TGF-β Inducible Early Gene 1 Regulates Osteoclast Differentiation and Survival by Mediating the NFATc1, AKT, and MEK/ERK Signaling Pathways

TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment. As reported previously, TIEG1−/− mice have decreased cortical bone thickness and vertebral bone volume and have increased spacing between the trabeculae in the femoral head relative to wildtype controls. Here, we have investigated the role of TIEG1 in osteoclasts to further determine their potential role in mediating this phenotype. We have found that TIEG1−/− osteoclast precursors differentiated more slowly compared to wildtype precursors in vitro and high RANKL doses are able to overcome this defect. We also discovered that TIEG1−/− precursors exhibit defective RANKL-induced phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. Higher RANKL concentrations reversed defective NFATc1 signaling and restored differentiation. After differentiation, wildtype osteoclasts underwent apoptosis more quickly than TIEG1−/− osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1−/− osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1−/− cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1−/− precursors and eliminated the differentiation and apoptosis defects. Suppression of TIEG1 with siRNA in wildtype cells reduced differentiation and NFATc1 activation. Together, these data provide evidence that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway activation and reduces osteoclast survival by suppressing AKT and MEK/ERK signaling

Towards a combined prognostic index for survival in HIV infection: the role of 'non-HIV' biomarkers

BACKGROUND: As those with HIV infection live longer, ‘non-AIDS’ condition associated with immunodeficiency and chronic inflammation are more common. We ask whether ‘non-HIV’ biomarkers improve differentiation of mortality risk among individuals initiating combination antiretroviral therapy (cART). METHODS: Using Poisson models, we analysed data from the Veterans Aging Cohort Study (VACS) on HIV-infected veterans initiating cART between 1 January 1997 and 1 August 2002. Measurements included: HIV biomarkers (CD4 cell count, HIV RNA and AIDS-defining conditions); ‘non-HIV’ biomarkers (haemoglobin, transaminases, platelets, creatinine, and hepatitis B and C serology); substance abuse or dependence (alcohol or drug); and age. Outcome was all cause mortality. We tested the discrimination (C statistics) of each biomarker group alone and in combination in development and validation data sets, over a range of survival intervals, and adjusting for missing data. RESULTS: Of veterans initiating cART, 9784 (72%) had complete data. Of these, 2566 died. Subjects were middle-aged (median age 45 years), mainly male (98%) and predominantly black (51%). HIV and ‘non-HIV’ markers were associated with each other (P<0.0001) and discriminated mortality (C statistics 0.68–0.73); when combined, discrimination improved (P<0.0001). Discrimination for the VACS Index was greater for shorter survival intervals [30-day C statistic 0.86, 95% confidence interval (CI) 0.80–0.91], but good for intervals of up to 8 years (C statistic 0.73, 95% CI 0.72–0.74). Results were robust to adjustment for missing data. CONCLUSIONS: When added to HIV biomarkers, ‘non-HIV’ biomarkers improve differentiation of mortality. When evaluated over similar intervals, the VACS Index discriminates as well as other established indices. After further validation, the VACS Index may provide a useful, integrated risk assessment for management and research

Acid bone lysate activates TGFβ signalling in human oral fibroblasts

Abstract Demineralized bone matrix is a widely used allograft from which not only the inorganic mineral but also embedded growth factors are removed by hydrochloric acid (HCl). The cellular response to the growth factors released during the preparation of demineralized bone matrix, however, has not been studied. Here we investigated the in vitro impact of acid bone lysate (ABL) prepared from porcine cortical bone chips on oral fibroblasts. Proteomic analysis of ABL revealed a large spectrum of bone-derived proteins including TGF-β1. Whole genome microarrays and RT-PCR together with the pharmacologic blocking of TGF-β receptor type I kinase with SB431542 showed that ABL activates the TGF-β target genes interleukin 11, proteoglycan 4, and NADPH oxidase 4. Interleukin 11 expression was confirmed at the protein level by ELISA. Immunofluorescence and Western blot showed the nuclear localization of Smad2/3 and increased phosphorylation of Smad3 with ABL, respectively. This effect was independent of whether ABL was prepared from mandible, calvaria or tibia. These results demonstrate that TGF-β is a major growth factor that is removed upon the preparation of demineralized bone matrix

Interventions to Address Chronic Disease and HIV: Strategies to Promote Exercise and Nutrition Among HIV-Infected Individuals

Food insecurity, micronutrient deficits, dyslipidemia, insulin resistance, obesity, cardiovascular disease, and bone disorders complicate the treatment of HIV infection. Nutrition and exercise interventions can be effective in ameliorating these symptoms that are associated with HIV and antiretroviral therapy (ART). In this literature review, we examine the most recent nutrition and exercise interventions for HIV-infected patients. Macronutrient supplementation can be useful in treating malnutrition and wasting. Multivitamin (vitamin B complex, vitamin C, and vitamin E) supplements and vitamin D may improve quality of life and decrease morbidity and mortality. Nutritional counseling and exercise interventions are effective for treating obesity, fat redistribution, and metabolic abnormalities. Physical activity interventions improve body composition, strength, and fitness in HIV-infected individuals. Taken collectively, the evidence suggests that a proactive approach to nutrition and physical activity guidance and interventions can improve outcomes and help abrogate the adverse metabolic, cardiovascular, and psychological consequences of HIV and its treatments

Geriatric Syndromes in People Living with HIV Associated with Ageing and Increasing Comorbidities: Implications for Neurocognitive Complications of HIV Infection

Long-term survival of treated people living with HIV (PLWH) currently approaches that of the general population. The average age of PLWH is currently in the mid-50s in resource-rich countries and is predicted that over 40% of PLWH will be older than 60 within a decade. Similar trends have been confirmed in all communities of PLWH with access to antiretroviral therapies. However, the positive impact on survival has been challenged by several developments. Ageing PLWH have clinical features similar to the general population about 5-10&nbsp;years older. In addition to the earlier occurrence of common age-related conditions common geriatric syndromes have also impacted this population prematurely. These are often difficult to evaluate and manage conditions usually of multifactorial aetiology. They include polypharmacy, frailty, impaired mobility and falls, sarcopenia, sensory impairment, and increasingly, non-dementing cognitive decline. Cognitive decline is of particular concern to PLWH and their care providers. In the general geriatric population cognitive impairment increases with age and occurs in all populations with a prevalence of over 25% in people over 80. Effective treatments are lacking and therefore minimizing risk factors plays an important role in maintaining healthspan. In the general population geriatric syndromes may increase the risk of cognitive decline. The corollary is that decreasing the risk of their development may limit cognitive impairment. Whether a similar status holds in PLWH is uncertain. This chapter will address the question of whether common geriatric syndromes in PLWH contribute to cognitive impairment. Common risk factors may provide clues to limit or delay cognitive decline