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Aim: This study was intended to establish the reference intervals of bone turnover markers (BTMs) for healthy populations. Methods: According to the Clinical Laboratory Standards Institute (CLSI) EP28-A3c, we recruited 774 healthy Chinese and investigated their clinical characteristics and relationships among gender, age, season and BTMs. The reference intervals of BTMs for healthy populations in Hebei of China were established through defining the central 95% range of all observations. Results: We found that gender were associated with 25(OH)D, OC, ß-CTX, and P1NP (P < 0.05), but not PTH1-84 (P=0.138). All serum BTMs showed differences among different age groups (P < 0.01). The level of 25 (OH) D in winter showed statistical differences with spring, summer, and autumn (P<0.05). The OC level showed statistical difference between summer and winter (P=0.000). The P1NP levels showed statistical difference between spring and winter (P=0.019), summer and winter (P=0.000), and summer and autumn (P=0.012), respectively. The PTH1-84 levels in winter showed statistical differences with spring, and summer (all P=0.000), while there was no statistically significant difference in ß- CTX levels between seasons. Conclusion: We have established the reference intervals of several BTMs for healthy individuals in Hebei of China, which have statistical significance across different age groups and genders, and there are also significant differences between different seasons. Therefore, the Chinese medical laboratories in different locations should group individuals according to gender and age groups in different seasons, and establish corresponding biological reference intervals.

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OBJECTIVE: The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. METHODS: In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), ß-CrossLaps (ß-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves. RESULTS: Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. ß-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model. CONCLUSION: BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.

Asunto(s)

Biomarcadores , Remodelación Ósea , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Anciano , Biomarcadores/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/epidemiología , Vitamina D/sangre , Vitamina D/análogos & derivados , Hormona Paratiroidea/sangre , Tasa de Filtración Glomerular , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Osteocalcina/sangre , Pronóstico , China/epidemiología , Estudios de Seguimiento , Procolágeno/sangre , Anciano de 80 o más Años

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Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD), common overlapping multisystemic conditions featuring symptomatic joint hypermobility, is challenging due to lack of established causes and diagnostic tools. Currently, the 2017 diagnostic criteria for hEDS are used, with non-qualifying cases classified as HSD, although the distinction remains debated. We previously showed extracellular matrix (ECM) disorganization in both hEDS and HSD dermal fibroblasts involving fibronectin (FN), type I collagen (COLLI), and tenascin (TN), with matrix metalloproteinase-generated fragments in conditioned media. Here, we investigated these fragments in patient plasma using Western blotting across diverse cohorts, including patients with hEDS, HSD, classical EDS (cEDS), vascular EDS (vEDS), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and healthy donors, uncovering distinctive patterns. Notably, hEDS/HSD displayed a shared FN and COLLI fragment signature, supporting their classification as a single disorder and prompting reconsideration of the hEDS criteria. Our results hold the promise for the first blood test for diagnosing hEDS/HSD, present insights into the pathomechanisms, and open the door for therapeutic trials focused on restoring ECM homeostasis using an objective marker. Additionally, our findings offer potential biomarkers also for OA, RA, and PsA, advancing diagnostic and therapeutic strategies in these prevalent joint diseases.

