RÉSUMÉ
Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using µCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.
Sujet(s)
Os spongieux , Os cortical , Lame épiphysaire , Souris knockout , Caractères sexuels , Tartrate-resistant acid phosphatase , Animaux , Tartrate-resistant acid phosphatase/métabolisme , Femelle , Mâle , Souris , Ostéoclastes/métabolisme , Taille d'organe , Facteur de croissance IGF-I/métabolisme , Tibia/métabolisme , Microtomographie aux rayons X , Souris de lignée C57BLRÉSUMÉ
BACKGROUND: The number of adult orthodontic patients is increasing, and studies have shown that autophagy is involved in regulating orthodontic tooth movement and plays an important role in aging-related changes. Therefore, we aimed to explore the role of autophagy in aging-related changes during orthodontic tooth movement by establishing a rat orthodontic tooth movement model. METHODS: Forty-five 6-week-old and sixty-five 8-month-old male Sprague-Dawley rats were selected to represent adolescents and adults and establish orthodontic tooth movement model. They were sacrificed on days 0,1,3,7 and 14. Immunohistochemistry, immunofluorescence and tartrate resistant acid phosphatase (TRAP) staining were applied to measure the expression level of osteogenesis, autophagy, aging factors and osteoclast number in periodontal membrane of left upper first molar during orthodontic tooth movement. Then, we regulated the autophagy level by injecting autophagy activator rapamycin during orthodontic tooth movement and measured these factors and tooth movement distance by micro-computed tomography. RESULTS: Aging factor levels in the periodontal membrane were higher in adult rats than in adolescent rats and the autophagy factor levels were lower. The levels of osteogenic factors were lower on the tension side in adult rats than in adolescent rats. The peak osteoclast number on the pressure side occurred later in adult rats than in adolescent rats. The injection of rapamycin increased autophagy, accelerated orthodontic tooth movement in adult rats, and reduced the levels of aging factors. The levels of osteogenic factors were higher and reached those in adolescent rats at some time points. The number of osteoclasts increased significantly in the early stage. CONCLUSIONS: Autophagy may play a substantial role in regulating aging-related changes in orthodontic tooth movement.
Sujet(s)
Vieillissement , Autophagie , Ostéoclastes , Rat Sprague-Dawley , Mouvement dentaire , Animaux , Autophagie/physiologie , Mâle , Rats , Vieillissement/physiologie , Vieillissement/anatomopathologie , Microtomographie aux rayons X , Sirolimus/pharmacologie , Ostéogenèse/physiologie , Tartrate-resistant acid phosphatase/métabolisme , MolaireRÉSUMÉ
BACKGROUND: Serum level of tartrate-resistant acid phosphatase 5b (TRACP5b) is an excellent serum marker of bone resorption. In patients with giant cell tumor of bone (GCTB), TRACP5b levels are reportedly elevated. This study investigated whether TRACP5b could be a diagnostic serum marker and be useful for detecting postoperative disease progression for GCTB. METHODS: Cohort 1: We abstracted data from 120 patients with TRACP5b measurements from our database: 49 patients with GCTB and 71 patients non-GCTB. We compared serum TRACP5b values between the GCTB and non-GCTB groups. Cohort 2 included 47 patients with GCTB who had more than 6 months of follow-up and multiple TRACP5b values. For patients with local recurrence, TRACP5b change rate was calculated by comparing the TRACP5b value just before progression (a) with the value at the time of progression (b): Change rate = [(b)-(a)]/(a). In the non-progression group, the change rate was calculated from the two consecutive TRACP5b values, (c) and (d): Change rate =[(c)-(d)]/(c). We compared TRACP5b change rates between the progression and non-progression groups. RESULTS: Cohort 1: The GCTB group had a significantly higher mean TRACP5b value (1756 ± 2021 mU/dL) than the non-GCTB group (415 ± 219 mU/dL) (p < 0.0001). Cohort 2: The mean TRACP5b change rate of the progression group was significantly higher than the non-progression group (8.53 ± 8.52 and 0.24 ± 0.27, respectively; p < 0.0001). CONCLUSION: TRACP5b is a useful diagnostic marker in GCTB. The rate of change in serum TRACP5b values is a highly sensitive marker for predicting local recurrence in GCTB.
