The PEA-15 protein regulates autophagy via activation of JNK.

PEA-15/PED (phosphoprotein enriched in astrocytes 15 kDa/phosphoprotein enriched in diabetes) is a death effector domain-containing protein which is known to modulate apoptotic cell death. The mechanism by which PEA-15 inhibits caspase activation and increases ERK (extracellular-regulated kinase) activity is well characterized. Here, we demonstrate that PEA-15 is not only pivotal in the activation of the ERK pathway but also modulates JNK (c-Jun N-terminal kinase) signaling. Upon overexpression of PEA-15 in malignant glioma cells, JNK is potently activated. The PEA-15-induced JNK activation depends on the phosphorylation of PEA-15 at both phosphorylation sites (serine 104 and serine 116). The activation of JNK is substantially inhibited by siRNA-mediated down-regulation of endogenous PEA-15. Moreover, we demonstrate that glioma cells overexpressing PEA-15 show increased signs of autophagy in response to classical autophagic stimuli such as ionizing irradiation, serum deprivation, or rapamycin treatment. In contrast, the non-phosphorylatable mutants of PEA-15 are not capable of promoting autophagy. The inhibition of JNK abrogates the PEA-15-mediated increase in autophagy. In conclusion, our data show that PEA-15 promotes autophagy in glioma cells in a JNK-dependent manner. This might render glioma cells more resistant to adverse stimuli such as starvation or ionizing irradiation.

The potential of digital X-ray radiogrammetry (DXR) in the assessment of osteopenia in children with chronic inflammatory bowel disease.

BACKGROUND: Loss of bone mass is a known complication of chronic inflammatory bowel disease (IBD) in children. The gold standard in the evaluation of bone mineral density (BMD) is dual energy X-ray absorptiometry (DXA). OBJECTIVE: In this preliminary study we evaluated digital X-ray radiogrammetry (DXR) which estimates BMD (DXR-BMD) from hand radiographs in children with IBD. MATERIALS AND METHODS: A total of 26 children with IBD (10 girls, 16 boys; age range 10-18 years) underwent DXR for the calculation of DXR-BMD and metacarpal index (DXR-MCI) using the Pronosco X-posure system. The results were compared with a local reference database and correlated with the results of DXA. RESULTS: DXR-BMD was 0.36-0.56 g/cm(2) (median 0.46 g/cm(2)) in Crohn disease patients and 0.38-0.63 g/cm(2) (median 0.48 g/cm(2)) in ulcerative colitis patients. DXR-MCI was 0.29-0.49 in Crohn disease patients and 0.28-0.53 in ulcerative colitis patients. The Z-scores were reduced to <-1 SD in five Crohn disease patients and in six ulcerative colitis patients. The coefficients (r) for the correlations between DXR-BMD and DXA-BMD were 0.78 for the lumbar spine and 0.61 for the proximal femur (P<0.01), and between DXR-MCI and DXA-BMD were 0.78 for the lumbar spine and 0.51 for the proximal femur (P<0.01). CONCLUSIONS: DXR seems to be able to estimate cortical osteopenia in children with chronic IBD. The DXR results showed a positive correlation with DXA results.

Metacarpal Index Estimated by Digital X-ray Radiogrammetry as a Tool for Differentiating Rheumatoid Arthritis Related Periarticular Osteopenia.

UNLABELLED: To investigate Metacarpal Index (MCI) and Bone Mineral Density (BMD) estimated by Digital X-ray Radiogrammetry (DXR) with respect to its ability to quantify severity-dependent variations of bone mineralisation in patients with early rheumatoid arthritis compared to Dual Energy X-ray Absorptiometry (DXA), 122 patients underwent a prospective analysis of BMD and MCI by DXR, whereas both DXR-parameters were estimated from plain radiographs of the non-dominant hand. In comparison DXA measured BMD on total femur and lumbar spine (L2-L4). Additionally Steinbrocker Stage was assessed to differentiate the severity of rheumatoid arthritis (RA). Disease activity of RA was estimated by C-reactive Protein (CRP; in mg/l), Erythrocyte Sedimentation Rate (ESR in mm/1st hour) and by the disease activity score with 28-joint count (DAS 28). In consequence, The DXR-parameters, in particular DXR-MCI, revealed significant associations to age, Body Mass Index, CRP, DAS 28 and Steinbrocker graduation; no significant associations could be verified between DXA-parameters and all characteristics of disease activity and severity of RA. The highest correlation was found between DXR-MCI and DXR-BMD with R=0.89 (independent from severity of RA). In all patients DXR-MCI significantly decreased (-14.3%) from 0.42 ± 0.09 (stage 1) to 0.36 ± 0.07 (stage 2) dependent on severity of RA. The comparable relative reduction of DXR-BMD was -11.1%. The group of patients with minor disease activity (DAS 28>5.1) showed a significant flattened reduction (-11.4%) for DXR-MCI from 0.44 ± 0.08 (stage 1) to 0.39 ± 0.08 (stage 2). For accentuated disease activity (DAS 28>5.1) the DXR-MCI revealed a pronounced reduction (-23.1 %). No significant declines were observed for DXA-BMD of the lumbar spine and total femur in all patients as well as dependent on disease activity. CONCLUSION: DXR can exactly quantify cortical thinning of the metacarpal bones and can identify cortical demineralisation in patients suffering from early rheumatoid arthritis surpassing DXA-measurements at axial bone sites. In this context DXR-MCI seems to be the most sensitive parameter for differentiation of patients with minor or accentuated disease activity following severity-dependent cortical bone loss.