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Osteoarthritis and Cartilage May 2024Osteoarthritis (OA) is a disease of joints, in which the bone under the articular cartilage undergoes increased remodelling activity. The question is whether a better... (Review)
Review
OBJECTIVE
Osteoarthritis (OA) is a disease of joints, in which the bone under the articular cartilage undergoes increased remodelling activity. The question is whether a better understanding of the causes and mechanisms of bone remodelling can predict disease-modifying treatments.
DESIGN
This review summarises the current understanding of the aetiology of OA, with an emphasis on events in the subchondral bone (SCB), and the cells and cytokines involved, to seek an answer to this question.
RESULTS
SCB remodelling across OA changes the microstructure of the SCB, which alters the load-bearing properties of the joint and seems to have an important role in the initiation and progression of OA. Bone remodelling is tightly controlled by numerous cytokines, of which Receptor Activator of NFκB ligand (RANKL) and osteoprotegerin are central factors in almost all known bone conditions. In terms of finding therapeutic options for OA, an important question is whether controlling the rate of SCB remodelling would be beneficial. The role of RANKL in the pathogenesis and progression of OA and the effect of its neutralisation remain to be clarified.
CONCLUSIONS
This review further makes the case for SCB remodelling as important in OA and for additional study of RANKL in OA, both its pathophysiological role and its potential as an OA disease target.
Topics: Humans; Cartilage, Articular; Cytokines; Ligands; Osteoarthritis; Osteoprotegerin; RANK Ligand
PubMed: 38160744
DOI: 10.1016/j.joca.2023.10.010 -
World Journal of Clinical Cases Nov 2020Gestational diabetes mellitus (GDM) raises the risk of high blood pressure and may cause a series of life-threatening complications in pregnant women. Screening and...
BACKGROUND
Gestational diabetes mellitus (GDM) raises the risk of high blood pressure and may cause a series of life-threatening complications in pregnant women. Screening and management of GDM and gestational hypertension (GH) in pregnancy helps to control and reduce these risks and prevent adverse effects on mothers and their fetuses. Currently, the majority criteria used for screening of diabetes mellitus is oral glucose tolerance tests, and blood pressure test is usually used for the screening and diagnosis of hypertension. However, these criteria might not anticipate or detect all GDM or GH cases. Therefore, new specific predictive and diagnostic tools should be evaluated for this population. This study selected three biomarkers of osteoprotegerin (OPG), interleukin (IL) and hepatocyte growth factor (HGF) for GDM and GH predication and diagnosis.
AIM
To explore the feasibility of changes in placental and serum OPG, IL and HGF as tools for prediction and diagnosis of diabetes and hypertension in pregnant women.
METHODS
From January 2018 to January 2019, 44 pregnant women with GDM and GH were selected as an observation group, and 44 healthy pregnant women were selected as a control group in the same period. Serum OPG, IL and HGF were compared between the two groups.
RESULTS
The levels of OPG and HGF in the observation group were lower than in the control group, and the level of IL-1β was higher in the observation group than in the control group (all < 0.05). Furthermore, OPG and HGF were negatively associated with gestational diabetes and gestational hypertension, while IL-1β was positively associated with GDM complicated with GH (all < 0.05).
CONCLUSION
The evaluation of serum OPG, HGF and IL-1β levels in patients with coexistent gestational diabetes complicated with hypertension can predict the degree of disease and play an important role in the follow-up treatment and prognosis prediction.
PubMed: 33344543
DOI: 10.12998/wjcc.v8.i22.5529 -
Medicina (Kaunas, Lithuania) Oct 2023: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the...
