° + VARFMA 3° + VALTMA 3° (14 knees, 28.6%) in the MA and NEUHKA 0° + NEUFMA 0° + NEUTMA 0° in the rKA group. The percentage of postoperative JLOA within ±3° from the floor was 27% and 72% in the MA and rKA groups, respectively (p < 0.001). The functional knee phenotype after rKA TKA was neutrally reproduced, and the joint line was more parallel to the ground in the standing position than that of MA. Between-group differences in clinical outcomes were not significant. CONCLUSION: The application of functional knee phenotyping to knee osteoarthritis in Japan suggested the presence of racial morphological characteristics. This classification could help better visualize potential femoral varus, contributing to protocol deviation in applying restricted KA TKA. LEVEL OF EVIDENCE: Level IV.