Aged-vascular niche hinders osteogenesis of mesenchymal stem cells through paracrine repression of Wnt-axis.

Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular and bone diseases in the elderly, the underlying mechanisms for the vascular-bone cross-talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt-driven-axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson-Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long-term inhibitory effects. microRNA-transcriptomics of HGPS patient plasma combined with aged-vascular niche analyses in progeria mice reveal abundant secretion of Wnt-repressive microRNA-31-5p. Moreover, we show that inhibition of microRNA-31-5p as well as selective Wnt-activator CHIR99021 boosts the osteogenic potential of BMSCs through de-repression and activation of the Wnt-signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA-based therapies of bone loss in elderly.

Histopathology of the Intervertebral Disc of Nothobranchius furzeri, a Fish Model of Accelerated Aging.

INTRODUCTION: Osteoarthritis is a classical age-related disease, which affects millions of patients worldwide. To further understand the pathophysiology and to develop therapeutic strategies for this disease, animal models play a significant role. Nothobranchius furzeri is an established model for accelerated aging that spontaneously develops spinal deformities. Although the bone properties of N. furzeri are well described, characteristics of the intervertebral discs are still unknown. The aim of this study was to investigate the characteristics of the intervertebral discs of healthy and deformed N. furzeri. MATERIAL AND METHODS: Intervertebral properties of healthy and deformed N. furzeri were investigated in 8-, 12-, 18- and 21.5-week-old male fish of the GRZ strain. For histological evaluations the fish were decalcified, paraffin-embedded and stained with (1) hematoxylin and eosin, (2) toluidine blue and (3) alcian blue/picrosirius red. RESULTS: 8-week-old and deformed N. furzeri showed spongy-like tissue containing vacuolated notochord cells and a beginning formation of fibrous tissue in the central area. Older healthy fish showed fibrous tissue in the central region and a spongy-like tissue in the peripheral region. CONCLUSION: Our study revealed age- and disease-related alterations of the vertebral discs in N. furzeri. Further studies should investigate the utility of N. furzeri as a model for degenerative spine diseases.

Moderate COVID-19 Disease Is Associated With Reduced Bone Turnover.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has been associated with musculoskeletal manifestations, including a negative effect on bone health. Bone formation was found to be reduced in coronavirus disease 2019 (COVID-19) patients. The aim of this case-control study was to determine whether bone metabolism is coupled or uncoupled in COVID-19 patients with moderately severe disease, the latter expressed by the requirement of hospitalization but not intensive care treatment, no need for mechanical ventilation, and a C-reactive protein level of (median [quartiles], 16.0 [4.0; 52.8]) mg/L in serum. Besides standard biochemical markers, serum levels of C-terminal telopeptide of type 1 collagen, tartrate-resistant acid phosphatase, osteocalcin, bone-specific alkaline phosphatase, sclerostin, dickkopf-1, and osteoprotegerin were evaluated in COVID-19-infected patients at the time of hospital admission, along with those of age- and sex-matched noninfected controls. The median age of the 14 female and 11 male infected patients included in the matched-pair analysis was (67 [53; 81]) years. C-terminal telopeptide of type 1 collagen was significantly lower in COVID-19 patients (0.172 [0.097; 0.375] ng/mL) than in controls (0.462 [0.300; 0.649] ng/mL; p = 0.011). The patients' osteocalcin levels (10.50 [6.49; 16.26] ng/mL) were also lower than those of controls (15.33 [11.85, 19.63] ng/mL, p = 0.025). Serum levels of sclerostin and dickkopf-1 were significantly higher in infected patients relative to controls. The remaining parameters did not differ between cases and controls. A limitation of the study was that patients and controls were recruited from different hospitals. Nevertheless, due to the geographical proximity of the two centers, we assume that this fact did not influence the results of the study. Given this limitation, the investigation showed that bone metabolism is altered but remains coupled in patients with moderately severe COVID-19. Therefore, it is important to evaluate bone turnover markers and fracture risk in these patients during the postinfection period. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Challenges in establishing animal models for studying osteoimmunology of hypoparathyroidism.

