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Abstract: Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Many of the proinflammatory cytokines and growth factors implicated in inflammatory processes have also been demonstrated to impact osteoclast differentiation and function. Recent evidence indicates that the TNF-related apoptosis-inducing ligand (TRAIL) of the TNF ligand superfamily, which was initially thought to induce apoptosis in many transformed cell lines, can serve as an effector molecule in activated T cells. We show in this work that TRAIL can induce osteoclast formation from human monocytes and murine RAW264.7 macrophages. We demonstrated that both cell models differentiate into osteoclast-like cells in the presence of TRAIL in a dose-dependent manner, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. The TRAIL-induced osteoclast differentiation is independent of caspase activation and apoptosis induction activity. However, TRAIL-induced osteoclastogenesis is dependent on activation of NF-κB, ERK, and p38 MAP kinase. Thus, our data demonstrate that TRAIL induces osteoclast differentiation via direct engagement with the TRAIL death receptor through a signaling pathway distinct from apoptosis. Our results indicate that in addition to triggering apoptosis, TRAIL induces osteoclast differentiation. It provides a novel role for TRAIL in regulating osteoclast differentiation and in osteoimmunology. [Copyright &y& Elsevier]

Abstract: Background: Epidemiologic data regarding the role of inflammation in atherosclerosis have been based mainly on Caucasian populations. Thus, we analyzed the cross-sectional relationships of inflammatory biomarkers to cardiovascular risk factors (CVRF) and related variables in a large group of healthy Chinese men, a population with a markedly lower heart disease mortality rate compared with Western populations. Methods: The study consisted of 8374 men aged 20–80 who attended a voluntary health examination at a metropolitan university center between 1997 and 2002. The relationships between serum high sensitivity C-reactive protein (hsCRP), total white blood cell (WBC), neutrophil, and monocyte counts to CVRF were analyzed using multivariate linear and logistic regression analyses. Whether a dose–response effect existed between elevated levels of each marker and increasing numbers of CVRF was also evaluated. Results: The distribution of hsCRP was similar to Western studies. Both multivariate regression analyses showed all four markers to have significant correlations with body mass index, triglycerides, and adverse high density lipoprotein/low density lipoprotein ratio. Smoking was associated with increased levels of all four markers. Elevated neutrophil count had the most markedly progressive dose–response effect with increasing numbers of CVRF, whereas elevated monocyte count showed a drop in risk with CVRF of five and above. Conclusion: We show in our study that with increasing numbers of standard CVRF, healthy Chinese men have progressive and increasing risks of having elevated levels of hsCRP, total WBC, and neutrophil counts. While the inflammatory markers surveyed were largely correlated with CVRF, the similar values of CRP between populations with divergent mortality rates suggest that a more complex relationship may exist between CRP and disease outcome. The possible utility of neutrophil count as a marker for cardiovascular disease risk in healthy men awaits further evaluation in prospective studies. [Copyright &y& Elsevier]

Estradiol has been considered as an L-type calcium channel blocker in animal studies. The concentration of estradiol decreases after menopause. Therefore, we hypothesized that human myocardial functional changes developed after menopause, and those changes could be evaluated through the use of cyclic variation of integrated backscatter (CVIBS). A total of 16 patients with menopause (native and surgical menopause), follicular stimulating hormone > 40 IU/L and estradiol < 20 pg/mL underwent dobutamine stress IBS examination (study group). Another 12 women with normal menstruation, follicular stimulating hormone < 40 IU/L and estradiol > 20 pg/mL were enrolled as a control group. All patients had a low likelihood of coronary artery disease and negative results of dobutamine stress echocardiography and 201thallium scintigraphy. To avoid the phenomenon of anisotropy, the amplitude and phase of IBS were acquired only in the midanteroseptal segment from the parasternal short axis view. The baseline amplitudes of CVIBS differed between the control and study groups (5.9 ± 1.2 dB vs. 8.1 ± 2.1 dB; p = 0.007). The amplitudes during low-dose (20 μg/kg-min) and peak-dose (40 μg/kg-min) dobutamine infusion were also different between these 2 groups (5.7 ± 0.9 dB vs. 8.4 ± 1.7 dB; p < 0.001; 6.0 ± 1.0 dB vs. 7.7 ± 2.4 dB; p = 0.026). However, there were no significant differences in amplitudes between these two groups after atropine injection (control group 4.5 ± 1.2 dB, study group 5.3 ± 1.0 dB; p = NS). No significant differences of phase were found either at baseline or under dobutamine infusion between the two groups. Multivariate linear regression analysis showed that only menopause status associated significantly with the amplitudes at different doses of dobutamine infusion (p < 0.05). In conclusion, human myocardial functional changes are observed by CVIBS after menopause. Postmenopausal women have higher values of amplitude than premenopausal women. These phenomena persist during low and peak doses of dobutamine infusion, but are abolished by atropine injection. [Copyright &y& Elsevier]

Abstract: Interactions between blood vessels and osteoblasts—bone-forming cells—are critical for successful bone development. We therefore investigated the endothelial differentiation capacity of mesenchymal stem cells (MSCs) derived from bone tissue. We found that fetal pre-osteoblast and adult trabecular bone-derived (TB) MSCs express similar surface markers as bone marrow (BM) MSCs and can differentiate into adipocytes, osteoblasts, and chondrocytes. However, when cultured in extracellular matrix (ECM) and endothelial differentiation conditions, bone-derived MSCs (B-MSCs) more readily form tubular structures and uptake acetylated low-density lipoproteins, fulfilling the functional criteria for endothelial cells (ECs). Moreover, addition of B-MSCs but not other cells significantly enhanced vessel formation in the in vivo chick chorioallantoic membrane assay. Mechanistically, this appears to be due to the upregulation of the endothelial transcription factor forkhead box protein C2 (FOXC2) and its downstream gene αvβ3 integrin/CD61in B-MSCs but not BMMSCs by laminin, a component protein of the ECM. Our findings not only reveal discrepant differentiation capacity for various tissue-specific MSCs, but also highlight the critical role of the niche—in this case, the ECM and its component proteins—in determining lineage commitment of stem cells. [Copyright &y& Elsevier]

Abstract: 3-dimensional microcarrier (3D-MC) cell culture systems are often used for expansion of stem cells including mesenchymal stem cells (MSCs) for high cell volumes required in clinical applications. However, compared to 2-dimensional (2D) cell culture, effects of 3D-MC systems on MSC differentiation have not been well studied. In this study, the behavior of various sources of MSCs from two species was observed and compared on 3D collagen I-coated-MCs (COL-MC) versus 2D culture. Proliferation of all MSCs cultured on 3D COL-MC was much decreased compared to 2D culture. Unexpectedly, COL-MC-cultured MSCs underwent spontaneous osteogenesis without exogenous addition of biochemical factors, as evidenced by increased osteogenic genes expression, ALP activity, calcium deposition, and collagen I secretion. Furthermore, MSCs cultured on 3D-MC alone without collagen I coating is sufficient to induce osteogenesis. The spontaneous lineage commitment induced by 3D-MC culture was mediated by increased cytoskeletal tension and actomyosin contraction of MSCs, which could be prevented by latrunculin B and blebbistatin, inhibitors of cytoskeletal tension and actomyosin contraction respectively. Our findings show that the combination of bioengineered MC and MSCs alone can induce specific lineage commitment very efficiently. These data have strong implications in simplifying tissue engineering strategies for therapeutic applications. [Copyright &y& Elsevier]