Age-Related Skeletal Dynamics and Decrease in Bone Strength in DNA Repair Deficient Male Trichothiodystrophy Mice

Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength

Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity

Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity

Plants used during pregnancy, childbirth and postpartum healthcare in Lao PDR: A comparative study of the Brou, Saek and Kry ethnic groups

<p>Abstract</p> <p>Background</p> <p>In many Southeast Asian cultures the activities and diet during the postpartum period are culturally dictated and a period of confinement is observed. Plants play an important role in recovery during the postpartum period in diet, traditional medicine, steam bath and mother roasting (where mother and child placed on a bed above a brazier with charcoal embers on which aromatic plants are laid). This research focuses on the use of plants during pregnancy, parturition, postpartum recovery and infant healthcare among three ethnic groups, the Brou, Saek and Kry. It aims to identify culturally important traditions that may facilitate implementation of culturally appropriate healthcare.</p> <p>Methods</p> <p>Data were collected in 10 different villages in Khammouane province, Lao PDR, through group and individual interviews with women by female interviewers.</p> <p>Results</p> <p>A total of 55 different plant species are used in women's healthcare, of which over 90% are used in postpartum recovery. Consensus Analysis rejects the hypothesis that the three ethnic groups belong to a single culture for postpartum plant use, and multidimensional scaling reveals non-overlapping clusters per ethnic group.</p> <p>Conclusion</p> <p>Medicinal plant use is common among the Brou, Saek and Kry to facilitate childbirth, alleviate menstruation problems, assist recovery after miscarriage, mitigate postpartum haemorrhage, aid postpartum recovery, and for use in infant care. The wealth of novel insights into plant use and preparation will help to understand culturally important practices such as confinement, dietary restrictions, mother roasting and herbal steam baths and their incorporation into modern healthcare.</p

Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice

Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism

Stikstofverontreiniging op de lokale en regionale schaal: de huidige stand der kennis en onderzoeksbehoefte

Uit onderzoek van de afgelopen tien jaar is gebleken dat stikstof- en zuurdepositie de stressgevoeligheid en biodiversiteit van bossen en natuurlijke vegetaties sterk negatief kunnen beinvloeden. De eutrofierende werking van stikstof-depositie speelt daarbij een hoofdrol. De kennis over de ruimtelijke verdeling en kwantiteit van de depositie zijn zodanig verbeterd dat op regionale en nationale schaal redelijk betrouwbare schattingen gemaakt kunnen worden. Ook over de grondwaterverontreiniging kunnen op deze schaal kwantitatieve conclusies getrokken worden. Over de aard en grootte van ecologische effecten is behoorlijk inzicht verkregen, het onderzoek is echter tot nu toe gericht geweest is op een beter begrip van werkingsmechanismen van stikstof. Andere stressfaktoren zoals droogte, vorst, ziekten en plagen zijn in mindere mate in het onderzoek betrokken. Op dit moment is voldoende kennis beschikbaar over stikstof-depositie en -effecten voor onderbouwing van het landelijke (generieke) en regionale beleid. Voor meer specifieke emissie beperkende maatregelen op lokale schaal is het inzicht in de processen en effecten op deze schaal echter beperkt. Dit laat zich vertalen in behoefte aan informatie over temporele en ruimtelijke variatie in emissie, depositie, en gevoeligheid van ecosystemen op lokale schaal. Ook is het van belang betere mogelijkheden te hebben dan nu het geval is om beleidsmaatregelen tegen elkaar af te wegen, zoals bijvoorbeeld bepaling van de noodzaak tot het nemen van lokale maatregelen (wegnemen van piekbelastingen) ten opzichte van regionale of landelijke maatregelen (wegnemen van de achtergrondbelasting) ; of bepaling van maatregelen ten aanzien van verkeer of industrie (NOx) ten opzichte van de landbouw (NH3). Daarvoor is het nodig te beschikken over blootstelling/respons relaties voor de invloed van stikstof-deposities op verschillende natuur-doeltypen, informatie over de mate en snelheid waarmee ecosystemen herstellen bij vermindering van N-depositie, kortom informatie waarmee de baten van emissie-redukties van gereduceerd en geoxideerd N met elkaar vergeleken kunnen worden. In dit rapport worden bovengenoemde vragen gerelateerd aan beschikbare informatie en aan de resultaten die van lopend onderzoek verwacht worden, en wordt beschreven welk onderzoek adequaat is om de kennishiaten op te vullen. Ook wordt een prioritering in het onderzoek aangegeven met als uitgangspunten dat er een directe relatie met de bovengenoemde beleidsvragen moet zijn, en dat er relevante resultaten geboekt moeten kunnen worden binnen een enkele jaren durend onderzoeksprogramma van een bescheiden omvang.Concerns the results of a feasibility study on the realisation of a nitrogen research programme for the local scale. This study, initiated by the Ministries of Housing, Physical Planning and Environment (VROM) and of Agriculture, Nature Management and Fisheries (LNV), was executed by a project group of Dutch scientists to provide an outline of a research programme proposal. It will be based on an inventory of the main policy questions, and on overviews of the state of knowledge of different parts of the nitrogen causal chain, and of the main gaps in knowledge and present research. The end product of the programme should be a set of modules which will enable the assessment of the risk on negative effects on current nature conservation in the Dutch Mainframe of Natural Landscapes (EHS) and the nature conservation target types in the EHS to be realised in the future. The modules represent parts of the causal chain, i.e. emission, dispersion and deposition, effects on different terrestrial and aquatic ecosystems and on tree species, groundwater pollution and the marine environment. The research in the programme will focus on refining and validating existing models for the individual elements of the causal chain. Experiments and model development will be focused on better estimating (changes) in key factors necessary to describe the main processes of these elements.DGM/LN