Hypoparathyroidism is a relatively rare human and veterinary disease characterized by deficient or absent production of parathyroid hormone (PTH). PTH is known as a classical regulator of calcium and phosphorus homeostasis. Nevertheless, the hormone also appears to modulate immune functions. For example, increased CD4:CD8 T-cell ratios and elevated interleukin (IL)-6 and IL-17A levels were observed in patients with hyperparathyroidism, whereas gene expression of tumor necrosis factor-α (TNF-α) and granulocyte macrophage-colony stimulating factor (GM-CSF) was decreased in patients with chronic postsurgical hypoparathyroidism. Various immune cell populations are affected differently. So, there is a need for validated animal models for the further characterization of this disease for identifying targeted immune-modulatory therapies. In addition to genetically modified mouse models of hypoparathyroidism, there are surgical rodent models. Parathyroidectomy (PTX) can be well performed in rats-for pharmacological and associated osteoimmunological research and bone mechanical studies, a large animal model could be preferable, however. A major drawback for successfully performing total PTX in large animal species (pigs and sheep) is the presence of accessory glands, thus demanding to develop new approaches for real-time detection of all parathyroid tissues.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

[Diagnosis and management of patients with diabetes and co-existing osteoporosis (Update 2023) : Common guideline of the Austrian Society for Bone and Mineral Research and the Austrian Diabetes Society]. / Diagnose und Management der Osteoporose bei Diabetes mellitus (Update 2023) : Gemeinsame Leitlinie der Österreichischen Gesellschaft für Knochen- und Mineralstoffwechsel und der Österreichischen Diabetes Gesellschaft.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. The identification and management of fracture risk in these patients remains challenging. This manuscript explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated areal bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (FRAX) in these patients. It further reviews the impact of diabetes drugs on bone tissue as well as the efficacy of osteoporosis treatments in this population. An algorithm for the identification and management of diabetic patients at increased fracture risk is proposed.

Pulse-echo ultrasound measurement in osteoporosis screening: a pilot study in older patients.

BACKGROUND: A mere 25% of patients who need treatment for osteoporosis receive appropriate therapy, partly due to the time-consuming and stressful diagnostic workup for older patients with functional decline. AIMS: The purpose of the present study was to investigate the accuracy of pulse-echo ultrasound measurement of the lower leg for the detection of osteoporosis in older patients, and evaluate the effect of a proposed diagnostic algorithm. METHODS: Cortical thickness and the so-called density index (DI) were measured prospectively on the lower leg with a pulse-echo ultrasound (PEUS) device. The accuracy of the device was compared with dual-energy X-ray absorptiometry (DXA) of the hip. We calculated algorithms combining FRAX® scores and PEUS measures as a guide for specific treatment of osteoporosis. RESULTS: Three hundred and thirty-three patients aged on average 81 years (82.1% women, 275/333) were included in the study. The sensitivity of the ultrasound device versus DXA for the detection of osteoporosis was 94.4% (84/89), and the specificity was 59% (144/247). The gender-specific sensitivity was 96.2% (75/78) for women and 81.8% (9/11) for men. DISCUSSION: Clinical decisions for the specific treatment of osteoporosis could be based on the proposed algorithm, without additional DXA measurements, in 90.9% (303/333) of the patients. CONCLUSION: Older patients with a similar risk profile as in our study population may benefit from PEUS, as it is a non-invasive, cost-effective, and efficient diagnostic tool with high accuracy in screening patients for osteoporosis and the risk of fractures.

Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies.

BACKGROUND: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. METHODS: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). RESULTS: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92-5.92, p < 0.001). CONCLUSION: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.

Circulating miRNAs Respond to Denosumab Treatment After 2 Years in Postmenopausal Women With Osteoporosis-the MiDeTe study.

