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Major depressive disorder has been linked to alterations in several interacting systems, particularly with respect to neuroendocrine and neuroinflammatory dysfunction. Increased levels of both cortisol and proinflammatory cytokines have regularly been described. This presents an apparent paradox, given the well-known anti-inflammatory properties of glucocorticoids, including inhibition of cytokine release. There are two competing theories to resolve this paradox: one proposes that reduced glucocorticoid signaling, as a result of glucocorticoid resistance, creates a permissive environment for an overactive innate immune system; the other theory focuses on evidence that glucocorticoids can be proinflammatory under some circumstances, depending on context and temporal factors. This review assesses the evidence base and limitations of both theories, discussing animal and clinical data, and preliminary work in human neural cells. Further work to delineate the relationship between neuroimmune and neuroendocrine systems in depression will be critical for understanding the biological perturbations underpinning depression, and therefore, for discerning treatment targets, and we include suggestions for future directions. [ABSTRACT FROM AUTHOR]

Obesity has been associated with high bone mineral density (BMD) but a greater propensity to fracture. Some obese individuals have increased marrow adipose tissue (MAT), but the impact of MAT on bone turnover remains controversial, as do changes in BMD associated with a high fat diet (HFD). In this study we hypothesized that MAT volume would increase in response to HFD but would be independent of changes in BMD. Hence, we fed C57BL/6J (B6) male mice at 3 weeks of age either a high fat diet (60 kcal %) or regular diet (10 kcal %) for 12 weeks (n = 10/group). We measured MAT volume by osmium staining and micro-CT (µCT) as well as bone parameters by µCT, histomorphometry, and dual-energy X-ray absorptiometry. We also performed a short-term pilot study using 13-week-old B6 males and females fed a HFD (58 kcal %) for 2 weeks (n = 3/sex). Both long- and short-term HFD feedings were associated with high MAT volume, however, femoral trabecular bone volume fraction (BV/TV), bone formation rate and cortical bone mass were not altered in the long-term study. In the short-term pilot study, areal BMD was unchanged after 2 weeks of HFD. We conclude that, for B6 mice fed a HFD starting at wean or 13 weeks of age, MAT increases whereas bone mass is not altered. More studies are needed to define the mechanism responsible for the rapid storage of energy in the marrow and its distinction from other adipose depots. J. Cell. Physiol. 230: 2032-2037, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Emerging data suggest that megakaryocytes (MKs) play a significant role in skeletal homeostasis. Indeed, osteosclerosis observed in several MK-related disorders may be a result of increased numbers of MKs. In support of this idea, we have previously demonstrated that MKs increase osteoblast (OB) proliferation by a direct cell-cell contact mechanism and that MKs also inhibit osteoclast (OC) formation. As MKs and OCs are derived from the same hematopoietic precursor, in these osteoclastogenesis studies we examined the role of the main MK growth factor, thrombopoietin (TPO) on OC formation and bone resorption. Here we show that TPO directly increases OC formation and differentiation in vitro. Specifically, we demonstrate the TPO receptor (c-mpl or CD110) is expressed on cells of the OC lineage, c-mpl is required for TPO to enhance OC formation in vitro, and TPO activates the mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappaB signaling pathways, but does not activate the PI3K/AKT pathway. Further, we found TPO enhances OC resorption in CD14+CD110+ human OC progenitors derived from peripheral blood mononuclear cells, and further separating OC progenitors based on CD110 expression enriches for mature OC development. The regulation of OCs by TPO highlights a novel therapeutic target for bone loss diseases and may be important to consider in the numerous hematologic disorders associated with alterations in TPO/c-mpl signaling as well as in patients suffering from bone disorders. J. Cell. Physiol. 230: 2142-2151, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