Sujet(s)
Marqueurs biologiques tumoraux , Tumeurs osseuses , Tumeur osseuse à cellules géantes , Tartrate-resistant acid phosphatase , Humains , Tartrate-resistant acid phosphatase/sang , Mâle , Femelle , Adulte , Adulte d'âge moyen , Tumeur osseuse à cellules géantes/sang , Tumeur osseuse à cellules géantes/diagnostic , Tumeur osseuse à cellules géantes/anatomopathologie , Tumeurs osseuses/sang , Tumeurs osseuses/diagnostic , Tumeurs osseuses/anatomopathologie , Pronostic , Marqueurs biologiques tumoraux/sang , Évolution de la maladie , Récidive tumorale locale , Sujet âgé , Adolescent , Jeune adulte , Isoenzymes/sangRÉSUMÉ
The aim of this study was to evaluate the influence of implant macrodesign and surface hydrophilicity on osteoclast (OC) differentiation, activation, and survival in vitro. Titanium disks were produced with a sandblasted, dual acid-etched surface, with or without additional chemical modification for increasing hydrophilicity (SAE-HD and SAE, respectively) and different macrodesign comprising trapezoidal (HLX) or triangular threads (TMX). This study evaluated 7 groups in total, 4 of which were experimental: HLX/SAE-HD, HLX-SAE, TMX/SAE-HD, and TMX/SAE; and 3 control groups comprising OC differentiated on polystyrene plates (CCPC): a positive CCPC (+), a negative CCPC (-), and a lipopolysaccharide-stimulated assay positive control group, CCPC-LPS. Murine macrophage RAW264.7 cells were seeded on the disks, differentiated to OC (RAW-OC) by receptor activator of nuclear factor-κB ligand (RANKL) treatment and cultured for 5 days. Osteoclast differentiation and cell viability were respectively assessed by specific enzymatic Tartrate-Resistant Acid Phosphatase (TRAP) activity and MTT assays. Expression levels of various OC-related genes were measured at the mRNA level by quantitative polymerase chain reaction (qPCR). HLX/SAE-HD, TMX/SAE-HD, and HLX/SAE significantly suppressed OC differentiation when compared to CCPC (+). Cell viability was significantly increased in TMX/SAE and reduced in HLX/SAE-HD. In addition, the expression of Interleukin (IL)-6 and Tumour Necrosis Factor (TNF)-α was upregulated in TMX/SAE-HD compared to CCPC (+). Hydrophilic surfaces negatively modulate macrophage/osteoclast viability. Specifically, SAE-HD with double triangular threads increases the cellular pro-inflammatory status, while surface hydrophilicity and macrodesign do not seem to have a distinct impact on osteoclast differentiation, activation, or survival.
Sujet(s)
Différenciation cellulaire , Survie cellulaire , Interactions hydrophobes et hydrophiles , Ostéoclastes , Propriétés de surface , Titane , Titane/composition chimique , Ostéoclastes/effets des médicaments et des substances chimiques , Différenciation cellulaire/effets des médicaments et des substances chimiques , Animaux , Survie cellulaire/effets des médicaments et des substances chimiques , Souris , Facteurs temps , Mordançage à l'acide , Ostéogenèse/effets des médicaments et des substances chimiques , Ostéogenèse/physiologie , Test de matériaux , Reproductibilité des résultats , Tartrate-resistant acid phosphatase/analyse , Analyse de variance , Ligand de RANK/analyse , Réaction de polymérisation en chaine en temps réel , Cellules RAW 264.7 , Valeurs de référence , Macrophages/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Myocardial infarction (MI) leads to enhanced activity of cardiac fibroblasts (CFs) and abnormal deposition of extracellular matrix proteins, resulting in cardiac fibrosis. Tartrate-resistant acid phosphatase 5 (ACP5) has been shown to promote cell proliferation and phenotypic transition. However, it remains unclear whether ACP5 is involved in the development of cardiac fibrosis after MI. The present study aimed to investigate the role of ACP5 in post-MI fibrosis and its potential underlying mechanisms. METHODS: Clinical blood samples were collected to detect ACP5 concentration. Myocardial fibrosis was induced by ligation of the left anterior descending coronary artery. The ACP5 inhibitor, AubipyOMe, was administered by intraperitoneal injection. Cardiac function and morphological changes were observed on Day 28 after injury. Cardiac CFs from neonatal mice were extracted to elucidate the underlying mechanism in vitro. The expression of ACP5 was silenced by small interfering RNA (siRNA) and overexpressed by adeno-associated viruses to evaluate its effect on CF activation. RESULTS: The expression of ACP5 was increased in patients with MI, mice with MI, and mice with Ang II-induced fibrosis in vitro. AubipyOMe inhibited cardiac fibrosis and improved cardiac function in mice after MI. ACP5 inhibition reduced cell proliferation, migration, and phenotypic changes in CFs in vitro, while adenovirus-mediated ACP5 overexpression had the opposite effect. Mechanistically, the classical profibrotic pathway of glycogen synthase kinase-3ß (GSK3ß)/ß-catenin was changed with ACP5 modulation, which indicated that ACP5 had a positive regulatory effect. Furthermore, the inhibitory effect of ACP5 deficiency on the GSK3ß/ß-catenin pathway was counteracted by an ERK activator, which indicated that ACP5 regulated GSK3ß activity through ERK-mediated phosphorylation, thereby affecting ß-catenin degradation. CONCLUSION: ACP5 may influence the proliferation, migration, and phenotypic transition of CFs, leading to the development of myocardial fibrosis after MI through modulating the ERK/GSK3ß/ß-catenin signaling pathway.