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Primary open angle glaucoma (POAG) is currently the most prevalent cause of irreversible blindness globally. To date, there are few in vitro models that can faithfully recapitulate the complex architecture of the trabecular meshwork (TM) and the specialized trabecular meshwork cell (TMC) characteristics that are local to structurally opposing regions. This study aimed to investigate the parameters that govern TMC phenotype by adapting the extracellular matrix structure to mimic the juxtacanalicular tissue (JCT) region of the TM. Initially, TMC phenotypic characteristics were investigated within type I collagen matrices of controlled fiber density and anisotropy, generated through confined plastic compression (PC). Notably, PC-collagen presented biophysical cues that induced JCT cellular characteristics (elastin, α-ß-Crystallin protein expression, cytoskeletal remodeling and increased mesenchymal and JCT-specific genetic markers). In parallel, a pathological mesenchymal phenotype associated with POAG was induced through localized transforming growth factor -beta 2 (TGFß-2) exposure. This resulted in a profile of alternative mesenchymal states (fibroblast/smooth muscle or myofibroblast) displayed by the TMC in vitro. Overall, the study provides an advanced insight into the biophysical cues that modulate TMC fate, demonstrating the induction of a JCT-specific TMC phenotype and transient mesenchymal characteristics that reflect both healthy or pathological scenarios. STATEMENT OF SIGNIFICANCE: Glaucoma is the most prevalent cause of blindness, with a lack of efficacy within current drug candidates. Reliable trabecular meshwork (TM) in vitro models will be critical for enhancing the fields understanding of healthy and disease states for pre-clinical testing. To date, trabecular meshwork cells (TMCs) display heterogeneity throughout the hierarchical TM, however our understanding into recapitulating these phenotypes in vitro, remains elusive. This study hypothesizes the importance of specific matrix/growth factor spatial stimuli in governing TMC phenotype. By emulating certain biophysical/biochemical in vivo parameters, we introduce an advanced profile of distinct TMC phenotypic states, reflecting healthy and disease scenarios. A notion that has not be stated prior and a fundamental consideration for future TM 3D in vitro modelling.

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PURPOSE: Pulmonary fibrosis is an irreversible scar-forming condition for which there is a lack of non-invasive and specific methods for monitoring its progression and therapy efficacy. However, the disease is known to be accompanied by collagen accumulation. Here, we developed a novel positron emission tomography (PET) probe targeting type I collagen to evaluate its utility for the non-invasive assessment of pulmonary fibrosis. METHODS: We designed a 18F-labeled PET probe ([18F]AlF-CBP) to target type I collagen and evaluated its binding affinity, specificity and stability in vitro. PET with [18F]AlF-CBP, CT, histopathology, immunofluorescence, and biochemical indice were performed to assess and quantify type I collagen levels and pulmonary fibrosis progression and treatment in murine models. Dynamic PET/CT studies of [18F]AlF-CBP were conducted to assess lung fibrosis in non-human primate models. RESULTS: [18F]AlF-CBP was successfully prepared, and in vitro and in vivo tests showed high stability (> 95%) and type I collagen specificity (IC50 = 0.36 µM). The lungs of the fibrotic murine model showed more elevated probe uptake and retention compared to the control group, and there was a positive correlation between the radioactivity uptake signals and the degree of fibrosis (CT: R2 = 0.89, P < 0.0001; hydroxyproline levels: R2 = 0.89, P < 0.0001). PET signals also correlated well with mean lung density in non-human primate models of pulmonary fibrosis (R2 = 0.84, P < 0.0001). CONCLUSION: [18F]AlF-CBP PET imaging is a promising non-invasive method for specific monitoring of lung fibrosis progression and therapy efficacy.

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Numerous small biomolecules exist in the human body and play roles in various biological and pathological processes. Small molecules are believed not to induce intrafibrillar mineralization alone. They are required to work in synergy with noncollagenous proteins (NCPs) and their analogs, e.g. polyelectrolytes, for inducing intrafibrillar mineralization, as the polymer-induced liquid-like precursor (PILP) process has been well-documented. In this study, we demonstrate that small charged molecules alone, such as sodium tripolyphosphate, sodium citrate, and (3-aminopropyl) triethoxysilane, could directly mediate fibrillar mineralization. We propose that small charged molecules might be immobilized in collagen fibrils to form the polyelectrolyte-like collagen complex (PLCC) via hydrogen bonds. The PLCC could attract CaP precursors along with calcium and phosphate ions for inducing mineralization without any polyelectrolyte additives. The small charged molecule-mediated mineralization process was evidenced by Cryo-TEM, AFM, SEM, FTIR, ICP-OES, etc., as the PLCC exhibited both characteristic features of collagen fibrils and polyelectrolyte with increased charges, hydrophilicity, and density. This might hint at one mechanism of pathological biomineralization, especially for understanding the ectopic calcification process.

