Preventive strategies in endocrinology focus on five major fields (the big five): thyroid gland disorders, obesity and diabetes mellitus, dyslipidemia, arterial hypertension and osteoporosis. These highly prevalent conditions have a high morbidity and mortality. As many can be prevented by relatively simple nonpharmacological measures or effectively mitigated by low-threshold pharmacological interventions, they represent model diseases for prevention in internal medicine. This article outlines the current options and discusses them in the context of current prevention strategies. Endocrine and diabetic diseases are among the most common and consequential chronic disorders in industrialized countries and essentially contribute to the total morbidity and mortality. Principal preventive strategies include structural prevention (environmental prevention), such as promoting anti-adipogenic and anti-diabetogenic social structures and behavioral prevention. The emphasis of preventive strategies is on population-related measures, structured screening programs and evidence-based lifestyle interventions. Based on current epidemiological data and guidelines, practical approaches are presented, ranging from iodine prophylaxis, lipid and blood pressure screening to promotion of healthy bone and obesity preventive structures. The concepts discussed demonstrate that effective endocrine and diabetological prevention requires coordinated action across clinical medicine, public health and health policy to realize its full potential.

Osteoporosis, a prevalent age-related disease, is characterized by impaired bone formation and an increased risk of fractures. Current anabolic treatments primarily rely on biologics, which are costly and require inconvenient administration. Identifying regulators of osteoblastogenesis that are amenable to small-molecule targeting is essential for developing more accessible therapies. Through an unbiased kinome-wide RNAi screen in primary murine calvarial osteoblasts, we identified the AXL receptor tyrosine kinase (Axl) as a negative regulator of osteoblast differentiation. Axl is most highly expressed in undifferentiated and early differentiated osteoblasts, with a rapid decline in expression during osteoblast maturation. siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro. In mice, BGB324 treatment significantly increased bone mass by promoting bone formation. Mechanistically, Axl knockdown or inhibition upregulated interferon-stimulated gene 15 (Isg15), while Isg15 knockdown impaired osteoblast differentiation and enhanced Erk phosphorylation, leading to increased expression of osteoblast-specific genes. Consistently, double knockdown experiments demonstrated that simultaneous loss of Axl with either Isg15 or Mapk1, but not other interferon-related genes, reversed the Axl knockdown-induced increase in osteoblast differentiation, reinforcing their mechanistic involvement. Collectively, our study identifies Axl as a promising therapeutic target for osteoporosis and other bone-related disorders.

Die Präventionsfelder in der Endokrinologie umfassen fünf wichtige Bereiche („The Big Five“): Schilddrüsenerkrankungen, Adipositas und Diabetes mellitus, Fettstoffwechselstörungen, arterielle Hypertonie und Osteoporose. Diese Krankheitsbilder sind häufige „Volkskrankheiten“ und weisen eine hohe Folgemorbidität und -mortalität auf. Sie lassen sich zum Teil durch relativ einfache nichtpharmakologische Maßnahmen vermeiden oder durch niederschwellige pharmakologische Interventionen in ihren Auswirkungen deutlich verringern, sodass sie generell Modellkrankheiten für die Prävention und Vorsorge darstellen. Diesbezügliche Optionen werden in unserem Beitrag aufgezeigt und im Kontext der derzeitigen Präventionsstrategien diskutiert. Endokrine und diabetologische Erkrankungen zählen zu den häufigsten und folgenschwersten chronischen Erkrankungen in industrialisierten Ländern und tragen maßgeblich zur Gesamtmorbidität und -mortalität bei. Prinzipielle Präventionsstrategien umfassen die Verhältnisprävention, beispielsweise die Förderung „antiadipogener“ und „antidiabetogener“ Gesellschaftsstrukturen, sowie die Verhaltensprävention. Im Vordergrund der Präventionsstrategien stehen populationsbezogene Maßnahmen, strukturierte Screeningprogramme und evidenzbasierte Lebensstilinterventionen. Anhand aktueller epidemiologischer Daten und Leitlinien werden konkrete Maßnahmen und Erfahrungen beschrieben – von der Jodprophylaxe über Lipid- und Blutdruckscreening bis hin zu knochengesundheitsfördernden und adipositaspräventiven Maßnahmen. Die dargestellten Konzepte zeigen, dass endokrinologische und diabetologische Prävention nur im Zusammenspiel von Medizin, Public Health und Gesundheitspolitik ihr volles Potenzial entfalten kann.