Sujet(s)
Prolifération cellulaire , Fibrose , Infarctus du myocarde , Tartrate-resistant acid phosphatase , Animaux , Infarctus du myocarde/métabolisme , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/génétique , Souris , Humains , Tartrate-resistant acid phosphatase/métabolisme , Tartrate-resistant acid phosphatase/génétique , Mâle , Modèles animaux de maladie humaine , Fibroblastes/métabolisme , Myocarde/anatomopathologie , Myocarde/métabolisme , Glycogen synthase kinase 3 beta/métabolisme , Souris de lignée C57BL , Transduction du signal , Mouvement cellulaireRÉSUMÉ
Osteoporosis is characterized by bone loss and deterioration in bone microstructure, leading to bone fragility. It is strongly correlated with menopause in women. Previously, we reported that diets supplemented with a kudzu (Pueraria lobata) vine extract suppressed bone resorption in ovariectomized (OVX) mice, a postmenopausal model. The main isoflavone in kudzu is puerarin (daidzein-8-C-glycoside). Puerarin (daidzein-8-C-glycoside), which is main isoflavone of kudzu, probably contributes to the beneficial effect. However, the underlying mechanism is unclear. Therefore, the nutrikinetics of puerarin and the comparison with the suppressive effects of kudzu isoflavones on osteoclast differentiation was examined in this study. We demonstrated that orally administered puerarin was absorbed from the gut and entered the circulation in an intact form. In addition, puerarin accumulated in RAW264.7 pre-osteoclast cells in a time-dependent manner. Tartrate-resistant acid phosphatase activity was decreased by puerarin treatment in a concentration-dependent manner in RAW264.7 cells stimulated with the receptor activator of nuclear factor kappa-B ligand. Ovariectomy-induced elevated bone resorption was suppressed, and the fragile bone strength was improved by puerarin ingestion in the diet. These findings suggested that orally administered puerarin was localized in bone tissue and suppressed bone resorption and osteoclastogenesis in ovariectomized mice.
Sujet(s)
Différenciation cellulaire , Fémur , Isoflavones , Ostéoclastes , Ovariectomie , Pueraria , Animaux , Isoflavones/pharmacologie , Isoflavones/administration et posologie , Ostéoclastes/effets des médicaments et des substances chimiques , Femelle , Souris , Fémur/effets des médicaments et des substances chimiques , Fémur/métabolisme , Pueraria/composition chimique , Différenciation cellulaire/effets des médicaments et des substances chimiques , Cellules RAW 264.7 , Résorption osseuse/prévention et contrôle , Extraits de plantes/pharmacologie , Extraits de plantes/administration et posologie , Ostéoporose/prévention et contrôle , Ostéoporose/traitement médicamenteux , Tartrate-resistant acid phosphatase/métabolismeRÉSUMÉ
Osteoclasts are multinucleated cells of hematopoietic origin, with a pivotal role in bone development and remodeling. Failure in osteoclast differentiation and activation leads to various bone disorders; thus, attention has focused on a search of molecules involved in osteoclast regulatory pathways. Caspase-8 appears to be an interesting candidate for further exploration, due to its potential function in bone development and homeostasis. Mouse bone marrow cells were differentiated into osteoclasts by RANKL stimulation. Increased activation of caspase-8 and its downstream executioner caspases (caspase-3 and caspase-6) was found during osteoclastogenesis. Subsequent inhibition of caspase-8, caspase-3, or caspase-6, respectively, during osteoclast differentiation showed distinct changes in the formation of TRAP-positive multinucleated cells and reduced expression of osteoclast markers including Acp5, Ctsk, Dcstamp, and Mmp9. Analysis of bone matrix resorption confirmed significantly reduced osteoclast function after caspase inhibition. The results clearly showed the role of caspases in the proper development of osteoclasts and contributed new knowledge about non-apoptotic function of caspases.