Asunto(s)

Citrato de Sodio , Citrato de Sodio/química , Citrato de Sodio/metabolismo , Animales , Humanos , Citratos/química , Colágeno/química , Colágeno/metabolismo , Calcinosis/metabolismo , Calcinosis/patología , Propilaminas/química

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Bone tissue engineering (BTE) aims to promote bone regeneration by means of the synergistic effect of biomaterials, cells, and other factors, as potential alternative to conventional treatments for bone fractures. To this aim, a composite material was developed, based on collagen type I, strontium-enriched mesoporous bioactive glasses, and hydroxyapatite nanorods as bioactive and biomimetic components. Nanostructured scaffolds were 3D printed and subsequently chemically crosslinked with genipin to improve mechanical properties and stability. The developed nanostructured system was maintained in culture until 3 weeks with a co-culture of human bone cells to provide anex vivomodel of bone microenvironment and examine the cellular crosstalk and signaling pathways through paracrine cell activities. Human osteoblasts (OBs), derived from trabecular bone, and human osteoclast precursors (OCs), isolated from buffy coat samples were involved, with OBs seeded on the scaffold and OC precursors seeded in a transwell device. When compared to the material without inorganic components, the bioactive and biomimetic scaffold positively influenced cell proliferation and cell metabolic activity, boosting alkaline phosphatase activity of OBs, and reducing OC differentiation. Thus, the bioactive and biomimetic system promoted an enhanced cellular response, highlighting its potential application in BTE.

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Materiales Biocompatibles , Diferenciación Celular , Proliferación Celular , Durapatita , Nanotubos , Osteoblastos , Osteoclastos , Impresión Tridimensional , Estroncio , Ingeniería de Tejidos , Andamios del Tejido , Ingeniería de Tejidos/métodos , Humanos , Andamios del Tejido/química , Estroncio/química , Osteoblastos/citología , Osteoclastos/citología , Osteoclastos/metabolismo , Durapatita/química , Nanotubos/química , Diferenciación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Vidrio/química , Huesos/metabolismo , Osteogénesis/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Colágeno/química , Técnicas de Cocultivo , Células Cultivadas , Fosfatasa Alcalina/metabolismo , Iridoides

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The clinical treatment of bone defects includes allogeneic bone transplantation and autologous bone transplantation. However, they all have their own limitations, and the scope of application is limited. In recent years, bone tissue engineering scaffolds based on a variety of materials have been well developed and achieved good bone regeneration ability. However, most scaffold materials always face problems such as high biotoxicity, leading to inflammation and poor bioactivity, which limits the bone regeneration effect and prolongs the bone regeneration time. In our work, we prepared hydroxyapatite, erythropoietin (EPO), and osteogenic growth peptide (OGP) codoped type-I collagen (Col I) polypeptide nanofiber membranes (NFMs) by electrostatic spinning. In cell experiments, the composite NFMs had low cytotoxicity and promoted osteogenic differentiation of rat bone marrow mesenchymal stem cells. Quantitative real-time polymerase chain reaction and alkaline phosphatase staining confirmed the high expression of osteogenic genes, and alizarin red S staining directly confirmed the appearance of calcium nodules. In animal experiments, the loaded hydroxyapatite formed multiple independent mineralization centers in the defect center. Under the promotion of Col I, EPO, and OGP, the bone continued to grow along the mineralization centers as well as inward the defect edge, and the bone defect completely regenerated in about two months. The hematological and histological analyses proved the safety of the experiments. This kind of design to promote bone regeneration by simulating bone composition, introducing mineralization center and signal molecules, can shorten repair time, improve repair effect, and has good practical prospects in the future.

