Bone marrow-derived c-jun N-terminal kinase-1 (JNK1) mediates liver regeneration.

Liver regeneration is controlled by a complex network of signaling molecules, and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study, we aimed to characterize and define the cell-type-specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1(Δhepa)) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1(Δhepa) and JNK1(-/-) animals and investigated time-points up to 72 h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1(-/-) compared to JNK1(Δhepa) and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48 h after PH in JNK1(-/-) compared with JNK1(Δhepa) and WT livers. In JNK1(-/-) mice, our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL-6/STAT3/SAA-1 cascade. Additionally, CD11b(+)Ly6G(+)-cells were decreased in JNK1(-/-) compared with JNK1(Δhepa) and WT animals after PH. The transplantation of bone marrow-derived JNK1(-/-) into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1(-/-) into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration, and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response.

Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury.

BACKGROUND & AIMS: Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signalling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMO(Δhepa)), a genetic model of chronic inflammatory liver injury. METHODS: We generated Jnk1(-/-)/NEMO(Δhepa) and Jnk2(-/-)/NEMO(Δhepa) mice by crossing NEMO(Δhepa) mice with Jnk1 and Jnk2 global deficient animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analysed the expression of NEMO and p-JNK in human diseased-livers. RESULTS: Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMO(Δhepa) mice. Conversely, Jnk2(-/-)/NEMO(Δhepa) displayed hepatic inflammation. By using bone marrow transfer, we observed that Jnk1 in haematopoietic cells had an impact on the progression of chronic liver disease in NEMO(Δhepa) livers. These findings are of clinical relevance since NEMO expression was downregulated in hepatocytes of patients with HCC whereas NEMO and p-JNK were expressed in a large amount of infiltrating cells. CONCLUSIONS: A synergistic function of Jnk1 in haematopoietic cells and hepatocytes might be relevant for the development of chronic liver injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.

Tibial Slope Strongly Influences Knee Stability After Posterior Cruciate Ligament Reconstruction: A Prospective 5- to 15-Year Follow-up.

BACKGROUND: The reported failure rate after posterior cruciate ligament (PCL) reconstruction remains high. Previous studies have shown that the tibial slope (TS) influences sagittal plane laxity. Consequently, alterations of TS might have an effect on postoperative knee stability after PCL reconstruction. HYPOTHESIS: We hypothesized that flattening of TS is associated with increased posterior laxity after PCL reconstruction. STUDY DESIGN: Cohort study; Level of evidence 3. METHODS: This study consisted of 48 patients who underwent PCL reconstruction in a single-surgeon series. Eight patients underwent an isolated PCL reconstruction, 27 patients underwent an additional posterolateral corner reconstruction, and 13 patients underwent a combined reconstruction of the PCL, anterior cruciate ligament, and posterolateral corner. Three blinded observers measured TS and the side-to-side difference (SSD) of posterior tibial translation (PTT) before and after PCL reconstruction using standardized stress radiographs. The minimum follow-up was 5 years. RESULTS: At a mean follow-up of 103 months (range, 65-187), the mean SSD of PTT was significantly reduced (10.9 ± 2.9 vs 4.9 ± 4.3 mm; P < .0001). The mean TS was 8.0° ± 3.7° (range, 1°-14.3°) for the operated knee and 7.9° ± 3.2° (range, 2°-15.3°) for the contralateral knee. There was a statistically significant correlation between TS and PTT ( r = -0.77 and R2 = 0.59; P < .0001). In addition, there was a significant correlation between TS and the postoperative reduction of PTT ( r = 0.74 and R2 = 0.55; P < .0001). Subgrouping according to the number of operated ligaments showed no significant differences regarding TS or the mean reduction of PTT. CONCLUSION: Flattening of TS is associated with a significantly higher remaining PTT as well as a lower reduction of PTT. Notably, these results are irrespective of sex and number of ligaments addressed. Thus, isolated soft tissue procedures in PCL deficiency may only incompletely address posterior knee instability in patients with flattening of the posterior slope.