Sujet(s)
Cellules de la moelle osseuse , Inhibiteurs des caspases , Différenciation cellulaire , Ostéoclastes , Ligand de RANK , Animaux , Souris , Cellules de la moelle osseuse/métabolisme , Résorption osseuse/métabolisme , Caspase-3/métabolisme , Caspase-6/métabolisme , Caspase 8/métabolisme , Inhibiteurs des caspases/pharmacologie , Cellules cultivées , Souris de lignée C57BL , Ostéoclastes/métabolisme , Ligand de RANK/métabolisme , Tartrate-resistant acid phosphatase/métabolismeRÉSUMÉ
INTRODUCTION: Preclinical and animal studies have suggested that excess catecholamines can lead to bone mineral loss. However, to date, no systematic review is available that has analyzed the impact of catecholamine excess in the context of pheochromocytoma/paraganglioma (PPGL) on bone metabolism. We conducted this meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched for studies evaluating bone metabolism, including assessments of bone mineral density (BMD), quantitative computed tomography (qCT), trabecular bone score (TBS), or bone turnover markers in patients with PPGL. These markers included those of bone resorption, such as tartrate-resistant acid phosphatase 5b (TRACP-5b) and cross-linked C-telopeptide of type I collagen (CTx), as well as markers of bone formation, such as bone-specific alkaline phosphatase (BS ALP). RESULTS: Out of the initially screened 1614 articles, data from six studies published in four different patient cohorts with PPGL that met all criteria were analysed. Individuals with PPGL had significantly lower TBS [Mean Difference (MD) -0.04 (95% CI: -0.05--0.03); p < 0.00001; I2â¯=â¯0%], higher serum CTx [MD 0.13 ng/ml (95% CI: 0.08-0.17); p < 0.00001; I2â¯=â¯0%], and higher BS-ALP [MD 1.47 U/L (95% CI: 0.30-2.64); pâ¯=â¯0.01; I2â¯=â¯1%]. TBS at 4-7 months post-surgery was significantly higher compared to baseline [MD 0.05 (95% CI: 0.02-0.07); p < 0.0001]. A decrease in CTx has been documented post-surgery. CONCLUSION: Bone health deterioration is a major concern in patients with PPGL. In addition to providing a definitive cure for catecholamine excess, monitoring and treating osteoporosis is essential for individuals with secondary osteoporosis due to PPGL. Long-term studies on bone health outcomes in PPGL are warranted.
Sujet(s)
Tumeurs de la surrénale , Densité osseuse , Remodelage osseux , Paragangliome , Phéochromocytome , Humains , Tumeurs de la surrénale/imagerie diagnostique , Tumeurs de la surrénale/métabolisme , Phéochromocytome/imagerie diagnostique , Phéochromocytome/métabolisme , Paragangliome/imagerie diagnostique , Phosphatase alcaline/sang , Os spongieux/imagerie diagnostique , Résorption osseuse/imagerie diagnostique , Tomodensitométrie , Os et tissu osseux/métabolisme , Os et tissu osseux/imagerie diagnostique , Collagène de type I/sang , Tartrate-resistant acid phosphatase/sang , Tartrate-resistant acid phosphatase/métabolisme , PeptidesRÉSUMÉ
BACKGROUND: We investigated the utility of specific biomarkers-namely, c-terminal telopeptide (CTX), n-telopeptide (NTX), deoxypyridinoline (DPD), and tartrate-resistant acid phosphatase (TRAP)-compared to conventional diagnostic methods. We hy-pothesized that these novel biomarkers could hold substantial value in the diagnosis, treatment, and monitoring of osteoporosis. METHODS: The study was conducted over a three-year period, from January 1, 2020, to January 1, 2023. We enrolled a total of 520 patients aged 50 years or older who had been diagnosed with osteoporosis. Patients undergoing steroid treatments, which are known to contribute to osteoporosis, were excluded from the study. Additionally, we carefully selected and matched a control group consisting of 500 patients based on demographic characteristics relevant to the diagnosis of osteoporosis. This meticulous selection process resulted in a comprehensive cohort comprising 1,020 patients. Throughout the study, patients were closely monitored for a duration of one year to track the occurrence of pathological fractures and assess their overall prognosis. RESULTS: As a result of our rigorous investigation, we identified CTX, NTX, DPD, and TRAP as pivotal biomarkers that play a crucial role in evaluating bone health, monitoring treatment effectiveness, and detecting pathological fractures in the context of osteoporosis. CONCLUSION: Our study underscores the significance of these biomarkers in advancing the diagnosis and management of osteo-porosis, offering valuable insights into the disease's progression and treatment outcomes.