GATA-1low/low mice have an increase in megakaryocytes (MKs) and trabecular bone. The latter is thought to result from MKs directly stimulating osteoblastic bone formation while simultaneously inhibiting osteoclastogenesis. Osteoprotegerin (OPG) is known to inhibit osteoclastogenesis and OPG−/− mice have reduced trabecular and cortical bone due to increased osteoclastogenesis. Interestingly, GATA-1low/low mice have increased OPG levels. Here, we sought to determine whether GATA-1 knockdown in OPG−/− mice could rescue the observed osteoporotic bone phenotype. GATA-1low/low mice were bred with OPG−/− mice and bone phenotype assessed. GATA-1low/low × OPG−/− mice have increased cortical bone porosity, similar to OPG−/− mice. Both OPG−/− and GATA-1low/low × OPG−/− mice, were found to have increased osteoclasts localized to cortical bone, possibly producing the observed elevated porosity. Biomechanical assessment indicates that OPG−/− and GATA-1low/low × OPG−/− femurs are weaker and less stiff than C57BL/6 or GATA-1low/low femurs. Notably, GATA-1low/low × OPG−/− mice had trabecular bone parameters that were not different from C57BL/6 values, suggesting that GATA-1 deficiency can partially rescue the trabecular bone loss observed with OPG deficiency. The fact that GATA-1 deficiency appears to be able to partially rescue the trabecular, but not the cortical bone phenotype suggests that MKs can locally enhance trabecular bone volume, but that MK secreted factors cannot access cortical bone sufficiently to inhibit osteoclastogenesis or that OPG itself is required to inhibit osteoclastogenesis in cortical bone. J. Cell. Physiol. 230: 783-790, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Recent studies suggest that megakaryocytes (MKs) may play a significant role in skeletal homeostasis, as evident by the occurrence of osteosclerosis in multiple MK related diseases (Lennert et al., 1975; Thiele et al., 1999; Chagraoui et al., 2006). We previously reported a novel interaction whereby MKs enhanced proliferation of osteoblast lineage/osteoprogenitor cells (OBs) by a mechanism requiring direct cell-cell contact. However, the signal transduction pathways and the downstream effector molecules involved in this process have not been characterized. Here we show that MKs contact with OBs, via beta1 integrin, activate the p38/MAPKAPK2/p90RSK kinase cascade in the bone cells, which causes Mdm2 to neutralizes p53/Rb-mediated check point and allows progression through the G1/S. Interestingly, activation of MAPK (ERK1/2) and AKT, collateral pathways that regulate the cell cycle, remained unchanged with MK stimulation of OBs. The MK-to-OB signaling ultimately results in significant increases in the expression of c-fos and cyclin A, necessary for sustaining the OB proliferation. Overall, our findings show that OBs respond to the presence of MKs, in part, via an integrin-mediated signaling mechanism, activating a novel response axis that de-represses cell cycle activity. Understanding the mechanisms by which MKs enhance OB proliferation will facilitate the development of novel anabolic therapies to treat bone loss associated with osteoporosis and other bone-related diseases. J. Cell. Physiol. 230: 578-586, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company [ABSTRACT FROM AUTHOR]

Mice deficient in GATA-1 or NF-E2, transcription factors required for normal megakaryocyte (MK) development, have increased numbers of MKs, reduced numbers of platelets, and a striking high bone mass phenotype. Here, we show the bone geometry, microarchitecture, biomechanical, biochemical, and mineral properties from these mutant mice. We found that the outer geometry of the mutant bones was similar to controls, but that both mutants had a striking increase in total bone area (up to a 35% increase) and trabecular bone area (up to a 19% increase). Interestingly, only the NF-E2 deficient mice had a significant increase in cortical bone area (21%) and cortical thickness (27%), which is consistent with the increase in bone mineral density (BMD) seen only in the NF-E2 deficient femurs. Both mutant femurs exhibited significant increases in several biomechanical properties including peak load (up to a 32% increase) and stiffness (up to a 13% increase). Importantly, the data also demonstrate differences between the two mutant mice. GATA-1 deficient femurs break in a ductile manner, whereas NF-E2 deficient femurs are brittle in nature. To better understand these differences, we examined the mineral properties of these bones. Although none of the parameters measured were different between the NF-E2 deficient and control mice, an increase in calcium (21%) and an increase in the mineral/matrix ratio (32%) was observed in GATA-1 deficient mice. These findings appear to contradict biomechanical findings, suggesting the need for further research into the mechanisms by which GATA-1 and NF-E2 deficiency alter the material properties of bone. J. Cell. Physiol. 228: 1594-1600, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Regulation of skeletal remodeling appears to influence the differentiation of multipotent mesenchymal stem cells (MSC) resident in the bone marrow. As murine marrow cultures are contaminated with hematopoietic cells, they are problematic for studying direct effects of mechanical input. Here we use a modified technique to isolate marrow-derived MSC (mdMSC) from adult mice, yielding a population able to differentiate into adipogenic and osteogenic phenotypes that is devoid of hematopoietic cells. In pure mdMSC populations, a daily strain regimen inhibited adipogenic differentiation, suppressing expression of PPARγ and adiponectin. Strain increased β-catenin and inhibition of adipogenesis required this effect. Under osteogenic conditions, strain activated β-catenin signaling and increased expression of WISP1 and COX2. mdMSC were also generated from mice lacking caveolin-1, a protein known to sequester β-catenin: caveolin-1(−/−) mdMSC exhibited retarded differentiation along both adipogenic and osteogenic lineages but retained mechanical responses that involved β-catenin activation. Interestingly, caveolin-1(−/−) mdMSC failed to express bone sialoprotein and did not form mineralized nodules. In summary, mdMSC from adult mice respond to both soluble factors and mechanical input, with mechanical activation of β-catenin influencing phenotype. As such, these cells offer a useful model for studies of direct mechanical regulation of MSC differentiation and function. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1531-1538, 2010 [ABSTRACT FROM AUTHOR]