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Regeneración Ósea , Colágeno Tipo I , Durapatita , Células Madre Mesenquimatosas , Nanofibras , Osteogénesis , Nanofibras/química , Animales , Regeneración Ósea/efectos de los fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo I/química , Colágeno Tipo I/farmacología , Colágeno Tipo I/genética , Osteogénesis/efectos de los fármacos , Durapatita/química , Durapatita/farmacología , Ratas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular/efectos de los fármacos , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Péptidos/farmacología , Péptidos/química , Eritropoyetina/química , Ratas Sprague-Dawley , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , Membranas Artificiales , Histonas

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Background: The relationship between the levels of high-density lipoprotein (HDL) and bone mineral density (BMD) is controversial. Furthermore, the specific role of apolipoprotein A1 (APOA1), a primary HDL component, in regulating BMD remains unclear. This study aimed to elucidate the correlation between APOA1 levels and lumbar BMD in patients with osteoporotic fracture (OPF) for novel insights into potential therapeutic strategies against osteoporosis. Methods: This study included 587 OPF patients enrolled at the Kunshan Hospital, Affiliated with Jiangsu University between January 2017 and July 2022. The patient's serum APOA1 levels were determined, followed by the assessment of lumbar BMD and C-terminal telopeptide of type I collagen (ß-CTX) as outcome variables. The association of APOA1 levels with lumbar BMD and ß-CTX was assessed via Generalized Estimating Equations (GEE) and spline smoothing plot analyses. A generalized additive model (GAM) helped ascertain non-linear correlations. Moreover, a subgroup analysis was also conducted to validate the result's stability. Results: It was observed that APOA1 levels were positively correlated with lumbar BMD (ß = 0.07, 95% CI: 0.02 to 0.11, p = 0.0045), indicating that increased APOA1 levels were linked with enhanced lumbar BMD. Furthermore, APOA1 levels were negatively related to ß-CTX (ß = -0.19, 95% CI: -0.29 to -0.09, p = 0.0003), suggesting APOA1 might reduce osteolysis. In addition, these findings were robustly supported by subgroup and threshold effect analyses. Conclusion: This study indicated that increased APOA1 levels were correlated with enhanced lumbar BMD and decreased osteolysis in OPF patients. Therefore, APOA1 may inhibit osteoclast activity to prevent further deterioration in osteoporotic patients. However, further research I warranted to validate these conclusions and elucidate the underlying physiologies.

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Disruption of the extracellular matrix and dysregulation of the balance between Th17 and regulatory T cells are recognized as risk factors for recurrent spontaneous abortion (RSA). However, the interaction between matrix components and the Th17/Treg axis remains poorly elucidated. The result of this study revealed that the absence of type I collagen in the decidua is linked to Th17/Treg imbalance in RSA. Furthermore, we discovered that biomaterial recombinant humanized type I collagen (rhCOLI) promoted T cell differentiation into Tregs by inhibition the Notch1/Hes1 signaling pathway and enhanced the immunosuppressive function of Tregs, as indicated by increased secretion level of IL-10 and TGF-ß. Importantly, this study is the first to demonstrate that rhCOLI can modulate the Th17/Treg imbalance, reduce embryo resorption rates, reshape the immune microenvironment at the maternal-fetal interface, and improve fertility in an RSA mouse model. Collectively, these findings suggest that type I collagen deficiency may contribute to, rather than result from, RSA, and propose a potential intervention for RSA using rhCOLI.

Asunto(s)

Colágeno Tipo I , Decidua , Proteínas Recombinantes , Linfocitos T Reguladores , Células Th17 , Femenino , Colágeno Tipo I/metabolismo , Animales , Células Th17/inmunología , Embarazo , Decidua/inmunología , Decidua/metabolismo , Ratones , Humanos , Linfocitos T Reguladores/inmunología , Proteínas Recombinantes/farmacología , Aborto Habitual/inmunología , Diferenciación Celular/efectos de los fármacos