Sujet(s)
Marqueurs biologiques , Remodelage osseux , Collagène de type I , Ostéoporose , Humains , Marqueurs biologiques/sang , Femelle , Ostéoporose/diagnostic , Mâle , Adulte d'âge moyen , Sujet âgé , Collagène de type I/sang , Peptides/sang , Peptides/urine , Tartrate-resistant acid phosphatase/sang , Acides aminés/sang , Fractures ostéoporotiques/diagnostic , Fractures spontanées/diagnostic , Fractures spontanées/étiologieRÉSUMÉ
This study investigated whether Ki-Patlak derived from a shortened scan time for dynamic 18F-NaF PET/CT in chronic kidney disease (CKD) patients undergoing hemodialysis can provide predictive accuracy comparable to that obtained from a longer scan. Twenty-seven patients on chronic hemodialysis, involving a total of 42 scans between December 2021 and August 2023 were recruited. Dynamic 18F-NaF PET/CT scans, lasting 60-90 min, were immediately acquired post-injection, covering the mid-twelfth thoracic vertebra to the pelvis region. Ki-Patlak analysis was performed on bone time-activity curves at 15, 30, 45, 60, and 90 min in the lumbar spine (L1-L4) and both anterior iliac crests. Spearman's rank correlation (rs) and interclass correlation coefficient were used to assess the correlation and agreement of Ki-Patlak between shortened and standard scan times. Bone-specific alkaline phosphatase (BsAP) and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were tested for their correlation with individual Ki-Patlak. Strong correlations and good agreement were observed between Ki-Patlak values from shortened 30-min scans and longer 60-90-min scans in both lumbar spine (rs = 0.858, p < 0.001) and anterior iliac crest regions (rs = 0.850, p < 0.001). The correlation between BsAP and Ki-Patlak in the anterior iliac crests was weak and statistically insignificant. This finding suggests that a proposed shortened dynamic 18F-NaF PET/CT scan is effective in assessing bone metabolic flux in CKD patients undergoing hemodialysis, offering a non-invasive alternative approach for bone turnover prediction.
Sujet(s)
Tomographie par émission de positons couplée à la tomodensitométrie , Dialyse rénale , Insuffisance rénale chronique , Fluorure de sodium , Humains , Tomographie par émission de positons couplée à la tomodensitométrie/méthodes , Mâle , Femelle , Adulte d'âge moyen , Insuffisance rénale chronique/thérapie , Insuffisance rénale chronique/métabolisme , Insuffisance rénale chronique/complications , Insuffisance rénale chronique/imagerie diagnostique , Sujet âgé , Radio-isotopes du fluor , Remodelage osseux , Vertèbres lombales/imagerie diagnostique , Vertèbres lombales/métabolisme , Adulte , Phosphatase alcaline/métabolisme , Tartrate-resistant acid phosphatase/métabolisme , Ilium/imagerie diagnostique , Ilium/métabolismeRÉSUMÉ
OBJECTIVE: Studies have highlighted numerous benefits of ozone therapy in the field of medicine and dentistry, including its antimicrobial efficacy against various pathogenic microorganisms, its ability to modulate the immune system effectively, reduce inflammation, prevent hypoxia, and support tissue regeneration. However, its effects on dental extraction healing remain to be elucidated. .Therefore, this study aimed to evaluate the effects of systemically administered ozone (O3) at different doses in the healing of dental extraction sockets in rats. METHODOLOGY: To this end, 72 Wistar rats were randomly divided into four groups after extraction of the right upper central incisor: Group C - control, no systemic treatment; Group OZ0.3 - animals received a single dose of 0.3 mg/kg O3; Group OZ0.7 - a single dose of 0.7 mg/kg O3; and Group OZ1.0 - a single dose of 1.0 mg/kg O3, intraperitoneally. In total, six animals from each group were euthanized at 7, 14, and 21 days after the commencement of treatment. Bone samples were harvested and further analyzed by descriptive histology, histomorphometry, and immunohistochemistry for osteocalcin (OCN) and tartrate-resistant acid phosphatase (TRAP) protein expression. RESULTS: All applied doses of O3 were shown to increase the percentage of bone tissue (PBT) after 21 days compared to group C. After 14 days, the OZ0.7 and OZ1.0 groups showed significantly higher PBT when compared to group C. The OZ1.0 group presented the most beneficial results regarding PBT among groups, which denotes a dose-dependent response. OCN immunostaining was higher in all groups at 21 days. However, after seven and 14 days, the OZ1.0 group showed a significant increase in OCN immunostaining compared to C group. No differences in TRAP+ osteoclasts were found between groups and time points. CONCLUSION: Therefore, O3 therapy at higher doses might be beneficial for bone repair of the alveolar socket following tooth extraction.