Only three decades ago adipose tissue was considered inert, with little relationship to insulin resistance. Similarly, bone has long been thought of purely in its structural context. In the last decade, emerging evidence has revealed important endocrine roles for both bone and adipose tissue. The interaction between these two tissues is remarkable. Bone marrow mesenchymal stem cells give rise to both osteoblasts and adipocytes. Leptin and adiponectin, two adipokines secreted by fat tissue, control energy homeostasis, but also have complex actions on the skeleton. In turn, the activities of bone cells are not limited to their bone remodelling activities but also to modulation of adipose cell sensitivity and insulin secretion. This review will discuss these new insights linking bone remodelling to the control of fat metabolism and the association between diabetes mellitus and osteoporosis. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) control cell fate and regulate tissue function. Some of the NRs are expressed in a circadian and tissue-specific manner. Clock genes are part of the circadian network and fine-tune gene expression in adipose and skeletal tissues. Pparg, a master transcription factor that determines adipogenesis, exhibits a circadian expression pattern in white adipose tissue and liver. Here we report the finding that the message and protein for a peripheral clock gene, nocturnin, is markedly upregulated with Pparg activation in adipocytes and bone marrow stromal cells. Nocturnin is also expressed in relatively high amounts in other tissues that may have physiologic relevance for bone, including the brain and hypothalamus. Of importance, we found polymorphic strain differences in bone marrow nocturnin expression that relate to phenotypic determinants of skeletal acquisition. Defining the function of nocturnin in peripheral tissues should provide new insights into lineage allocation and the intimate relationship between nuclear receptors and physiologic timekeeping. [ABSTRACT FROM AUTHOR]

Mesenchymal lineage cells arise from pluripotent stem cells in the bone marrow (BM) and transition through a series of developmental stages resulting in mature functional cells. This specification results in the development of osteoblast, adipocytes, myoblasts, chondroblasts, and stromal cells (part of the recticular network). The osteoblast developmental pathway is well understood particularly at the later stages of development. However, less is known about the very early stages, where cell fate decisions that lead to commitment to the osteoblast lineage occur. Adipocytes, the cells that produce fat, likely share a common early progenitor with osteoblasts, although little is known about the molecular control of this lineage bifurcation. Growing evidence indicates that transcription factors required for B lymphocyte development from hematopoietic stem cells are critical for proper skeletal development although as yet none have been implicated in osteoblast differentiation. We have discovered that O/E-1, a transcription factor essential for B cell development, is expressed in osteoblasts and plays a critical role in controlling osteoblast development. O/E-1-deficient mice are runted, have increased bone formation parameters, and have a striking increase in osteoblasts. Remarkably, these mice also exhibit a dramatic expansion of adipocytes in the medullary canal of long bones. [ABSTRACT FROM AUTHOR]