Studies using the 11β-HSD2 transgenic mouse model have established that endogenous glucocorticoids in bone forming cells are important for normal trabecular and cortical bone mass and structure. However, the role of the glucocorticoid receptor in mature osteoblasts and osteocytes for maintaining the skeleton remains unknown. We generated two glucocorticoid receptor knockout models targeting mature osteoblasts and osteocytes (by utilizing the Col2.3-Cre or OG2-Cre). We found that deletion of the glucocorticoid receptor using either knockout model profoundly reduced vertebral bone volume fraction across various ages from 7 to 26 weeks in male and female mice compared to wild-type animals. At the tibia we found sex-specific differences in trabecular bone volume fraction, which was reduced in male but not female Col2.3-Cre and OG2-Cre glucocorticoid receptor knockout mice. Compared to trabecular bone, changes in cortical bone mass and structure in glucocorticoid receptor knockout mice were age and model dependent. Young male and female Col2.3-Cre glucocorticoid receptor knockout mice exhibited a reduction in cortical area and thickness. However, in male but not female OG2-Cre glucocorticoid receptor knockout mice, cortical area fraction and cortical thickness were increased compared to control animals. By 26 weeks of age, cortical bone structure was comparable in Col2.3-Cre and OG2-Cre glucocorticoid receptor knockout mice compared to wild-type animals. Our results provide evidence that glucocorticoid receptor signalling in mature osteoblasts and osteocytes is critical for the maintenance of trabecular and cortical bone mass and structure.

Glucocorticoids (GCs) regulate diverse physiological processes, comprising metabolism, immune responses, stress adaptation, and inflammation. Synthetic GCs are widely used for their powerful anti-inflammatory and immunosuppressive effects, in the treatment of autoimmune diseases, allergies, and inflammation. Here, we investigated the role of the glucocorticoid receptor (GR) in B cell development and survival using both B cell-specific GR-deficient mice and continuous in vivo GR agonist treatments. Deletion of the GR in B cells altered splenic B cell subpopulations, increasing follicular and CD21(lo) B cells and leading to the accumulation of IgM(-)/IgD(-) B cells. In vivo treatment with GR agonists, such as Dexamethasone (Dex) and Prednisolone (Pred), selectively depleted IgD(hi) follicular while enriching IgM(hi) marginal zone B cells. IgM(hi) B cells, which were more resistant to GC-induced cell death, showed an increased expression of IL-10 and genes involved in survival, suggesting a potential regulatory function. In vitro, B cell activation via CpG or lipopolysaccharide (LPS) altered IgM/IgD expression and B cell sensitivity to GR agonists, thereby leading to improved B cell survival and increased plasma cell differentiation. Together, these findings suggest that IgD downregulation and IgM upregulation are critical for B cell survival under GC exposure and that GR agonists promote the enrichment of IgM(hi) cells resistant to apoptosis.

Die Versorgung von Patienten mit Seltenen Erkrankungen in Deutschland stellt eine Herausforderung dar; das endogene Cushing-Syndrom verdeutlicht diese Problematik. Eine Analyse der Versorgungssituation soll Verbesserungspotenziale aufzeigen. Eine systematische Literaturrecherche zur Versorgungssituation wurde mit Verordnungsdaten aus Deutschland und Frankreich sowie Ärztestatistiken aus europäischen Ländern verglichen. In Deutschland besteht eine geringere Versorgungsdichte mit Endokrinologen, eine niedrigere Behandlungsprävalenz als in Frankreich und eine längere Zeit bis zur Diagnosestellung als in anderen Ländern mit vergleichbar gut entwickelten Gesundheitssystemen. Um eine bedarfsgerechte Versorgung von Seltenen Erkrankungen zu gewährleisten, sind Investitionen in die Aus- und Weiterbildung von Spezialisten, wie Fachärzte für Endokrinologie, und in neue, sektorenübergreifende Versorgungsformen notwendig.

Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria.

Musculoskeletal disorders, affecting as many as 1.3 billion people worldwide, are the leading cause of disability and impose a substantial health and socioeconomic burden. Despite the high prevalence of these conditions, translational research in this field is far from optimal, highlighting the need for stronger collaboration between basic and clinical scientists. This paper, authored by members of the basic and clinical action groups of the European Calcified Tissue Society (ECTS) and endorsed by the Board of the ECTS, examines the key barriers to effective translational research in musculoskeletal diseases, including clinician workload, differences in professional language and culture, physical distance between research sites, and insufficient interdisciplinary funding. Through interviews with eight institutional managers across five European countries, we observed that in some institutions, the collaboration between basic scientists and clinicians was regarded as no concern (but with room for improvement), and in most institutions it was recognised as a serious issue. We found consensus on the importance of collaboration yet identified discrepancies in the provision of structural and financial support. Based on these findings, we propose strategic initiatives to bridge the gap between basic and clinical research. Suggested measures include dedicated translational funding, integrated research facilities, collaborative scientific forums, strategic collaborations, establishment of physician-scientists, and, finally, bringing basic and clinical researchers together in the same building or even in a combined department. Notable successes, such as the development of the anti-osteoporotic drugs, romosozumab and denosumab, underscore the value of a coordinated approach and exemplify how shared insights between laboratory research and clinical practice can lead to impactful therapeutic advances. Moving forward, we advocate for institutional commitments to foster a robust translational research environment, as well as tailored funding initiatives to support such efforts. This paper serves as a call for discussion and action to enhance interdisciplinary cooperation to advance musculoskeletal medicine and improve outcomes for patients with debilitating musculoskeletal diseases.

