Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization

The mobilization of hematopoietic stem cells does not require osteoclasts, which may even have an inhibitory effect

The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte–induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets ‘osteoclastic’ molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1–Bcl6–osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies

Diversity of Nitrite Reductase Genes in “Candidatus Accumulibacter phosphatis”-Dominated Cultures Enriched by Flow-Cytometric Sorting▿

“Candidatus Accumulibacter phosphatis” is considered a polyphosphate-accumulating organism (PAO) though it has not been isolated yet. To reveal the denitrification ability of this organism, we first concentrated this organism by flow cytometric sorting following fluorescence in situ hybridization (FISH) using specific probes for this organism. The purity of the target cells was about 97% of total cell count in the sorted sample. The PCR amplification of the nitrite reductase genes (nirK and nirS) from unsorted and sorted cells was performed. Although nirK and nirS were amplified from unsorted cells, only nirS was detected from sorted cells, indicating that “Ca. Accumulibacter phosphatis” has nirS. Furthermore, nirS fragments were cloned from unsorted (Ba clone library) and sorted (Bd clone library) cells and classified by restriction fragment length polymorphism analysis. The most dominant clone in clone library Ba, which represented 62% of the total number of clones, was not found in clone library Bd. In contrast, the most dominant clone in clone library Bd, which represented 59% of the total number of clones, represented only 2% of the total number of clones in clone library Ba, indicating that this clone could be that of “Ca. Accumulibacter phosphatis.” The sequence of this nirS clone exhibited less than 90% similarity to the sequences of known denitrifying bacteria in the database. The recovery of the nirS genes makes it likely that “Ca. Accumulibacter phosphatis” behaves as a denitrifying PAO capable of utilizing nitrite instead of oxygen as an electron acceptor for phosphorus uptake

Long-term prognosis and clinical characteristics of young adults (≤40 years old) who underwent percutaneous coronary intervention

AbstractBackgroundLimited data exist regarding the long-term prognosis of percutaneous coronary intervention (PCI) in young adults. The aim of this study was to retrospectively assess the long-term clinical outcomes in young patients who underwent PCI.Methods and resultsBetween 1985 and 2011, 7649 consecutive patients underwent PCI, and data from 69 young adults (age ≤40 years) and 4255 old adults (age ≧65 years) were analyzed. A Cox proportional hazards regression analysis was used to determine the independent predictors of a composite endpoint that included all-cause death and acute coronary syndrome (ACS) during the follow-up period. The mean age of the 69 young patients was 36.1±4.9 years, and 96% of them were men. Approximately 30% were current smokers, and their body mass index (BMI) was 26.7±5.0kg/m2. The prevalence of diabetes and hypertension was 33% and 48%, respectively. All patients had ≥1 conventional cardiovascular risk factor. At a median follow-up of 9.8 years, the overall death rate was 5.8%, and new-onset ACS occurred in 8.7%. Current smoking was an independent predictor of the composite endpoint (hazard ratio 4.46, confidence interval 1.08–19.1, p=0.04) for young adults.ConclusionCurrent smoking and obesity (high BMI) are the important clinical characteristics in young Japanese coronary heart disease patients who undergo PCI. The long-term prognosis in young patients is acceptable, but current smoking is a significant independent predictor of death and the recurrence of ACS in young Japanese coronary heart disease patients who are obese

The IRE1alpha-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix

During skeletal development, osteoblasts produce large amounts of extracellular matrix proteins and must therefore increase their secretory machinery to handle the deposition. The accumulation of unfolded protein in the endoplasmic reticulum induces an adoptive mechanism called the unfolded protein response (UPR). We show that one of the most crucial UPR mediators, inositol-requiring protein 1alpha (IRE1alpha), and its target transcription factor X-box binding protein 1 (XBP1), are essential for bone morphogenic protein 2-induced osteoblast differentiation. Furthermore, we identify Osterix (Osx, a transcription factor that is indispensible for bone formation) as a target gene of XBP1. The promoter region of the Osx gene encodes two potential binding motifs for XBP1, and we show that XBP1 binds to these regions. Thus, the IRE1alpha-XBP1 pathway is involved in osteoblast differentiation through promoting Osx transcription

Clinical indicators and coronary angiographic features of expansive arterial remodelling in patients with abdominal aortic aneurysms.