CONTEXT: MicroRNAs (miRNAs)-short, single-stranded, noncoding RNAs-regulate several biological processes, including bone metabolism. OBJECTIVE: We investigated circulating miRNAs as promising biomarkers for treatment monitoring in women with postmenopausal osteoporosis on denosumab (DMAB) therapy. METHODS: In this prospective, observational, single-center study, 21 postmenopausal women treated with DMAB were included for a longitudinal follow-up of 2 years. Next-generation sequencing (NGS) was performed to screen for serological miRNAs at baseline, month 6, and month 24. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to confirm NGS findings in the entire cohort. Bone turnover markers (BTM) P1NP and CTX, and bone mineral density (BMD) by dual x-ray absorptiometry were assessed and correlated to miRNAs. RESULTS: BMD at the hip (5.5%, P = 0.0006) and lumbar spine significantly increased (11.4%, P = 0.017), and CTX (64.1%, P < 0.0001) and P1NP (69.3%, P < 0.0001) significantly decreased during treatment. NGS analysis revealed significant changes in miRNAs after 2 years of DMAB treatment but not after 6 months. Seven miRNAs were confirmed by RT-qPCR to be significantly changed during a 2-year course of DMAB treatment compared to baseline. Four of these were mainly transcribed in blood cells, including monocytes. Correlation analysis identified significant correlation between change in miRNA and change in BTMs as well as BMD. Based on effect size and correlation strength, miR-454-3p, miR-26b-5p, and miR-584-5p were defined as top biomarker candidates, with the strongest association to the sustained effect of denosumab on bone in osteoporotic patients. CONCLUSION: Two years of DMAB treatment resulted in upregulation of 7 miRNAs, 4 of which are mainly transcribed in monocytes, indicating a potential impact of DMAB on circulating osteoclast precursor cells. These changes were associated to BMD gain and BTM suppression and could therefore be useful for monitoring DMAB treatment response.

Assessment of Bone Microstructure by Micro CT in C57BL/6J Mice for Sex-Specific Differentiation.

It remains uncertain which skeletal sites and parameters should be analyzed in rodent studies evaluating bone health and disease. In this cross-sectional mouse study using micro-computed tomography (µCT), we explored: (1) which microstructural parameters can be used to discriminate female from male bones and (2) whether it is meaningful to evaluate more than one bone site. Microstructural parameters of the trabecular and/or cortical compartments of the femur, tibia, thoracic and lumbar vertebral bodies, and skull were evaluated by µCT in 10 female and 10 male six-month-old C57BL/6J mice. The trabecular number (TbN) was significantly higher, while the trabecular separation (TbSp) was significantly lower in male compared to female mice at all skeletal sites assessed. Overall, bone volume/tissue volume (BV/TV) was also significantly higher in male vs. female mice (except for the thoracic spine, which did not differ by sex). Most parameters of the cortical bone microstructure did not differ between male and female mice. BV/TV, TbN, and TbSp at the femur, and TbN and TbSp at the tibia and lumbar spine could fully (100%) discriminate female from male bones. Cortical thickness (CtTh) at the femur was the best parameter to detect sex differences in the cortical compartment (AUC = 0.914). In 6-month-old C57BL/6J mice, BV/TV, TbN, and TbSp can be used to distinguish male from female bones. Whenever it is not possible to assess multiple bone sites, we propose to evaluate the bone microstructure of the femur for detecting potential sex differences.

Differential Expression of Dickkopf 1 and Periostin in Mouse Strains with High and Low Bone Mass.

By expressing different genes and proteins that regulate osteoclast as well as osteoblast formation, osteocytes orchestrate bone metabolism. The aim of this project was the evaluation of the differences in the osteocytes' secretory activity in the low bone mass mouse strain C57BL/6J and the high bone mass strain C3H/J. The femura of eight- and sixteen-week-old male C57BL/6J and C3H/J mice­six animals per group­were analyzed. Using immunohistochemistry, osteocytes expressing dickkopf 1, sclerostin, periostin, fibroblast growth factor 23 (FGF23), and osteoprotegerin were detected. By means of the OsteoMeasure-System, 92.173 osteocytes were counted. At the age of eight weeks, approximately twice as many cortical and trabecular osteocytes from the C57BL/6J mice compared to the C3H/J mice expressed dickkopf 1 (p < 0.005). The number of cortical osteocytes expressing sclerostin was also higher in the C57BL/6J mice (p < 0.05). In contrast, the cortical and trabecular osteocytes expressing periostin were twice as high in the C3H/J mice (p < 0.005). The dickkopf 1 expressing osteocytes of the C57BL/6J mice decreased with age and showed a strain-specific difference only in cortical bone by 16 weeks of age (p < 0.05). In the C3H/J mice, the amount of osteocytes expressing periostin tended to increase with age. Thus, strain-related differences were maintained in 16-week-old rodents (p < 0.005). No strain-specific differences in the expression of FGF23 or osteoprotegerin in the cortical compartment could be detected. This experimental study showed that the osteocytes' protein expression reflects differences in bone characteristics and strain-related differences during skeletal maturation. Besides the osteocytes' expression of sclerostin, their expression of dickkopf 1 and periostin seems to be important for bone properties as well.

Osteoporosis treatment in Austria-assessment of FRAX-based intervention thresholds for high and very high fracture risk.