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INTRODUCTION: This randomized, cross-over trial assessed the effect of a single bout of high-impact exercise on serum markers of bone formation and bone resorption over a 24 h period. METHODS: Twenty healthy males and females performed a single bout of brief jumping exercise (EXC) or no exercise (CON), 55 min following consumption of a standard breakfast. Blood markers of bone formation (P1NP) and bone resorption (CTX-I) were assessed before (t = 0 h) and over a 5 h period after breakfast, and following 24 h of post-exercise recovery (t = 24 h). RESULTS: Serum CTX-I concentrations decreased during the 5 h postprandial period (time-effect, P < 0.001) with no differences between conditions (time x condition, P = 0.14). After a ~ 16 % decline during the first 30 min following breakfast, serum P1NP concentrations gradually returned to baseline values during the 5 h postprandial period, with no differences in the overall response between conditions (time-effect, P < 0.001; time x condition, P = 0.25). Fasted serum CTX-I concentrations decreased from 0.33 ± 0.15 and 0.35 ± 0.15 ng/mL at baseline, to 0.31 ± 0.13 and 0.31 ± 0.16 ng/mL at t = 24 h in CON and EXC, respectively, with no differences between conditions (time-effect, P < 0.01; time x condition, P = 0.70). Fasted serum P1NP concentrations did not change from baseline to t = 24 h in both CON (baseline: 76 ± 27 ng/mL, t = 24 h: 79 ± 26 ng/mL) and EXC (baseline: 80 ± 24 ng/mL, t = 24 h: 77 ± 29 ng/mL; time-effect, P = 0.89), with no differences between conditions (time x condition, P = 0.22). CONCLUSION: High-impact exercise does not modulate the concentrations of the serum marker of bone formation P1NP and the serum marker of bone resorption CTX-I throughout a 24 h recovery period in healthy adults.

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Biomarcadores , Resorción Ósea , Ejercicio Físico , Osteogénesis , Humanos , Masculino , Resorción Ósea/sangre , Femenino , Ejercicio Físico/fisiología , Biomarcadores/sangre , Osteogénesis/fisiología , Adulto , Adulto Joven , Estudios Cruzados , Colágeno Tipo I/sangre , Periodo Posprandial/fisiología , Procolágeno/sangre , Factores de Tiempo , Fragmentos de Péptidos/sangre , Péptidos

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This study assessed the biocompatibility of two types of nanogold composites: fibronectin-gold (FN-Au) and collagen-gold (Col-Au). It consisted of three main parts: surface characterization, in vitro biocompatibility assessments, and animal models. To determine the structural and functional differences between the materials used in this study, atomic force microscopy, Fourier-transform infrared spectroscopy, and ultraviolet-visible spectrophotometry were used to investigate their surface topography and functional groups. The F-actin staining, proliferation, migration, reactive oxygen species generation, platelet activation, and monocyte activation of mesenchymal stem cells (MSCs) cultured on the FN-Au and Col-Au nanocomposites were investigated to determine their biological and cellular behaviors. Additionally, animal biocompatibility experiments measured capsule formation and collagen deposition in female Sprague-Dawley rats. The results showed that MSCs responded better on the FN-Au and Col-AU nanocomposites than on the control (tissue culture polystyrene) or pure substances, attributed to their incorporation of an optimal Au concentration (12.2 ppm), which induced significant surface morphological changes, nano topography cues, and better biocompatibility. Moreover, neuronal, endothelial, bone, and adipose tissues demonstrated better differentiation ability on the FN-Au and Col-Au nanocomposites. Nanocomposites have a crucial role in tissue engineering and even vascular grafts. Finally, MSCs were demonstrated to effectively enhance the stability of the endothelial structure, indicating that they can be applied as promising alternatives to clinics in the future.

Asunto(s)

Materiales Biocompatibles , Diferenciación Celular , Oro , Células Madre Mesenquimatosas , Nanocompuestos , Ratas Sprague-Dawley , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Oro/química , Animales , Nanocompuestos/química , Diferenciación Celular/efectos de los fármacos , Ratas , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Femenino , Proliferación Celular/efectos de los fármacos , Colágeno/química , Biopolímeros/química , Fibronectinas/metabolismo , Células Cultivadas , Nanopartículas del Metal/química , Ensayo de Materiales , Ingeniería de Tejidos/métodos , Especies Reactivas de Oxígeno/metabolismo , Movimiento Celular/efectos de los fármacos

