Effects of vascular endothelial growth factor-C and -D on osteoclast differentiation and function in human peripheral blood mononuclear cells

ObjectiveThe purpose of this study was to clarify the interaction of vascular endothelial growth factors (VEGFs)-C and -D with cell surface foetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-4 (Flt-4) receptors in the induction and activity of osteoclasts in cultured human peripheral blood mononuclear cells (PBMCs).DesignPBMCs were cultured on chamber slides or on ivory discs for 2 or 3 weeks in the presence of macrophage-colony stimulating factor (M-CSF), VEGF-A, -C or -D, or placental growth factor (PlGF) with or without receptor activator of nuclear factor kappa-B ligand (RANKL). The number of osteoclasts in each group was counted and the area of ivory resorption was measured. In addition, osteoclast differentiation was further analysed under the same conditions, but with the addition of specific neutralizing antibodies against Flk-1 and Flt-4.ResultsRANKL was essential for the induction of osteoclasts in PBMCs. However, significant differences were found in the number of osteoclasts induced by VEGF-A, -C, -D or M-CSF with RANKL compared with control groups lacking or containing RANKL. Blocking of either Flk-1 or Flt-4 resulted in a reduction in the enhancement of osteoclast differentiation in PBMCs by VEGF-C or -D with RANKL. The osteoclasts induced by VEGF-A, -C, -D or M-CSF with RANKL formed significantly larger resorption lacunae than those formed by osteoclasts induced by RANKL alone.ConclusionsThis study showed that VEGF-C and -D play a role in the induction of osteoclast differentiation through both Flk-1 and Flt-4 receptors and influence the area of the ivory resorption in PBMCs.     

Facilitation of experimental tooth movement by NOC-18, a long-acting nitric oxide donor

PurposeIn orthodontic tooth movement, osteoclasts play a crucial role in bone resorption on the compression side of the alveolar bone. It has been reported that nitric oxide is involved in bone remodeling caused by mechanical loading, and we previously reported that NOC-18, a long-acting nitric oxide donor, augmented RANKL-induced osteoclast differentiation in mouse monocytic RAW264 cells as well as mouse bone marrow macrophages. In this study, we investigated whether NOC-18 facilitated experimental tooth movement in mice.Materials and methodsEight-week-old male ddY mice were used. Experimental tooth movement was induced by the insertion of an orthodontic elastic between the left maxillary first molar and second molar. Just after the insertion of the elastic, NOC-18 was intraperitoneally administered once, and mice were killed after 3 days. For the detection of osteoclasts, HE staining, TRAP staining, and immunostaining for cathepsin K were performed.ResultsAn intraperitoneal injection of NOC-18 significantly increased the distance of experimental tooth movement. Furthermore, the number and area of osteoclasts on the compression side of the alveolar bone surface was significantly higher in the NOC-18 group.ConclusionThese results suggested that systemic administration of NOC-18 might have some effect to facilitate experimental tooth movement in mice via the augmentation of osteoclast differentiation on the compression side of the alveolar bone.     

Benidipine reduces ischemia reperfusion-induced systemic oxidative stress through suppression of aldosterone production in mice

Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T- and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30?min of left ascending coronary I/R. Benidipine was administered orally at 3?mg?kg(-1) daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2' deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels.     

Impact of combined assessment of coronary artery calcium score, carotid artery plaque score, and brachial-ankle pulse wave velocity for early coronary revascularization in patients with suspected coronary artery disease