The adoption of the management pathway proposed by the National Osteoporosis Guideline Group (NOGG), UK applied using the Austrian FRAX® tool in a referral population of Austrian women categorises 22-29% of women age 40 years or more eligible for treatment of whom 28-34% are classified at very high risk. PURPOSE: The aim of this study is to provide a reference document for the further development of existing guidelines for the management of osteoporosis in Austria, considering FRAX-based intervention thresholds for high and very high fracture risk. METHODS: The model development was based on two Austrian hospital referral cohorts. Baseline information was collected to compute the 10-year probability (using the Austrian FRAX model) of a major osteoporotic fracture (MOF) and hip fracture both with and without the inclusion of femoral neck bone mineral density (BMD). Assessment thresholds for BMD testing were defined, as well as intervention thresholds. In addition, thresholds that characterise men and women at high and very high fracture risk were established. The management pathway followed that currently recommended by the UK National Osteoporosis Guideline Group (NOGG). RESULTS: The two cohorts comprised a total of 1306 women and men with a mean age of 66.7 years. Slightly more than 50% were eligible for treatment by virtue of a prior fragility fracture. In those women without a prior fracture, 22% (n = 120) were eligible for treatment based on MOF probabilities. Of these, 28% (n = 33) were found to be at very high risk. When both MOF and hip fracture probabilities were used to characterise risk, 164 women without a prior fracture were eligible for treatment (29%). Of these, 34% (n = 56) were found to be at very high risk. Fewer men without prior fracture were eligible for treatment compared with women. CONCLUSION: The management pathway as currently outlined is expected to reduce inequalities in patient management. The characterisation of very high risk may aid in the identification of patients suitable for treatment with osteoanabolic agents.

Denosumab for Prevention of Acute Onset Immobilization-Induced Alterations of Bone Turnover: A Randomized Controlled Trial.

Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of early administration of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to 4 weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Regarding serum levels of CTX-1, changes over time averaged -0.45 ng/mL (95% confidence interval [CI] -0.72, -0.18) for the denosumab group and 0.29 ng/mL (95% CI -0.01, 0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged -0.74 ng/mL (95% CI -1.14, -0.34; p = 0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged -5.60 ng/mL (95% CI -11.2, -0.04; p = 0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (-1.77 mmol/L [95% CI -3.48, -0.06; p = 0.044]). No adverse events could be attributed to the study medication. The investigation proved that a single application of denosumab early after admission to an ICU prevents acute immobilization-associated increase in bone resorption among previously healthy individuals. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Combination of Caloric Restriction and a Mixed Training Protocol as an Effective Strategy to Counteract the Deleterious Effects in Trabecular Bone Microarchitecture Caused by a Diet-Induced Obesity in Sprague Dawley Rats.

The association of obesity with changes in bone mass is not clear. Obese individuals tend to have an increased bone mineral density, but other studies have shown that obesity is a major risk factor for fractures. The mechanisms of bone response during a weight loss therapy as well as the possible osteoprotective effect of exercise should be analyzed. The aim of this study was to test the effects of a weight-loss program based on the combination of caloric restriction and/or a mixed training protocol on different parameters of bone morphology and functionality in a DIO rat model. Three stages were established over a 21-week period (obesity induction 0-12 w, weight loss intervention 12-15 w, weight maintenance intervention 15-21 w) in 88 male Sprague Dawley rats. Bone microarchitecture, total mineral and elemental composition, and bone metabolism parameters were assessed. Weight loss interventions were associated to healthy changes in body composition, decreasing body fat and increasing lean body mass. On the other hand, obesity was related to a higher content of bone resorption and inflammatory markers, which was decreased by the weight control interventions. Caloric restriction led to marked changes in trabecular microarchitecture, with a significant decrease in total volume but no changes in bone volume (BV). In addition, the intervention diet caused an increase in trabeculae number and a decrease in trabecular spacing. The training protocol increased the pore diameter and reversed the changes in cortical porosity and density of BV induced by the high protein diet at diaphysis level. Regarding the weight-maintenance stage, diminished SMI values indicate the presence of more plate-like spongiosa in sedentary and exercise groups. In conclusion, the lifestyle interventions of caloric restriction and mixed training protocol implemented as weight loss strategies have been effective to counteract some of the deleterious effects caused by a dietary induction of obesity, specifically in trabecular bone morphometric parameters as well as bone mineral content.