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Microvesicles (MVs) are a subtype of extracellular vesicles that can transfer biological information over long distances, affecting normal and pathological processes including skin wound healing. However, the diffusion of MVs into tissues can be impeded by the extracellular matrix (ECM). We investigated the diffusion of dermal wound myofibroblast-derived MVs into the ECM by using hydrogels composed of different ECM molecules such as fibrin, type III collagen and type I collagen that are present during the healing process. Fluorescent MVs mixed with hydrogels were employed to detect MV diffusion using fluorometric methods. Our results showed that MVs specifically bound type I collagen and diffused freely out of fibrin and type III collagen. Further analysis using flow cytometry and specific inhibitors revealed that MVs bind to type I collagen via the α2ß1 integrin. These data demonstrate that MV transport depends on the composition of the wound environment.

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The aim of this study was to describe the morphology of the tongue of the okapi, and to compare the results with other ruminants including browsers, intermediates and grazers. The material was collected post-mortem from two animals from a Zoological Garden. The structure of the okapi tongue, focusing of the shape of the tongue, lingual surface, its papillae and lingual glands, was examined using gross morphology, light and polarized microscopy, and by scanning electron microscopy. The okapi tongue was characterized by dark pigmentation on the lingual dorsum (except lingual torus) and on the whole ventral surface. Two types of filiform papillae were observed, with additional, even 6-8 projections at their base. The round fungiform papillae were present at a higher density, up to 16/cm2, on the ventro-lateral area of the lingual apex. Round and elongate vallate papillae were arranged in two parallel lines between the body and root of the tongue. Numerous taste buds were detected within the epithelium of their vallum, while fungiform papillae had sparse taste buds. A lack of foliate papillae was noted. Very small conical papillae, some lenticular in shape, were present on the lingual torus. Thick collagen type I fibers were dominant over collagen type III fibers in the connective tissue of the lingual papillae. The mucous acini units were dominant among lingual glands, indicating that the secretion of okapi lingual glands was mostly mucous. In many aspects, the tongue of okapi resembles the tongue of other ruminants. The specific lingual shape and lingual surface, together with the lingual glands, support the processing of plant food, such as young and soft leaves. Although okapi tongue is characterized by smaller conical papillae compared to other ruminants, its high number of vallate papillae is similar that found in other browsers, intermediate and grazers. Thus the number of gustatory papillae rather indicates that this feature is not related to the type of feeding.

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Papilas Gustativas , Lengua , Animales , Lengua/ultraestructura , Lengua/anatomía & histología , Papilas Gustativas/ultraestructura , Papilas Gustativas/anatomía & histología , Microscopía Electrónica de Rastreo , Jirafas/anatomía & histología , Artiodáctilos/anatomía & histología , Adaptación Fisiológica

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Qualitative alterations in type I collagen due to pathogenic variants in the COL1A1 or COL1A2 genes, result in moderate and severe Osteogenesis Imperfecta (OI), a rare disease characterized by bone fragility. The TGF-ß signaling pathway is overactive in OI patients and certain OI mouse models, and inhibition of TGF-ß through anti-TGF-ß monoclonal antibody therapy in phase I clinical trials in OI adults is rendering encouraging results. However, the impact of TGF-ß inhibition on osteogenic differentiation of mesenchymal stem cells from OI patients (OI-MSCs) is unknown. The following study demonstrates that pediatric skeletal OI-MSCs have imbalanced osteogenesis favoring the osteogenic commitment. Galunisertib, a small molecule inhibitor (SMI) that targets the TGF-ß receptor I (TßRI), favored the final osteogenic maturation of OI-MSCs. Mechanistically, galunisertib downregulated type I collagen expression in OI-MSCs, with greater impact on mutant type I collagen, and concomitantly, modulated the expression of unfolded protein response (UPR) and autophagy markers. In vivo, galunisertib improved trabecular bone parameters only in female oim/oim mice. These results further suggest that type I collagen is a tunable target within the bone ECM that deserves investigation and that the SMI, galunisertib, is a promising new candidate for the anti-TGF-ß targeting for the treatment of OI.