Sujet(s)
Immunohistochimie , Ostéocalcine , Ozone , Répartition aléatoire , Rat Wistar , Tartrate-resistant acid phosphatase , Extraction dentaire , Alvéole dentaire , Cicatrisation de plaie , Animaux , Ozone/pharmacologie , Alvéole dentaire/effets des médicaments et des substances chimiques , Cicatrisation de plaie/effets des médicaments et des substances chimiques , Tartrate-resistant acid phosphatase/analyse , Ostéocalcine/analyse , Facteurs temps , Mâle , Reproductibilité des résultats , Résultat thérapeutique , Valeurs de référenceRÉSUMÉ
BACKGROUND: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5's two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. METHODS: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. RESULTS: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. CONCLUSIONS: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia-osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD.
Sujet(s)
Maladie de Gaucher , Isoformes de protéines , Tartrate-resistant acid phosphatase , Maladie de Gaucher/métabolisme , Maladie de Gaucher/génétique , Humains , Tartrate-resistant acid phosphatase/métabolisme , Isoformes de protéines/métabolisme , Isoformes de protéines/génétique , Femelle , Mâle , Adulte d'âge moyen , Adulte , Densité osseuse , Macrophages/métabolisme , Marqueurs biologiques/métabolisme , Marqueurs biologiques/sang , Isoenzymes/métabolisme , Isoenzymes/génétiqueRÉSUMÉ
Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. µ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-ß/Smad pathway by increasing TGF-ß as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-ß/Smad pathway.
Sujet(s)
Ginsénosides , Ostéoporose , Ovariectomie , Rat Sprague-Dawley , Transduction du signal , Facteur de croissance transformant bêta , Ginsénosides/pharmacologie , Ginsénosides/usage thérapeutique , Animaux , Femelle , Ostéoporose/traitement médicamenteux , Ostéoporose/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Facteur de croissance transformant bêta/métabolisme , Fémur/effets des médicaments et des substances chimiques , Fémur/métabolisme , Fémur/anatomopathologie , Protéines Smad/métabolisme , Rats , Collagène de type I/métabolisme , Microtomographie aux rayons X , Tartrate-resistant acid phosphatase/métabolisme , Ostéocalcine/métabolisme , Ostéocalcine/sang , Modèles animaux de maladie humaine , Procollagène/métabolisme , Procollagène/sangRÉSUMÉ
Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.
Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.
Sujet(s)
Résorption osseuse , Dénosumab , Ostéoclastes , Ligand de RANK , Animaux , Ostéoclastes/métabolisme , Ostéoclastes/effets des médicaments et des substances chimiques , Ligand de RANK/antagonistes et inhibiteurs , Ligand de RANK/métabolisme , Dénosumab/pharmacologie , Souris , Résorption osseuse/anatomopathologie , Résorption osseuse/traitement médicamenteux , Résorption osseuse/sang , Facteurs temps , Tartrate-resistant acid phosphatase/métabolisme , Femelle , Souris de lignée C57BL , Marqueurs biologiques/métabolisme , Marqueurs biologiques/sangRÉSUMÉ
INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.
