Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-β accumulation causing full-blown AD phenotype by the age of 8 months. Micro-computed tomography indicated significantly lower trabecular and cortical bone parameters in 8-month-old male, but not female, 5xFAD mice than sex-matched wild-type littermates. Dynamic histomorphometry revealed reduced bone formation and increased bone resorption, and quantitative RT-PCR showed elevated skeletal RANKL gene expression in 5xFAD males. These mice also had diminished body fat percentage with unaltered lean mass, as determined by dual-energy X-ray absorptiometry (DXA), and elevated Ucp1 mRNA levels in brown adipose tissue, consistent with increased sympathetic tone, which may contribute to the osteopenia observed in 5xFAD males. Nevertheless, no significant changes could be detected between male 5xFAD and wild-type littermates regarding the serum and skeletal concentrations of norepinephrine. Thus, brain-specific amyloid-β pathology is associated with osteopenia and appears to affect both bone formation and bone resorption. Our findings shed new light on the pathophysiologic link between Alzheimer's disease and osteoporosis.

1Department of Dermatology, Medical University of Vienna, Vienna, Austria 2Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany 3Department of Dermatology and Venerology, University Medical Center HamburgEppendorf, Hamburg, Germany 4Department of Dermatology, University of Marburg, Marburg, Germany 5Institute of Virology, Technical University of Munich, Munich, Germany 6Lübeck Institute of Experimental Dermatology and Department of Dermatology, Allergology and Venereology, University of Lübeck, Lübeck, Germany 7Institute of Experimental Oncology (IEO), University Hospital Bonn, Bonn, Germany 8Department of Dermatology, University Hospital, Technical University Dresden, Dresden, Germany 9Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, HansKnoellInstitute, Jena, Germany 10Department of Biological Sciences, Friedrich Schiller University, Jena, Germany 11Department of Dermatology, University Hospital Erlangen, FriedrichAlexander University of ErlangenNürnberg, Research Module II, Erlangen, Germany 12Department of Dermatology, Venereology and Allergology, Section of Clinical and Molecular Dermatology, and European Center for Angioscience (ECAS), University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany 13Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany 14Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin Berlin, Berlin, Germany 15Department of Dermatology, University Hospital Essen, University DuisburgEssen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany 16Department of Dermatology and Venereology, MartinLutherUniversity HalleWittenberg, Halle (Saale), Germany 17Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 18Department of Dermatology, University of Magdeburg, Magdeburg, Germany 19Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany

Bis zu 10–40 % der Bevolkerung weltweit leiden aktuell an einer Form der Allergie, wie Asthma oder auch die atopische Dermatitis. Mehr als 80 Mrd. US Dollar werden allein in den USA durch Behandlungskosten, Arbeitsausfall und Invaliditat verursacht. Allergische Erkrankungen verursachen hierdurch eine betrachtliche gesellschaftliche Belastung – und der Anteil an Erkrankten nimmt, vor allem in Industrie- und Schwellenlandern, stetig zu. Die genauen Hintergrunde hierfur sind bisher unbekannt, ein Zusammenhang mit veranderten Lebensgewohnheiten der westlichen Welt im Zuge der Urbanisierung liegt jedoch nahe. Um die rasante Ausbreitung von allergischen Erkrankungen einzudammen, ist die Identifikation von Risikofaktoren essenziell: Umweltfaktoren wie Feinstaub, die Ernahrung, die Zusammensetzung unseres Mikrobioms und die Pflege unserer Hautbarriere mochten wir im Folgenden als Ansatzpunkte zur Entwicklung praventiver Strategien im Kampf gegen die steigende Inzidenz allergischer Erkrankungen diskutieren.

Benign bone tumors and tumor-like lesions are frequently diagnosed in children and adolescents. The immature skeleton is at risk for growth disturbances and deformity because of the effects of the lesions on normal bone architecture and the physis. The development, manifestation, and severity of the limb length inequality and deformity differs between the various bone pathologies. Distraction osteogenesis, osteotomy, and guided growth are key tools in the treatment of limb inequality and deformity using a combination of external and internal fixation devices.

Since the field-changing invention of noncemented hip arthroplasty fixation in the 1980s, noncemented fixation has been progressively replacing cemented fixation. However, analyses of fixation frequencies reveal new patterns in cement versus noncemented preferences. Although cementation is again gaining ground in the United States, noncemented models remain the dominant fixation mode, seen in more than 90% of all hip arthroplasties. This stark preference is likely driven by concerns regarding implant durability and patient safety. Although advances in surgical techniques, intensive perioperative care, and improved instrument have evolved in both methods, data from large arthroplasty registries reveal shifting risks in contemporary hip arthroplasty, calling the use of noncemented fixation into question. Varying risk profiles regarding sex, age, or health comorbidities and morphological and functional differences necessitate personalized risk assessments. Furthermore, certain patient populations, based on the literature and data from large registries, have superior outcomes from cemented hip arthroplasty techniques. Therefore, we wanted to critically evaluate the method of arthroplasty fixation in primary hip arthroplasties for unique patient populations.

Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. We here demonstrate that together with amplification of human Th17 cell signature properties, NaCl gave rise to a stable anti-inflammatory Th17 cell fate that we found to be restricted to distinct pathogen specificities. The p38/MAPK pathway involving NFAT5 and SGK1regulated FoxP3 and IL-17 expression in high NaCl conditions. The NaCl induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in the mouse model of experimental autoimmune encephalomyelitis (EAE), which demonstrated strongly reduced disease symptoms upon transfer of NaCl-treated encephalitogenic Th17 cells. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-b low cytokine microenvironment. This revealed a context dependent dichotomous role for NaCl in shaping the pathogenicity of Th17 cells. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in collaboration with cytokine blocking drugs.

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-beta-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17A-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF-β-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Fibroblast growth factor-23 (FGF23) is critical for phosphate and vitamin D homeostasis. Cellular and molecular mechanisms underlying FGF23 production remain poorly defined. The extra-large Gα subunit (XLαs) is a variant of the stimulatory G protein alpha-subunit (Gsα), which mediates the stimulatory action of parathyroid hormone in skeletal FGF23 production. XLαs ablation causes diminished FGF23 levels in early postnatal mice. Herein we found that plasma FGF23 levels were comparable in adult XLαs knockout (XLKO) and wild-type littermates. Upon adenine-rich diet-induced renal injury, a model of chronic kidney disease, both mice showed increased levels of plasma FGF23. Unexpectedly, XLKO mice had markedly higher FGF23 levels than WT mice, with higher blood urea nitrogen and more severe tubulopathy. FGF23 mRNA levels increased substantially in bone and bone marrow in both genotypes; however, the levels in bone were markedly higher than in bone marrow. In XLKO mice, a positive linear correlation was observed between plasma FGF23 and bone, but not bone marrow, FGF23 mRNA levels, suggesting that bone, rather than bone marrow, is an important contributor to severely elevated FGF23 levels in this model. Upon folic acid injection, a model of acute kidney injury, XLKO and WT mice exhibited similar degrees of tubulopathy; however, plasma phosphate and FGF23 elevations were modestly blunted in XLKO males, but not in females, compared to WT counterparts. Our findings suggest that XLαs ablation does not substantially alter FGF23 production in adult mice but increases susceptibility to adenine-induced kidney injury, causing severe FGF23 elevations in plasma and bone.

Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the Gq/11α-like, extralarge Gα subunit (XLαs), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms α and δ (PKCα and PKCδ) were diminished. XLαs ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKCα/PKCδ proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gqα-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation-induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XLαs ablation significantly, but modestly, reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hitherto-unknown mechanism of FGF23 synthesis involving a G protein-coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels.

Th2 cells have evolved to protect from large helminth infections and to exert tissue protective functions in response to nonmicrobial noxious stimuli. The initiation, maintenance, and execution of these functions depend on the integration of diverse polarizing cues by cellular sensors and molecular programs as well as the collaboration with cells that are coopted for signal exchange. The complexity of input signals and cellular collaboration generates tissue specific Th2 cell heterogeneity and specialization. In this review, we aim to discuss the advances and recent breakthroughs in our understanding of Th2 cell responses and highlight developmental and functional differences among T cells within the diversifying field of type 2 immunity. We will focus on factors provided by the tissue microenvironment and highlight factors with potential implications for the pathogenesis of allergic skin and lung diseases. Especially new insights into the role of immunometabolism, the microbiota and ionic signals enhance the complexity of Th2 cell regulation and warrant a critical evaluation. Finally, we will discuss how this ensemble of established knowledge and recent breakthroughs about Th2 immunobiology advance our understanding of the pathogenesis of allergic diseases and how this could be exploited for future immunotherapies.