The co-existence of expansive arterial remodelling in both coronary arteries (CAs) and the abdominal aorta has already been reported, although the clinical indicators and quantitative analysis have not been well studied. We therefore aimed to clarify the clinical and anatomical characteristics of patients with abdominal aortic aneurysms (AAAs). 123 AAA patients who underwent coronary angiography were compared to 123 control patients selected by propensity score matching. CA diameters of all 3 vessels were measured by quantitative coronary angiographic analysis. Coronary artery ectasia (CAE) was defined as local or generalized aneurysmal change of the CAs. Excessive expansive CA remodelling was defined as the maximal diameter of the right or left circumflex artery in the upper 75th percentile (>4.8 mm). Multivariable logistic regression analyses were used to determine predictors of CAE and excessive expansive CA remodelling. The prevalences of CAE and excessive expansive CA remodelling were significantly higher in the AAA group than in the non-AAA group (28% vs. 8% and 31% vs. 19%; both p<0.05). On multivariable analysis, the presence of AAA (odds ratio (OR), 4.56; 95% confidence intervals (95%CI) 2.18-10.4) and body mass index (BMI) (OR, 1.11; 95%CI 1.03-1.21) were independently associated with CAE, and higher high-sensitivity C-reactive protein (OR, 2.19; 95%CI 1.08-4.52) and BMI (OR, 1.11; 95%CI 1.02-1.21) were independently associated with excessive expansive CA remodelling. In conclusions, this study showed a higher prevalence of ectatic CA disease in AAA patients and suggests that higher inflammation and obesity are associated with expansive arterial remodelling in coronary arteries

Residual Inflammation Indicated by High-Sensitivity C-Reactive Protein Predicts Worse Long-Term Clinical Outcomes in Japanese Patients after Percutaneous Coronary Intervention

The aim of this study was to investigate the long-term clinical impact of residual inflammatory risk (RIR) by evaluating serial high-sensitivity C-reactive protein (hs-CRP) in Asian patients with coronary artery disease (CAD). We evaluated 2032 patients with stable CAD undergoing percutaneous coronary intervention (PCI) with serial hs-CRP measurements (2 measurements, 6&ndash;9 months apart) from the period 2000 to 2016. A high-RIR was defined as hs-CRP &gt; 0.9 mg/L according to the median value. Patients were assigned to four groups: persistent-high-RIR, increased-RIR, attenuated-RIR, or persistent-low-RIR. Major adverse cardiac events (MACE) and all-cause death were evaluated. MACE rates in patients with persistent high, increased and attenuated RIR were significantly higher than in patients with persistent low RIR (p &lt; 0.001). Moreover, the rate of all-cause death was significantly higher among patients with persistent high and increased RIR than among patients with attenuated and persistent low RIR (p &lt; 0.001). After adjustment, the presence of persistent high RIR (hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.37&ndash;3.67, p = 0.001), increased RIR (HR 2.25, 95%CI 1.09&ndash;4.37, p = 0.029), and attenuated RIR (HR 1.94, 95%CI 1.14&ndash;3.32, p = 0.015) were predictive for MACE. In addition, presence of persistent high RIR (HR 2.07, 95%CI 1.41&ndash;3.08, p &lt; 0.001) and increased RIR (HR 1.94, 95%CI 1.07&ndash;3.36, p = 0.029) were predictive for all-cause death. A high RIR was significantly associated with MACE and all-cause death among Japanese CAD patients. An evaluation of changes in inflammation may carry important prognostic information and may guide the therapeutic approach