Sujet(s)
Agents de maintien de la densité osseuse , Densité osseuse , Humains , Dénosumab/pharmacologie , Agents de maintien de la densité osseuse/pharmacologie , Agents de maintien de la densité osseuse/usage thérapeutique , Calcium/pharmacologie , Tartrate-resistant acid phosphatase , Remodelage osseux , Phosphatase alcaline , Dialyse rénale , Marqueurs biologiquesRÉSUMÉ
BACKGROUND: Mesenchymal stem cells (MSCs) have been highlighted as a potent therapeutic option for conditions with excessive osteoclast activity such as systemic and local bone loss in rheumatic disease. In addition to their immunomodulatory functions, MSCs also directly suppress osteoclast differentiation and activation by secreting osteoprotegerin (OPG) and IL-10 but the underlying mechanisms are still to be clarified. Tumor necrosis factor-stimulated gene-6 (TSG-6) is a potent anti-inflammatory molecule that inhibits osteoclast activation and has been shown to mediate MSC's immunomodulatory functions. In this study, we aimed to determine whether adipose tissue-derived MSC (ADMSC) inhibits the differentiation from osteoclast precursors to mature osteoclasts through TSG-6. METHODS: Human ADMSCs were co-cultured with bone marrow-derived monocyte/macrophage (BMMs) from DBA/1J or B6 mouse in the presence of osteoclastogenic condition (M-CSF 10 ng/mL and RANKL 10 ng/mL). In some co-culture groups, ADMSCs were transfected with siRNA targeting TSG-6 or OPG to determine their role in osteoclastogenesis. Tartrate-resistant acid phosphatase (TRAP) activity in culture supernatant and mRNA expression of osteoclast markers were investigated. TRAP+ multinucleated cells and F-actin ring formation were counted. RESULTS: ADMSCs significantly inhibited osteoclast differentiation under osteoclastogenic conditions. Suppression of TSG-6 significantly reversed the inhibition of osteoclast differentiation in a degree similar to that of OPG based on TRAP activity, mRNA expression of osteoclast markers, and numbers of TRAP+ multinucleated cell and F-actin ring formation. CONCLUSION: This study demonstrated that ADMSCs inhibit osteoclast differentiation through TSG-6 under osteoclastogenic conditions.
Sujet(s)
Tissu adipeux , Molécules d'adhérence cellulaire , Différenciation cellulaire , Cellules souches mésenchymateuses , Ostéoclastes , Ostéoclastes/métabolisme , Ostéoclastes/cytologie , Cellules souches mésenchymateuses/métabolisme , Cellules souches mésenchymateuses/cytologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Humains , Animaux , Tissu adipeux/cytologie , Tissu adipeux/métabolisme , Souris , Molécules d'adhérence cellulaire/métabolisme , Ostéoprotégérine/métabolisme , Techniques de coculture , Souris de lignée C57BL , Ostéogenèse/effets des médicaments et des substances chimiques , Tartrate-resistant acid phosphatase/métabolisme , Macrophages/métabolisme , Macrophages/cytologieRÉSUMÉ
Rosavin, a phenylpropanoid in Rhodiola rosea's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9). It also impedes the nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), c-Fos, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis and osteoblast differentiation and increases mouse runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) expression. In vivo studies show its effectiveness in enhancing bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) mice, restraining osteoclast maturation, and increasing the active osteoblast percentage in bone tissue. It modulates mRNA expressions by increasing eukaryotic translation elongation factor 2 (EEF2) and decreasing histone deacetylase 1 (HDAC1), thereby activating osteoprotective epigenetic mechanisms, and alters many serum markers, including decreasing cross-linked C-telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator for nuclear factor κ B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and TRAP, while increasing alkaline phosphatase (ALP) and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic matrix metallopeptidase 3 (MMP-3), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), and enhances anti-osteoporotic interleukin 10 (IL-10) and tissue inhibitor of metalloproteinase 3 (TIMP3) expressions. This paper aims to systematically review rosavin's impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions.
Sujet(s)
Résorption osseuse , Diholoside , Ostéoclastes , Animaux , Souris , Ostéoclastes/métabolisme , Tartrate-resistant acid phosphatase/métabolisme , Ostéogenèse , Résorption osseuse/métabolisme , Différenciation cellulaire , Facteur de transcription NF-kappa B/métabolisme , Metalloproteases/métabolisme , Ligand de RANK/métabolisme , Facteurs de transcription NFATC/métabolismeRÉSUMÉ
Trichophyton mentagrophytes is a zoophilic dermatophyte that can cause dermatophytosis in humans and animals. Antimicrobial peptides (AMPs) are considered as a promising agent to overcome the drug-resistance of T. mentagrophytes. Our findings suggest that cationic antimicrobial peptide (ACP5) not only possesses stronger activity against T. mentagrophytes than fluconazole, but also shows lower toxicity to L929 mouse fibroblast cells than terbinafine. Notably, its resistance development rate after resistance induction was lower than terbinafine. The present study aimed to evaluate the fungicidal mechanism of ACP5 in vitro and its potential to treat dermatophyte infections in vivo. ACP5 at 1 ×MIC completely inhibited T. mentagrophytes spore germination in vitro. ACP5 severely disrupts the mycelial morphology, leading to mycelial rupture. Mechanistically, ACP5 induces excessive ROS production, damaging the integrity of the cell membrane and decreasing the mitochondrial membrane potential, causing irreversible damage in T. mentagrophytes. Furthermore, 1% ACP5 showed similar efficacy to the commercially available drug 1% terbinafine in a guinea pig dermatophytosis model, and the complete eradication of T. mentagrophytes from the skin by ACP5 was verified by tissue section observation. These results indicate that ACP5 is a promising candidate for the development of new agent to combat dermatophyte resistance.
