Liver X receptor activation inhibits osteoclastogenesis by suppressing NF-κB activity and c-Fos induction and prevents inflammatory bone loss in mice

Authors

Hyun-Ju Kim, Kyung-Ae Yoon, Hye-Jin Yoon, Jung Min Hong, Min-Jung Lee, In-Kyu Lee and Shin-Yoon Kim

Abstract

LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-κB without affecting IκBα degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL-induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARγ ligand-induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARγ. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases.

Link to Article

http://dx.doi.org/10.1189/jlb.1112601

Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population

Authors

Iman Al-Saleh, Neptune Shinwari, Abdullah Mashhour, Abdullah Rabah

Abstract

This cross-sectional study was conducted to assess the association between exposure to heavy metals (lead, cadmium and mercury) during pregnancy and birth outcomes in 1578 women aged 16–50 years who delivered in Al-Kharj hospital, Saudi Arabia, in 2005 and 2006. The levels of lead, cadmium and mercury were measured in umbilical cord blood, maternal blood and the placenta. Outcome variables were anthropometric measures taken at birth, along with the risk of being small-for-gestational age (SGA). We selected the 10th percentile as the cutoff for dichotomizing measures of birth outcome. Cadmium, despite its partial passage through the placenta had the most prominent effect on several measures of birth outcome. After adjustment for potential confounders, logistic regression models revealed that crown-heel length (p = 0.034), the Apgar 5-minute score (p = 0.004), birth weight (p = 0.015) and SGA (p = 0.049) were influenced by cadmium in the umbilical cord blood. Significant decreases in crown-heel length (p = 0.007) and placental thickness (p = 0.022) were seen with higher levels of cadmium in maternal blood. As placental cadmium increased, cord length increased (p = 0.012) and placental thickness decreased (p = 0.032). Only lead levels in maternal blood influenced placental thickness (p = 0.011). Mercury in both umbilical cord and maternal blood was marginally associated with placental thickness and placental weight, respectively. Conversely, placental mercury levels significantly influenced head circumference (p = 0.017), the Apgar 5-minute score (p = 0.01) and cord length (p = 0.026). The predictions of these models were further assessed with the area under the curve (AUC) of the receiver operating curves (ROCs), which were modest (larger than 0.5 and smaller than 0.7). The independence of gestational age or preterm births on the observed effect of metals on some measures of birth outcome, suggested detrimental effects of exposure on fetal development. The magnitude of the estimated effects might not necessarily be of clinical significance for infants but may have a considerable public-health relevance given the high prevalence of exposure to heavy metals. Further research should be conducted to confirm these findings and to evaluate their long-term risks, if any.

Link to Article

http://dx.doi.org/10.1016/j.ijheh.2013.04.009

Uridine Prodrug Improves Memory in Tg2576 and TAPP Mice and Reduces Pathological Factors associated with Alzheimer's Disease in Related Models

Authors

Joel A. Saydoff, Ana Olariu, Jin Sheng, Zhongyi Hu, Qin Li, Rolando Garcia, Jiong Pei, Grace Y. Sun, Reid von Borstel

Abstract

Uridine prodrug PN401 has been shown to have neuroprotective effects in models of Parkinson's disease and Huntington's disease. These age-related neurodegenerative diseases including Alzheimer's disease (AD) are associated with mitochondrial dysfunction, oxidative stress, and inflammation. Attenuation of these pathological factors in AD, in addition to amyloid fibrils and neurofibrillary tangles, is critical to prevent cognitive impairment. The effects of PN401 treatment were tested in the Tg2576 and Tg2576 X P301L (TAPP) mouse models of AD. Treatment with PN401 reduced impairments in the Tg2576 mice in contextual fear conditioning and novel object recognition. In the TAPP mice, PN401 reduced the impairments in novel object recognition and social transmission of food preference. PN401 also improved motor behavior and reduced anxiety-like behavior in the TAPP mice. TAPP mouse hippocampal tau phosphorylation and lipid peroxidation were reduced by PN401 treatment. Increased tau phosphorylation was significantly correlated with worsening novel object recognition memory. PN401 did not affect amyloid plaque area in the AD mice. In other AD-related animal studies, PN401 treatment reduced blood-brain barrier damage due to intracortical LPS, elevation of serum TNFα due to systemic LPS, and hippocampal CA1 neuronal loss in the gerbil stroke model. Uridine dose-dependently protected cells from chemical hypoxia and ceramide, and decreased formation of reactive oxygen species and mitochondrial DNA damage due to hydrogen peroxide. These protective effects were achieved by raising uridine levels to at least 25–50 μM and serum uridine levels in this range in humans were obtained with oral PN401.

