Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Lytic bone diseases and in particular osteoporosis are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, osteoporosis poses a major global health-care problem due to the growth of the elderly population. Recently, it was found that the gene regulatory transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is involved in bone metabolism. C/EBPβ occurs as different protein isoforms of variable amino terminal length, and regulation of the C/EBPβ isoform ratio balance was found to represent an important factor in osteoclast differentiation and bone homeostasis. Interestingly, adjustment of the C/EBPβ isoform ratio by the process of translational control is downstream of the mammalian target of rapamycin kinase (mTOR), a sensor of the nutritional status and a target of immunosuppressive and anticancer drugs. The findings imply that modulating the process of translational control of C/EBPβ isoform expression could represent a novel therapeutic approach in osteolytic bone diseases, including cancer and infection-induced bone loss

JunD/AP-1-Mediated Gene Expression Promotes Lymphocyte Growth Dependent on Interleukin-7 Signal Transduction

Interleukin-7 (IL-7) is an essential cytokine for lymphocyte growth that has the potential for promoting immune reconstitution. This feature makes IL-7 an ideal candidate for therapeutic development. As with other cytokines, signaling through the IL-7 receptor induces the JAK/STAT pathway. However, the broad scope of IL-7 regulatory targets likely necessitates the use of other signaling components whose identities remain poorly defined. To this end, we used an IL-7 dependent T-cell line to examine how expression of the glycolytic enzyme, Hexokinase II (HXKII) was regulated by IL-7 in a STAT5-independent manner. Our studies revealed that IL-7 promoted the activity of JNK (Jun N-terminal Kinase), and that JNK, in turn, drove the expression of JunD, a component of the Activating Protein 1 (AP-1) transcription factors. Gel shifts showed that the AP-1 complex induced by IL-7 contained JunD but not c-Fos or c-Jun. Inhibition of JNK/JunD blocked glucose uptake and HXKII gene expression, indicating that this pathway was responsible for promoting HXKII expression. Because others had shown that JunD was a negative regulator of cell growth, we performed a bioinformatics analysis to uncover possible JunD-regulated gene targets. Our search revealed that JunD could control the expression of proteins involved in signal transduction, cell survival and metabolism. One of these growth promoters was the oncogene, Pim-1. Pim-1 is an IL-7-induced protein that was inhibited when the activities of JNK or JunD were blocked, showing that in IL-7 dependent T-cells JunD can promote positive signals transduced through Pim-1. This was confirmed when the IL-7-induced proliferation of CD8 T-cells was impaired upon JunD inhibition. These results show that engagement of the IL-7 receptor drives a signal that is more complex than the JAK/STAT pathway, activating JNK and JunD to induce rapid growth stimulation through the expression of metabolic and signaling factors like HXKII and Pim-1

Description of participants in the "Atout Age Mobility" prevention workshops at the University Hospital Center of La Réunion : a prospective study

Introduction As the population ages, loss of autonomy is becoming a priority public health issue. "Atout Age Mobility" prevention interventions for seniors aim to limit frailty, which is a predictive and reversible factor in the loss of autonomy and disability. Objectives The objective of this study is to describe the impact of these interventions on the physical performance and quality of life of a pilot sample of participants. Design We conducted a prospective study named 5P PILOT with 3 months of follow up. Settings Subjects were recruited by convenience sampling from participants in the "Atout Age Mobility" workshops at Saint Joseph from 04/09/2017 to 29/01/2019. Participants Retired people over 55 years old with no contraindications to physical activity recruited from participants in the "Atout Age Mobility" workshops in Saint Joseph. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): All participants completed 12 weeks of physical exercise called the "Atout Age Mobility" workshop, which lasted 60 minutes each week and was supervised by physical activity coaches. Main Outcome(s) and Measure(s) Physical performance was assessed by Short physical performance battery (SPPB), 10-m gait speed and grip strength measurement. Quality of life through the SF-36 test. Results Ninety-six patients were included and 55 (57.3%) completed the study. There was a significant improvement in gait speed (1.35 +/- 0.26m/s vs. 1.27 +/- 0.24m/s; p=0.008). There was no significant change in SF-36, grip strength dominant arm and SPPB at the 0.01 significance level. Conclusion The "Atout Ages Mobility" workshops seem to significantly improve gait speed but not other aspects of physical performance or quality of life