Singularity and Commonality in Response to SARS-CoV-2 in Lung and Colon Cell Models.

The systemic nature of COVID-19 with multiple extrapulmonary manifestations of disease, largely due to the wide tissue expression of SARS-CoV-2 major entry factors, as well as the patient-specific features of COVID-19 pathobiology, determine important directions for basic and translational research. In the current study, we addressed the questions of singularities and commonalities in cellular responses to SARS-CoV-2 and related SARS-CoV on the basis of compendium-wide analysis of publicly available transcriptomic datasets as part of the herein implemented multi-modular UNCOVIDING approach. We focused on cellular models attributed to the epithelial cells of the respiratory system, the Calu-3 cell line, and epithelial cells of the gastrointestinal tract, the Caco-2 cell line, infected with either SARS-CoV-2 or SARS-CoV. Here, we report the outcome of a comparative analysis based on differentially expressed genes in terms of perturbations and diseases, Canonical pathways, and Upstream Regulators. We furthermore performed compendium-wide analysis across more than 19,000 mRNASeq datasets and dissected the condition-specific gene signatures. Information was gained with respect to common and unique cellular responses and molecular events. We identified that in cell lines of colon or lung origin, both viruses show similarities in cellular responses; by contrast, there are cell type-specific regulators that differed for Calu-3 and Caco-2 cells. Among the major findings is the impact of the interferon system for lung Calu-3 cells and novel links to the liver- and lipid-metabolism-associated responses for colon Caco-2 cells as part of the extrapulmonary pathomechanisms in the course of COVID-19. Among differently expressed genes, we specifically dissected the expression pattern of the APOBEC family members and propose APOBEC3G as a promising intrinsic antiviral factor of the host response to SARS-CoV-2. Overall, our study provides gene expression level evidence for the cellular responses attributed to pulmonary and gastrointestinal manifestations of COVID-19.

Self-reported Resistance Training Is Associated With Better HR-pQCT-derived Bone Microarchitecture in Vegan People.

CONTEXT: A plant-based lifestyle is a global trend; lower bone mineral density and increased fracture risk in vegan people are reported. OBJECTIVE: The primary objective was to assess trabecular and cortical bone microarchitecture in vegans and omnivores. Secondary objectives were to evaluate relationships between bone microarchitecture, nutrition parameters, and physical activity. METHODS: This was an observational study at the Medical Department II, St. Vincent Hospital (tertiary referral center for gastrointestinal, metabolic, and bone diseases, and teaching hospital of the Medical University of Vienna), including 43 healthy nonobese female and male subjects on a plant-based diet for at least 5 years, and 45 healthy nonobese female and male subjects on an omnivore diet for at least 5 years. The main outcome measures were the parameters of trabecular and cortical bone microarchitecture (high-resolution peripheral quantitative computed tomography), serum markers of bone turnover, nutrient intake (nutrition protocol), and self-reported resistance training (physical activity questionnaires). RESULTS: In the vegan group, trabecular and cortical structure were altered compared with omnivores. Vegans not reporting resistance training had diminished bone microarchitecture compared with omnivores not reporting resistance training. In vegans and omnivores reporting resistance training, bone structure was similar. In both vegan subgroups (resistance training and not resistance training), a small number of correlations between nutrient intake and bone microarchitecture were observed without a conclusive pattern. CONCLUSION: Bone microarchitecture in vegans differed from matched omnivores but could not be explained solely by nutrient uptake. These differences were attenuated between the subgroups reporting resistance training. In addition to a well-planned diet, progressive resistance training on a regular basis should be part of the vegan lifestyle.

Mechanisms of Systemic Osteoporosis in Rheumatoid Arthritis.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with RA, was delineated. Autoimmune inflammatory processes, which lead to a systemic upregulation of inflammatory and osteoclastogenic cytokines, the production of autoantibodies, and Th cell senescence with a presumed disability to control the systemic immune system's and osteoclastogenic status, may play important roles in the pathophysiology of osteoporosis in RA. Consequently, osteoclast activity increases, osteoblast function decreases and bone metabolic and mechanical properties deteriorate. Although a number of disease-modifying drugs to treat joint inflammation are available, data on the ability of these drugs to prevent fragility fractures are limited. Thus, specific treatment of osteoporosis should be considered in patients with RA and an associated increased risk of fragility fractures.