Link to Article

http://dx.doi.org/10.3233/JAD-130059

Long time exposure to soy/isoflavone-rich diet enhances testicular and prostate health in Long-Evans rats

Authors

Crystal Blake, Trevor Hansen, Trent C. Simmons, Edwin D. Lephart

Abstract

Soy isoflavone consumption appears to be beneficial for several health parameters. We report the influence of (lifelong exposure to) a high soy/isoflavone (High-Iso) compared to a low soy/isoflavone (Low-Iso) diet on body weight (BW), white adipose tissue (WAT) deposition, prostate weight (PW), testicular weight (TW), and testosterone levels in young adult male Long-Evans rats. WAT deposition and the WAT/BW ratios were significantly less in High-Iso vs. the Low-Iso fed animals. TW and TW/BW ratios were significantly greater in High-Iso vs. Low-Iso fed animals. Sertoli cell area, seminiferous tubule lumens and seminiferous tubule areas were significantly greater in High-Iso vs. Low-Iso animals. These data suggest that consumption of a soy diet high in isoflavone/polyphenolic molecules from conception appear to be beneficial in decreasing PW and WAT deposition while increasing TW, Sertoli cell area and seminiferous tubule volume.

Link to Article

http://dx.doi.org/10.1016/j.jff.2013.04.009

Expression of C-fos in hilar mossy cells of the dentate gyrus in vivo

Authors

Aine M. Duffy, Michael J. Schaner, Jeannie Chin, Helen E. Scharfman

Abstract

Granule cells (GCs) of the dentate gyrus (DG) are considered to be quiescent—they rarely fire action potentials. In contrast, the other glutamatergic cell type in the DG, hilar mossy cells (MCs) often have a high level of spontaneous activity based on recordings in hippocampal slices. MCs project to GCs, so activity in MCs could play an important role in activating GCs. Therefore, we investigated whether MCs were active under basal conditions in vivo, using the immediate early gene c-fos as a tool. We hypothesized that MCs would exhibit c-fos expression even if rats were examined randomly, under normal housing conditions. Therefore, adult male rats were perfused shortly after removal from their home cage and transfer to the laboratory. Remarkably, most c-fos immunoreactivity (ir) was in the hilus, especially temporal hippocampus. C-fos-ir hilar cells co-expressed GluR2/3, suggesting that they were MCs. C-fos-ir MCs were robust even when the animal was habituated to the investigator and laboratory where they were euthanized. However, c-fos-ir in dorsal MCs was reduced under these circumstances, suggesting that ventral and dorsal MCs are functionally distinct. Interestingly, there was an inverse relationship between MC and GC layer c-fos expression, with little c-fos expression in the GC layer in ventral sections where MC expression was strong, and the opposite in dorsal hippocampus. The results support the hypothesis that a subset of hilar MCs are spontaneously active in vivo and provide other DG neurons with tonic depolarizing input.

Link to Article

http://dx.doi.org/10.1002/hipo.22138

Heat and radiofrequency plasma glow discharge pretreatment of a titanium alloy promote bone formation and osseointegration

Authors

Daniel E. MacDonald, Bruce E. Rapuano, Parth Vyas, Joseph M. Lane, Kathleen Meyers, Timothy Wright

Abstract

Orthopedic and dental implants manifest increased failure rates when inserted into low density bone. We determined whether chemical pretreatments of a titanium alloy implant material stimulated new bone formation to increase osseointegration in vivo in trabecular bone using a rat model. Titanium alloy rods were untreated or pretreated with heat (600 °C) or radiofrequency plasma glow discharge (RFGD). The rods were then coated with the extracellular matrix protein fibronectin (1 nM) or left uncoated and surgically implanted into the rat femoral medullary cavity. Animals were euthanized 3 or 6 weeks later, and femurs were removed for analysis. The number of trabeculae in contact with the implant surface, surface contact between trabeculae and the implant, and the length and area of bone attached to the implant were measured by histomorphometry. Implant shear strength was measured by a pull-out test. Both pretreatments and fibronectin enhanced the number of trabeculae bonding with the implant and trabeculae-to-implant surface contact, with greater effects of fibronectin observed with pretreated compared to untreated implants. RFGD pretreatment modestly increased implant shear strength, which was highly correlated (r2 = 0.87 − 0.99) with measures of trabecular bonding for untreated and RFGD-pretreated implants. In contrast, heat pretreatment increased shear strength 3 to 5-fold for both uncoated and fibronectin-coated implants at 3 and 6 weeks, suggesting a more rapid increase in implant-femur bonding compared to the other groups. In summary, our findings suggest that the heat and RFGD pretreatments can promote the osseointegration of a titanium alloy implant material.

Link to Article

http://dx.doi.org/10.1002/jcb.24585