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Colágeno Tipo I , Regulación hacia Abajo , Células Madre Mesenquimatosas , Osteogénesis Imperfecta , Osteogénesis , Pirazoles , Quinolinas , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Animales , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Femenino , Quinolinas/farmacología , Ratones , Niño , Pirazoles/farmacología , Masculino , Diferenciación Celular/efectos de los fármacos , Mutación , Modelos Animales de Enfermedad , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Preescolar , Células Cultivadas , Factor de Crecimiento Transformador beta/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacos , Transducción de Señal/efectos de los fármacos

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Introduction: Fracture of the proximal femur is common in elderly patients, in fact threatening their lives. Age-related sarcopenia may be involved in the imbalance resulting in the injury. Handy and readily accessible biochemical tests would be useful to assess the musculoskeletal system condition in daily practice. The aim of the study was to determine whether there is any relation between muscle decay and fracture of the proximal femur and to assess bone quality in elderly patients. Material and methods: In the study 22 patients who represented the treatment group were hospitalized due to proximal femur fracture. Eighteen patients from the control group with no fracture in their history were admitted to the Internal Medicine Department. Anyone treated for osteoporosis, immune disease affecting protein balance, neoplasm, mental illness, heart failure, or myocardial infarction was excluded from the study. In every case a blood sample from an elbow vein was drawn, collected in EDTA-K2 tubes, and then centrifuged to separate plasma from the whole blood. Subsequently, the concentrations of C-terminal cross-linked telopeptide of type I collagen (CTX-I), sex hormone binding globulin (SHBG) and creatine kinase (CK) in plasma were determined using commercial enzyme-linked immunosorbent assays. Results: The CK plasma concentration differed between the patient groups (p = 0.011). The SHBG plasma concentration was significantly higher in the treatment group (p = 0.006), whereas a slight difference in CTX-I plasma concentration between the groups was found (p = 0.038). No significant correlations between plasma CK, SHBG or CTX-I were found (p > 0.05). Conclusions: Creatine kinase is actually not an appropriate marker for the clinical assessment of muscle tissue quality in patients with or at risk of proximal femur fracture. Analyzing the quality of bone tissue, we can conclude it was poorer in patients with proximal femur fracture than in the control group.

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RATIONALE: Patients with schizophrenia with second-generation antipsychotics (SGAs) treatment have shown an increased risk of bone fragility and susceptibility to fracture; however, it is still unclear whether this risk is derived from the effect of antipsychotics on balance of bone metabolism. OBJECTIVES: We investigated the changes of two bone turnover biomarkers (BTMs) concentrations in people with schizophrenia receiving SGAs: procollagen type I aminoterminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) as BTMs of osteogenesis and bone resorption, respectively, to explore how antipsychotics contribute to bone fragility. METHODS: We recruited 59 Chinese male patients with schizophrenia (32 drug-naïve first-episode (DNFE) patients and 27 chronic patients) to undergo 8 weeks SGAs treatment. Fasting peripheral blood samples of pre- and posttreatment were collected, plasma levels of PINP and CTX-1 were measured. RESULTS: The interaction effects of group and time on PINP and CTX-1 concentrations were found (P = .016 and P = .008). There was a significant decrease for both BTMs concentrations of the posttreatment compared to the pretreatment (P<.001 and P = .003). Chronic patients had significantly higher changes of BTMs concentrations compared to DNFE patients (P = .048 and P = .024). There was a positive correlation of the two BTMs of pretreatment with disease course in DNFE group (r = .37, P = .039;r = .38, P = .035) and a negative correlation of PINP of pretreatment with age in the chronic group (r=-.40, P = .039). CONCLUSION: Long-term SGAs medication inhibited osteogenesis in a dose- and time-dependent manner and damaged the balance of bone formation and bone resorption.