Coronary artery calcium score (CACS) measured by multi-detector computed tomography, carotid plaque score (CPS) measured by carotid artery ultrasound, and brachial-ankle pulse wave velocity (baPWV) are noninvasive screening tools for coronary artery disease. The aim of this study was to determine whether the combination of CACS, CPS, and baPWV improves the prognostic value for future cardiac events. CACS, CPS, and baPWV were assessed in 77 patients (mean age, 65 years, 49 males) undergoing invasive coronary angiography. ECG-triggered MSCT was used to assess CACS. CPS was defined as the sum of all plaque heights in bilateral carotid arteries. The highest baPWV was used for analysis. Cardiac events were defined as cardiac death, nonfatal myocardial infarction, or coronary revascularization. Thirty-two cardiac events (41.6%) occurred during follow-up (23.6 ± 20.8 months), consisting of 28 PCIs and 4 CABGs. The best cutoff values of positive CACS, CPS, and baPWV for predicting cardiac events were ≥ 50, ≥ 5, and ≥1.6 m/second, respectively. For the combination of the 3 modalities, the positive test was defined as having at least 1 positive result by each method. The negative predictive value of all 3 modalities combined was better than that of CACS alone. The event-free rate was higher in patients with negative results for all 3 parameters compared with those that were positive (100% versus 44.8%, P < 0.0001). The prognostic value of using combined assessment of CACS, CPS, and baPWV is more effective for predicting cardiac events than CACS alone.     

Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis

Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-α-induced adipose-related protein (TIARP), plays a role in tumor necrosis factor (TNF)-dependent arthritis models. However, its role in rheumatoid arthritis (RA) is still obscure. This study explored such a role for STEAP4. The expressions of STEAP4, TNFα, and IL-6 were compared in synovia of RA and osteoarthritis patients. STEAP4 induction was examined in TNFα-stimulated fibroblast-like synoviocytes (FLS) in vitro. FLS (with/without TNFα stimulation) were also analyzed for IL-6 expression after STEAP4 knockdown, using siRNA or transfection with STEAP4-plasmid DNA. IL-8, cell proliferation, and apoptosis were also evaluated in STEAP4-overexpressing FLS. The expression of STEAP4 in joints correlated with TNFα expression, specifically in RA synovium. In the cultured FLS, STEAP4 protein expression was augmented by TNFα activation, and localized in endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3. The results indicated that human STEAP4 is regulated by TNFα in synovium, where it controls IL-6 secretion and proliferation of FLS, suggesting that STEAP4 might potentially suppress the pathogenesis of TNFα-induced arthritis such as RA.     

Multi-step hydration/dehydration mechanisms of rhombohedral Y2(SO4)3: a candidate material for low-temperature thermochemical heat storage

To evaluate rhombohedral Y₂(SO₄)₃ as a new potential material for low-temperature thermochemical energy storage, its thermal behavior, phase changes, and hydration/dehydration reaction mechanisms are investigated. Rhombohedral Y₂(SO₄)₃ exhibits reversible hydration/dehydration below 130 °C with relatively small thermal hysteresis (less than 50 °C). The reactions proceed via two reaction steps in approximately 0.02 atm of water vapor pressure, i.e. “high-temperature reaction” at 80–130 °C and “low-temperature reaction” at 30–100 °C. The high-temperature reaction proceeds by water insertion into the rhombohedral Y₂(SO₄)₃ host structure to form rhombohedral Y₂(SO₄)₃·xH₂O (x = ∼1). For the low-temperature reaction, rhombohedral Y₂(SO₄)₃·xH₂O accommodates additional water molecules (x > 1) and is eventually hydrated to Y₂(SO₄)₃·8H₂O (monoclinic) with changes in the host structure. At a water vapor pressure above 0.08 atm, intermediate Y₂(SO₄)₃·3H₂O appears. A phase stability diagram of the hydrates is constructed and the potential usage of Y₂(SO₄)₃ for thermal energy upgrades is assessed. The high-temperature reaction may act similarly to an existing candidate, CaSO₄·0.5H₂O, in terms of reaction temperature and water vapor pressure. Additionally, the hydration of rhombohedral Y₂(SO₄)₃·xH₂O to Y₂(SO₄)₃·3H₂O should exhibit a larger heat storage capacity. With respect to the reaction kinetics, the initial dehydration of Y₂(SO₄)₃·8H₂O to rhombohedral Y₂(SO₄)₃ introduces a microstructure with pores on the micron order, which might enhance the reaction rate.

To evaluate rhombohedral Y₂(SO₄)₃ as a new potential material for low-temperature thermochemical energy storage, its thermal behavior, phase changes, and hydration/dehydration reaction mechanisms are investigated.