Glucocorticoids are two-faced drugs:they have beneficial anti-inflammatory effects but,on the other hand,trigger compli-cations like osteoporosis;identifying glucocorticoid-mediated pathways responsible for side effects,while maintaining their anti-inflammatory action,has been a long-standing goal.Fu et al.discovered that Tau acts as a low-affinity glucocorticoid receptor to induce bone resorption.

Purpose (the aim of the study): Osteoarthritis (OA) is the most prevalent arthritic disease, affecting millions worldwide. During OA progression articular cartilage is gradually destroyed rendering pain and disability. Our accumulated research evidence supporting that healthy articular cartilage is largely dependent on the proper functioning of the multi-functional protein deacetylase Silent mating type Information Regulation 2 homolog (SIRT) 1. However, during the development of OA, SIRT1 activity is gradually reduced, partially due to its cleavage by cathepsin B under pro-inflammatory conditions.

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.

Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs) that include skeletal progenitors from mice undergoing HSCT. Such MSPCs showed reduced CFU-F frequency, increased DNA damage and enhanced occurrence of cellular senescence, while there was a reduced bone volume in animals that underwent HSCT. This reduced MSPC function correlated with elevated activation of the small RhoGTPAse Cdc42, disorganized F-actin distribution, mitochondrial abnormalities and impaired mitophagy in MSPCs. Changes and defects similar to those in mice were also observed in MSPCs from humans undergoing HSCT. A pharmacological treatment that attenuated the elevated activation of CDC42 restored F-actin fiber alignment, mitochondrial function, and mitophagy in MSPCs in vitro. Finally, targeting CDC42 activity in vivo in animals undergoing transplants improved MSPC quality to increase both bone volume and trabecular bone thickness. Our study shows that attenuation of CDC42 activity is sufficient to attenuate reduced function of MSPCs in a BM transplant setting.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs. Glucocorticoids reprogram the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and, as a consequence, inhibition of the inflammatory response.

Bone consists of a complex mineralised matrix that is maintained by a controlled equilibrium of synthesis and resorption by different cell types. Hyaluronan (HA) is an important glycosaminoglycan in many tissues including bone.Previously, the importance of HA synthesis for bone development during embryogenesis has been shown. We therefore investigated whether HA synthesis is involved in adult bone turnover and whether abrogation of HA synthesis in adult mice would alter bone quality.To achieve complete abrogation of HA synthesis in adult mice, we generated a novel Has-total knockout (Has-tKO) mouse model in which a constitutive knockout of Has1 and Has3 was combined with an inducible, Ubc-Cre-driven Has2 knockout.By comparing bone tissue from wild-type, Has1,3 double knockout and Has-tKO mice, we demonstrate that Has2-derived HA mainly contributes to the HA content in bone. Furthermore, Has-tKO mice show a significant decrease of bone integrity in trabecular and cortical bone, as shown by µ-CT analysis. These effects are detectable as early as five weeks after induced Has2 deletion, irrespective of sex and progress with age.Mesenchymal stem cells (MSC) during osteogenic differentiation in vitro showed that Has2 expression is increased while Has3 expression is decreased during differentiation. Furthermore, the complete abrogation of HA synthesis results in significantly reduced osteogenic differentiation as indicated by reduced marker gene expression (Runx-2, Tnalp, Osterix) as well as alizarin red staining. RNAseq analysis revealed that MSC from Has-tKO are characterised by decreased expression of genes annotated for bone and organ development, whereas expression of genes associated with chemokine related interactions and cytokine signalling is increased.Taken together, we present a novel mouse model with complete deletion of HA synthases in adult mice which has the potential to study HA function in different organs and during age-related HA reduction. With respect to bone, HA synthesis is important for maintaining bone integrity, presumably based on the strong effect of HA on osteogenic differentiation.