Nothobranchius furzeri, the Turquoise Killifish: A Model of Age-Related Osteoporosis?

INTRODUCTION: Osteoporosis is a frequent age-related disease, which affects millions of people worldwide. Despite significant progress in the treatment of the disease, a high number of patients still are underdiagnosed and undertreated. Therefore, novel animal models for the investigation of the disease are necessary. Nothobranchius furzeri is the shortest-lived vertebrate (with a lifespan of 3-7 months) that can be kept in captivity. Although it is an established model for aging research, studies on bone are lacking. The aim of this study was therefore to characterize N. furzeri as a potential model for age-related osteoporosis. MATERIALS AND METHODS: Bone properties of aging N. furzeri were investigated in male and female fish of the Gona Re Zhou strain, which were between 8 and 20 weeks old. Micro-computed tomography (Scanco Medical µCT35) was performed to determine the bone properties of the vertebral bodies. Bone structure and remodeling were investigated by different histological staining techniques and histomorphometry. The chemical composition of fish vertebrae and intervertebral discs was analyzed by Raman microspectroscopy. RESULTS: Osteoblasts, mono- and multinucleated osteoclasts but no osteocytes could be observed in the vertebral area of N. furzeri. Histomorphometric evaluations revealed a significant decrease of the number of osteoblasts/bone perimeter and for osteoid volume/bone volume (BV) a trend toward a decrease in old male N. furzeri. Comparing male and female fish, males showed higher BV densities and cortical thickness. The relative values of the bone volume density of 20-week-old male N. furzeri were significantly lower than 10-week-old ones. The mineral to matrix ratio increased with age in male and female fish. In the intervertebral discs, proteoglycans in relation to the organic matrix were significantly lower in older female fish. CONCLUSION: Our finding of a lack of osteocytes is in agreement with the fact that N. furzeri belongs to the evolutionarily advanced teleost fish. Furthermore, not only age-specific but also sex-specific differences were visible in the bone properties of N. furzeri, which can be taken into consideration for the study of gender aspects of age-related musculoskeletal diseases.

Microarchitecture of historic bone samples with tuberculosis.

Tuberculosis is among the leading causes of death from infectious diseases and affects many organ systems, including the skeleton. Skeletal tuberculosis is an extrapulmonary stage of tuberculosis, which occurs after the early and post-primary pulmonary stages of the disease. The aim of our study was to assess the microarchitecture of historic dry bone samples of subjects who have died of tuberculosis documented by post-mortem examinations. These preparations date to the pre-antibiotic era, and were provided by the Pathological-Anatomical Collection in the "Fools Tower" of the Natural History Museum Vienna (PASiN-NHM).We investigated macerated samples of 20 vertebral bodies, 19 femoral heads, and 20 tibiae of a total of 59 individuals diagnosed with tuberculosis from the nineteenth and early twentieth century. 10 femora and 10 tibiae from body donors that did not exhibit signs of infection and 10 (unaffected) vertebrae kept at the PASiN-NHM were studied as controls. The affected regions of the bone samples (and the corresponding regions of the control bones) were analyzed by microcomputed tomography using a Viscom X 8060 II system. Obtained images were analyzed semi-quantitatively. In samples with tuberculosis, independent of the investigated skeletal region, trabecular defects and decreased trabecular thickness were observed. Cortical porosity was seen in affected vertebrae and tibia; in tuberculous tibiae (but not in the femora) cortical thickness was decreased. In half of the individuals, cortical sclerosis was present; signs of ankylosis were observed mainly at the femoral heads affected with tuberculosis. We conclude that a combination of several alterations at the trabecular compartment could be suggestive of the presence of tuberculosis in historic skeletal remains.

Age Related Osteoporosis: Targeting Cellular Senescence.

Age-related chronic diseases are an enormous burden to modern societies worldwide. Among these, osteoporosis, a condition that predisposes individuals to an increased risk of fractures, substantially contributes to increased mortality and health-care costs in elderly. It is now well accepted that advanced chronical age is one of the main risk factors for chronical diseases. Hence, targeting fundamental aging mechanisms such as senescence has become a promising option in the treatment of these diseases. Moreover, for osteoporosis, the main pathophysiological concepts arise from menopause causing estrogen deficiency, and from aging. Here, we focus on recent advances in the understanding of senescence-related mechanisms contributing to age-related bone loss. Furthermore, treatment options for senile osteoporosis targeting senescent cells are reviewed.