Asunto(s)

Antipsicóticos , Biomarcadores , Resorción Ósea , Colágeno Tipo I , Osteogénesis , Fragmentos de Péptidos , Péptidos , Procolágeno , Esquizofrenia , Humanos , Masculino , Antipsicóticos/efectos adversos , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Procolágeno/sangre , Adulto , Colágeno Tipo I/sangre , Colágeno Tipo I/metabolismo , Fragmentos de Péptidos/sangre , Resorción Ósea/inducido químicamente , Resorción Ósea/metabolismo , Péptidos/sangre , Biomarcadores/sangre , Osteogénesis/efectos de los fármacos , Persona de Mediana Edad , Factores de Tiempo , Adulto Joven , Remodelación Ósea/efectos de los fármacos

RESUMEN

BACKGROUND: Assessing bone turnover in paediatric populations is crucial for understanding the physiological changes occurring during skeletal development and identifying potential abnormalities. The objective of this study was to assess osteocalcin (OC), bone alkaline phosphatase (BALP), and C-terminal telopeptide of type I collagen (CTX-I) levels reflecting bone formation and resorption for age and sex in Polish healthy children and adolescents. MATERIALS AND METHODS: A total of 355 healthy normal-weight children and adolescents (46.5% girls) aged 1-18 years old were recruited. Total body less head (TBLH) and spine L1-L4 were used in children to assess bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Bone marker concentrations were determined by immunoenzymatic methods. RESULTS: Bone marker levels in girls and boys started with higher values in the first year of life and subsequently decreased until reaching a nadir during the prepubertal period. The pubertal peak values of bone markers were reached at 11-13 years old in boys and at 9-11 years old in girls. After puberty, the adolescents showed a gradual decline in bone marker concentrations to the values observed in adults. We found positive correlations between OC level and TBLH-BMD (r = 0.329, p = 0.002), TBLH-BMD Z-score (r = 0.245, p = 0.023), and L1-L4 BMD (r = 0.280, p = 0.009) in the prepubertal group. CONCLUSIONS: We showed serum levels of bone turnover markers-BALP, OC, and CTX-I-in relation to age and sex in healthy Polish children and adolescents. The age intervals of these markers for girls and boys aged 1-18 years old may be clinically useful in the assessment of bone metabolism in individuals with skeletal disorders.

Asunto(s)

Densidad Ósea , Huesos , Masculino , Niño , Femenino , Humanos , Adolescente , Lactante , Preescolar , Polonia , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Biomarcadores , Fosfatasa Alcalina

RESUMEN

BACKGROUND: As a noninvasive alternative therapy, microfocused ultrasound (MFU) has become a research hotspot in recent years for its potential to enhance skin laxity. While several clinical studies have explored the effects of MFU on improving skin laxity, there is limited literature available on the histological changes resulting from MFU treatments. It has been established that the skin structure and composition of the Bama miniature pigs closely resembles that of humans, including collagen content, type I collagen distribution, and elastin distribution. METHODS: This study primarily focuses on examining the histological alterations in the skin tissue of Bama miniature pigs following MFU application. We also selected some typical clinical photographs of patients treated with MFU and compared the clinical effects with histological changes observed in porcine skin. The MFU device utilized in this study incorporates ultra-pulse technology and large focal area technology. RESULTS: Following the standard operating procedures provided by the manufacturer, different handles were used in different skin area of pigs. Biopsies were obtained immediately after treatment and 1 month after treatment. Significant histological changes were observed in the Bama miniature pigs skin, including collagen contraction and fragmentation, dilation and congestion of superficial dermal capillaries immediately after MFU treatment; dermal thickening, increased thickness and density of collagen fibers, elevated levels of elastin and type I collagen, as well as thickened fiber septa in the adipose layer 1 month later. These histological results corresponded to clinical findings in human, such as facial redness and swelling immediately after treatment, and improvement in facial relaxation after approximately 1 month after treatment. CONCLUSION: Collectively, these histological findings provide valuable evidence supporting the clinical application of MFU for enhancing skin laxity. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

RESUMEN

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 mo born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD ≥ 12.0 ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (P = <.0001, .0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups (P = .19, .08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.