Bone-resorbing osteoclasts (OCLs) are formed by differentiation and fusion of monocyte precursor cells, generating large multinucleated cells. Tightly regulated cell fusion during osteoclastogenesis leads to formation of resorption-competent OCLs, whose sizes fall within a predictable physiological range. The molecular mechanisms that regulate the onset of OCL fusion and its subsequent arrest are, however, largely unknown. We have previously shown that OCLs cultured from mice homozygous for the R51Q mutation in the vesicle trafficking-associated protein sorting nexin 10, a mutation that induces autosomal recessive osteopetrosis in humans and in mice, display deregulated and continuous fusion that generates gigantic, inactive OCLs. Fusion of mature OCLs is therefore arrested by an active, genetically encoded, cell-autonomous, and SNX10-dependent mechanism. To directly examine whether SNX10 performs a similar role in vivo, we generated SNX10-deficient (SKO) mice and demonstrated that they display massive osteopetrosis and that their OCLs fuse uncontrollably in culture, as do homozygous R51Q SNX10 (RQ/RQ) mice. OCLs that lack SNX10 exhibit persistent presence of DC-STAMP protein at their periphery, which may contribute to their uncontrolled fusion. To visualize endogenous SNX10-mutant OCLs in their native bone environment, we genetically labeled the OCLs of WT, SKO, and RQ/RQ mice with enhanced Green Fluorescent Protein (EGFP), and then visualized the 3D organization of resident OCLs and the pericellular bone matrix by 2-photon, confocal, and second harmonics generation microscopy. We show that the volumes, surface areas and, in particular, the numbers of nuclei in the OCLs of both mutant strains were on average 2-6-fold larger than those of OCLs from WT mice, indicating that deregulated, excessive fusion occurs in the mutant mice. We conclude that the fusion of OCLs, and consequently their size, is regulated in vivo by SNX10-dependent arrest of fusion of mature OCLs.

BACKGROUND:Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS. METHODS:We investigated gene expression signatures in periadrenal adipose tissue from patients with adrenal CS collected during adrenal surgery. RESULTS:During active CS we observed a downregulation of gene programs associated with inflammation in periadrenal adipose tissue. In addition, we observed a clustering of the patients based on tissue gene expression profiles into 2 groups that differed in blood pressure levels (CS low blood pressure and CS high blood pressure). The 2 clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system. Renin was the strongest regulated gene compared with control patients and its expression correlated with increased blood pressure observed in our patients with CS. In the CS high blood pressure group, systemic renin plasma levels were suppressed indicative of an abnormal blood pressure associated with periadrenal adipose tissue renin-angiotensin-aldosterone-system activation. CONCLUSIONS:Here, we show for the first time a relevant association of the local renin-angiotensin-aldosterone-system and systemic blood pressure levels in patients with CS. Patients from the CS high blood pressure group still had increased blood pressure levels after 6 months in remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.

OBJECTIVES:Previous efforts led to the development of two different polymeric biomaterials for periodontal regeneration with antibacterial photodynamic surface activity. The present study aimed to investigate osseointegration and bone formation of both materials in an ovine model. METHODS:Both biomaterials: 1) urethane dimethacrylate-based Biomaterial 1 (BioM1) and 2) tri-armed oligoester-urethane methacrylate-based Biomaterial 2 (BioM2) are enriched with beta-tri-calcium phosphate and the photosensitizer meso-tetra(hydroxyphenyl)chlorin (mTHPC). These materials were implanted in non-critical size bone defects in the sheep femur (n = 16) and tibia (n = 8). Empty defects served as controls (n = 16). Polyfluorochrome sequential bone labeling was carried out at baseline and after 3, 6, and 12 months. Animals were sacrificed after 12 months. Bone specimens (n = 40) were fixed and subjected to microtomographic analysis (µCT) for the evaluation of the bone-volume-fraction (BV/TV), trabecular number and trabecular thickness. Subsequently, histological sections were arranged and polyfluorochrome sequential bone labeling was analyzed by confocal laser scanning microscopy (cLSM). RESULTS:cLSM analysis revealed that highest remodeling and bone formation activity occurred during the second half of the study period (6-12 months). Bone formation in the tibia was significantly lower for the control (2.71 ± 1.26%) as compared to BioM1 (6.01 ± 2.99%) and BioM2 (6.45 ± 2.12%); (p = 0.006, p = 0004). Micro-computed tomography revealed a BV/TV volume fraction of 44.72 ± 9.01% in femur defects filled with BioM1 which was significantly higher compared to the control (32.27 ± 7.02%; p = 0.01). Bone architecture (trabecular number, trabecular thickness) did not significantly differ from the self-healed defects. SIGNIFICANCE:Both biomaterials, especially BioM1 showed good osseointegration and bone formation characteristics and can be recommended for further examination in periodontal regeneration studies.