Dysregulated actions of the bone-derived phosphaturic hormone FGF23 result in several inherited diseases and contribute substantially to the morbidity and mortality in renal failure. Molecular mechanisms governing FGF23 production are poorly defined. Parathyroid hormone (PTH) can stimulate FGF23 production via the alpha-stimulatory G protein (Gsα) and cAMP generation. The extra-large Gα-subunit (XLαs) is partially identical to Gsα, can mimic the latter regarding cAMP generation, and can couple to the PTH receptor. However, it has been shown that XLαs acts as a Gq/11α-like protein in kidney and stimulates IP3/PKC signaling. We have found that early postnatal XLαs knockout (XLKO) mice exhibit hyperphosphatemia due to diminished FGF23 production. We aimed to elucidate the mechanism of XLαs-mediated FGF23 synthesis. 2-hour PTH injection (50nM/kg body weight) increased serum FGF23 (WT+vehicle: 520.9±9.7, WT+PTH: 2848. 5±94.0, p<0.001; XLKO+vehicle: 260.8±18.4; XLKO+PTH: 3269.3±124.6 pg/mL, p<0.001; n=9~11 per group) and skeletal FGF23 mRNA (3.2-fold in WT, p<0.01, vs 8.1-fold in XLKO, p<0.001, over baseline; n=8 per group) levels in both genotypes, with no evidence of an impaired response in XLKO. In contrast, the femurs of XLKO mice showed significantly lower PKCα and PKCδ levels than in WT femurs. Likewise, XLαs ablation in osteocytic Ocy454 cells did not impair PTH-induced cAMP generation but suppressed baseline IP3 generation and PKCα/PKCδ protein levels. XLKO Ocy454 cells showed diminished FGF23 mRNA levels, which was rescued by treating the cells with the PKC activator phorbol myristate acetate (PMA). PMA also augmented FGF23 expression in WT cells (4.1-fold over baseline; p<0.05; n=6 per group). Moreover, 24-hour PMA injection (500 ng/g body weight) into WT and XLKO littermates raised FGF23 levels (WT+vehicle: 499. 9±29.9 WT+PMA: 1750.4±316.0; XLKO+vehicle: 281.0±25.9; XLKO+PMA: 846.0±191.7 pg/mL; n=10-13 per group) and caused hypophosphatemia. We then crossed Ocn-Cre or Dmp1-Cre mice with Rosa26-floxed stop-GNAQQ209L (GNAQQ209L) mice, which expresses a constitutively active Gqα mutant and activates PKC signaling upon Cre-mediated recombination. FGF23 levels were significantly increased in both GNAQQ209L/Ocn-Cre (2790.5±221.0 vs 355.3±8.7 pg/mL in controls; p<0.001; n=11-15 per group) and GNAQQ209L/Dmp1-Cre mice (452.2±20.1 vs 266.2±6.4 pg/mL in controls; p<0.01; n=11-14 per group). These results indicate that, rather than affecting PTH/cAMP signaling, XLαs mediates FGF23 production via promoting IP3/PKC signaling, and that PKC activation, directly or by constitutively active Gqα, enhances FGF23 production. These findings identify the XLαs/PKC axis as a novel mechanism governing FGF23 synthesis and a new paradigm for modulating the levels of this hormone in disease. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (TH17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes TH2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-γ (IFN-γ) production in memory T cells. It diverted alternative T cell fates into the TH2 cell phenotype and also induced de novo TH2 cell polarization from naïve T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated TH2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce TH2 cell responses, the orchestrators of atopic diseases.

Sodium chloride has recently been demonstrated to strongly enhance the generation of Th17 cells in both mouse and man. This finding has helped consolidate the epidemiological correlation of enhanced dietary salt intake with the increase in the incidence of autoimmune diseases such as multiple sclerosis. Our data support the Th17 cell promoting effect of sodium chloride on human Th17 cell priming. However, Th17 cells acquired anti-inflammatory properties upon stimulation in sodium chloride enriched micromilieus as evidenced by strong induction of FOXP3 expression and TGF-b production within IL-17 and ROR-gt positive T cells. In addition, sodium chloride also strongly suppressed cytotoxic functions of human T cells and induced T cell exhaustion. This functional modulation occurred at sodium chloride concentrations that are in the range of physiological skin and lymph levels but highly elevated compared to the blood. Tissue salt concentrations are also prone to a wide range of fluctuations depending on dietary habits, which suggests that sodium chloride can have an in vivo impact on functionalities of tissue residing T cells. Together, our data suggest that despite the reported association of salt with induction of pathogenic Th17 cells, sodium chloride instead is a potent inducer of the anti-inflammatory Th17 cell subset and also paralyzes cytotoxic T cell properties in humans. Therefore, our data suggest that reduction of sodium chloride levels by either dietary restriction or specific targeting of downstream signaling events could counteract T cell immunoparalysis and exhaustion in settings of malignancies or chronic infections.

Sodium chloride has recently been demonstrated to strongly enhance the generation of Th17 cells in both mouse and man, which provided mechanistic evidence for the epidemiological correlation of enhanced dietary salt intake and the increasing incidence of autoimmune diseases. Our data support the Th17 cell promoting effect of sodium chloride on human Th17 cell priming. However, Th17 cells acquired anti-inflammatory properties upon stimulation in sodium chloride enriched micromilieus. In addition, sodium chloride also strongly suppressed cytotoxic functions of human T cells. Together, our data suggest that despite the reported association of salt with induction of pathogenic Th17 cells, sodium chloride instead is a potent inducer of the anti-inflammatory Th17 cell subset and also paralyzes cytotoxic T cell properties. Therefore, our data suggest that reduction of sodium chloride levels by either dietary restriction or specific targeting of downstream signaling events could counteract T cell immunoparalysis and exhaustion in settings of chronic inflammatory skin diseases or malignancies.