Sujet(s)
Arthrodermataceae , Teigne , Humains , Souris , Animaux , Cochons d'Inde , Terbinafine/pharmacologie , Terbinafine/usage thérapeutique , Trichophyton , Teigne/traitement médicamenteux , Peptides antimicrobiens , Antifongiques/pharmacologie , Tartrate-resistant acid phosphatase/pharmacologieRÉSUMÉ
PURPOSE: Alveolar osteitis (dry sockets) is a painful condition characterized by a limited immune response. It is typically caused by the removal of blood clots from extracted tooth sockets, which leads to the fermentation of trapped food remnants by oral bacteria in the cavities, producing high concentrations of short-chain fatty acids (SCFAs). This study examined the effects of SCFAs on immunity and bone metabolism. METHODS: Mouse macrophage Raw264.7 cells were treated with oral bacteria supernatants or SCFA mixtures, and inducible nitric oxide synthase (iNOS) levels were determined by western blot. The same cells were treated with SCFA mixtures in the presence of receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoclast-like cells were counted. MC3T3-E1 cells were treated with SCFA mixtures and stained with alizarin red S. RESULTS: Raw264.7 cells treated with oral bacterial culture supernatants of Porphyromonas gingivalis and Fusobacterium nucleatum inhibited lipopolysaccharide (LPS)-induced iNOS production, likely due to SCFA content. SCFA mixtures mimicking these supernatants inhibited the number of RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive cells and MC3T3-E1 cell mineralization. CONCLUSION: These data suggest that SCFAs produced by P. gingivalis and F. nucleatum may reduce the inflammatory response and mildly induce mineralization of the alveolar walls. These results may contribute to the understanding of alveolar osteitis.
Sujet(s)
Alvéolite , Souris , Animaux , Alvéolite/métabolisme , Ostéoclastes , Porphyromonas gingivalis , Tartrate-resistant acid phosphatase/métabolisme , Acides gras volatils/métabolisme , Acides gras volatils/pharmacologieRÉSUMÉ
La espondiloencondrodisplasia con desregulación inmune relacionada a ACP5 (SPENCDI #607944, por la sigla de spondyloenchondrodysplasia with immune dysregulation y el número que le corresponde en OMIM, Online Mendelian Inheritance in Man) es una displasia inmuno-ósea poco frecuente con manifestaciones heterogéneas y gravedad variable. Presenta lesiones espondilometafisarias, disfunción inmune y compromiso neurológico. Se reportan aspectos clínicos, radiológicos y genéticos de cuatro niñas con SPENCDI en un hospital pediátrico. Todas presentaron manifestaciones esqueléticas y tres de ellas enfermedad inmunológica grave. Se encontró en tres pacientes la variante probablemente patogénica c.791T>A; p.Met264Lys en homocigosis, y en una paciente las variantes c.791T>A; p.Met264Lys y c.632T>C; p.lle211Thr (variante de significado incierto con predicción patogénica según algoritmos bioinformáticos) en heterocigosis compuesta en ACP5. La presencia de la variante repetida c.791T>A sugiere la posibilidad de un ancestro en común en nuestra población. El reconocimiento y diagnóstico de esta entidad es importante para lograr un oportuno abordaje, que deberá ser multidisciplinario, orientado hacia la prevención de posibles complicaciones.
Spondyloenchondrodysplasia with immune dysregulation related to ACP5 (SPENCDI, OMIM number 607944) is an uncommon immune-skeletal dysplasia with heterogeneous manifestations and variable severity. It is characterized by spondylar and metaphyseal lesions, immune dysfunction, and neurological involvement. Here we report the clinical, radiological and genetic aspects of 4 girls with SPENCDI treated at a children's hospital. They all had skeletal manifestations and 3 developed severe immune disease. In 3 patients, the likely pathogenic variant c.791T>A; p.Met264Lys (homozygous mutation) was observed, while 1 patient had variants c.791T>A; p.Met264Lys and c.632T>C; p.lle211Thr (variant of uncertain significance with pathogenic prediction based on bioinformatics algorithms) caused by a compound heterozygous mutation in ACP5. The repeated presence of variant c.791T>A suggests the possibility of a common ancestor in our population. The recognition and diagnosis of this disorder is important to achieve a timely approach, which should be multidisciplinary and aimed at preventing possible complications.