We mapped a quantitative trait locus (QTL) for BMD to mid-distal chromosome (Chr) 6 in a cross between C57BL/6J (B6) and C3H/HeJ (C3H). The B6.C3H-6T (6T) congenic was developed to map candidate genes in this QTL. Recently, a 25 cM paracentric inversion was discovered on Chr 6 in C3H/HeJ; we found 6T also carries this inversion. Microarrays from the liver of B6 and 6T uncovered two narrow bands of decreased gene expression in close proximity to the predicted locations of the inversion breakpoints. Changes in specific gene expression in 6T were consistent with its phenotype of low trabecular bone volume and marrow adipogenesis. The BXH recombinant inbred (RI) strains do not carry the C3H/HeJ inversion. To test if the inversion, or allelic effects, were responsible for the 6T phenotype, we made a new congenic, B.H-6, developed by introgressing a 30 Mb region of C3H genomic sequence from BXH6 onto a B6 background. While genetically identical to 6T, this new congenic had a distinct metabolic and skeletal phenotype, with more body fat and greater trabecular BV/TV compared to B6 or 6T. We conclude that the phenotype of 6Tcannot be explained by simple allelic differences in one or more genes from C3H. Rather, 6T demonstrates that disordered regulation of gene expression by genomic rearrangement can have a profound effect on a complex trait, such as BMD, and that genomic rearrangement can supersede the effects of various alleles. [ABSTRACT FROM AUTHOR]

For urologists who do not perform hypospadias surgery, the number of techniques which has been described may seem astonishing, but each one seems to have added something new to the art of penile and urethral reconstruction in these children. The authors from the USA describe the learning curve in this complicated technique. Authors from the UK present a large series of Y-type urethral duplication in the male and describe the surgical procedures required to correct this rare congenital anomaly. OBJECTIVE To provide an insight into the ‘learning curve’ of fellowship-trained paediatric urologists associated with hypospadias repair, as hypospadias surgery is one of the most common yet difficult procedures used by the paediatric urologist. PATIENTS AND METHODS Prospective data were collected on 231 consecutive hypospadias operations performed by one paediatric urologist (M.H.) over a 5-year period, beginning with his first year after completing his fellowship. All patients were having their first surgery and none had a staged repair. Fistula formation was used as a surrogate for the complication rate, as it is an objective measurable outcome that is easily identified with little interobserver or parental/physician variability. The follow-up included several visits in the 15 months after repair, during which virtually all complications could be identified and addressed. RESULTS The operative results improved throughout the 5 years of observation; there was a statistically significant decline in the fistula rate in each year of observation ( P < 0.001; Kruskal–Wallis exact test for ranked groups). The absolute reduction in fistula rates between the first 2 and the last 2 years was 12.7% ( P < 0.02; chi squared). CONCLUSIONS The science and surgery of hypospadiology is mostly and correctly delegated to the paediatric urologist. Even in the hands of a fellowship-trained paediatric urologist, a successful repair, as measured by complication rate, statistically improves with time and experience. [ABSTRACT FROM AUTHOR]

The molecules that regulate bone cell development, particularly at the early stages of development, are only partially known. Data are accumulating that indicate a complex relationship exists between B cells and bone cell differentiation. Although the exact nature of this relationship is still evolving, it takes at least two forms. First, factors that regulate B-cell growth and development have striking effects on osteoclast and osteoblast lineage cells. Similarly, factors that regulate bone cell development influence B-cell maturation. Second, a series of transcription factors required for B-cell differentiation have been identified, and these factors function in a developmentally ordered circuit. These transcription factors have unpredicted, pronounced, and non-overlapping effects on osteoblast and/or osteoclast development. These data indicate that at least a regulatory relationship exists between B lymphopoiesis, osteoclastogenesis, and osteoblastogenesis. [ABSTRACT FROM AUTHOR]

Based upon suggestions that the two cerebral hemispheres may be differentially involved in the perception and regulation of autonomic activity, three studies were designed to explore differences in the relationship between left versus right hand finger tapping and the heartbeat. In each study, right-handed subjects were asked to tap with either their left versus right forefingers regularly at the rate of approximately once per second. When the time from the R-spike immediately preceding their tap to the tap was examined, a significant difference between the two hands was obtained in two of the studies, with the left hand tapping closer to the last R-spike compared with the right. A variety of additional conditions in the experiments suggest that this effect may depend upon tapping rhythmically. The implications of these findings for the differential role of the left and right hemispheres in the perception and regulation of cardiac activity are considered. [ABSTRACT FROM AUTHOR]