: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the mediator in the process of vascular endothelial dysfunction. Impaired endothelial function has an intimate link with hypertension (HTN) and is associated with significant morbidity and mortality. This study was to investigate the connection between OPG and endothelial dysfunction in patients having HTN. : There are 102 patients with HTN included. For the purpose of determining the levels of OPG, a commercial enzyme-linked immunosorbent test kit was applied. The vascular reactivity index (VRI), which is assessed via the digital thermal monitoring, provides information on endothelial function. : Ten patients with HTN (9.8%) were classified as having poor vascular reactivity (VRI < 1.0), 46 HTN patients (45.1%) as having intermediate vascular reactivity (1.0 ≤ VRI < 2.0), and 46 HTN patients (45.1%) were classified as having high vascular reactivity (VRI ≥ 2.0). A greater serum OPG level ( < 0.001) and older age ( = 0.022) were linked to impaired vascular reactivity. The estimated glomerular filtration rate ( = 0.196, = 0.048) was positively correlated with VRI values in hypertensive participants, while advanced age ( = -0.222, = 0.025) and the log-transformed OPG level (log-OPG, = -0.357, < 0.001) were negatively correlated with VRI. Serum log-OPG level was shown to be strongly and independently correlated with VRI values in HTN individuals after multivariable forward stepwise linear regression analysis (β = -0.357, adjusted R change = 0.119, < 0.001). : In patients with HTN, serum OPG levels were adversely correlated with VRI and probably had a role in endothelial dysfunction.
Topics: Humans; Osteoprotegerin; Hypertension; Regression Analysis; Linear Models; Atherosclerosis; Biomarkers
PubMed: 37893512
DOI: 10.3390/medicina59101794 -
Annals of the Rheumatic Diseases Nov 2002The tumour necrosis factor family molecule RANKL (RANKL, TRANCE, ODF) and its receptor RANK are key regulators of bone remodelling and regulate T cell/dendritic cell... (Review)
Review
The tumour necrosis factor family molecule RANKL (RANKL, TRANCE, ODF) and its receptor RANK are key regulators of bone remodelling and regulate T cell/dendritic cell communications, and lymph node formation. Moreover, RANKL and RANK are expressed in mammary gland epithelial cells and control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Importantly, RANKL and RANK are essential for the development and activation of osteoclasts and bone loss in response to virtually all triggers tested. Therapeutically, inhibition of RANKL function via the decoy receptor osteoprotegerin completely prevents bone loss at inflammed joints and has partially beneficial effects on cartilage destruction in all arthritis models studied. Modulation of these systems provides a unique opportunity to design novel treatments to inhibit bone loss and crippling in arthritis.
Topics: Animals; Arthritis; Carrier Proteins; Glycoproteins; Humans; Immune System; Membrane Glycoproteins; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; T-Lymphocytes
PubMed: 12379618
DOI: 10.1136/ard.61.suppl_2.ii32 -
Biomedicines Jan 2023Osteopontin, an extracellular matrix protein involved in bone remodeling, tissue repair and inflammation, has previously been associated with increased inflammation and...
BACKGROUND
Osteopontin, an extracellular matrix protein involved in bone remodeling, tissue repair and inflammation, has previously been associated with increased inflammation and neurodegeneration in multiple sclerosis (MS), promoting a worse disease course. Osteopontin is also likely involved in acute MS relapses.
METHODS
In 47 patients with relapsing-remitting MS, we explored the correlation between the time elapsed between the last clinical relapse and lumbar puncture, and the cerebrospinal fluid (CSF) levels of osteopontin and a group of inflammatory cytokines and adipokines such as resistin, plasminogen activator inhibitor-1, osteoprotegerin, interleukin (IL)-1β, IL-2, IL-6 and IL-1 receptor antagonist (IL-1ra). We also analyzed the correlations between CSF levels of osteopontin and the other CSF molecules considered.
RESULTS
Osteopontin CSF concentrations were higher in patients with a shorter time interval between the last clinical relapse and CSF withdrawal. In addition, CSF levels of osteopontin were positively correlated with the proinflammatory cytokines IL-2 and IL-6 and negatively correlated with the anti-inflammatory molecule IL-1ra.
CONCLUSIONS
Our results further suggest the role of osteopontin in acute MS relapses showing that, in proximity to relapses, osteopontin expression in CSF may be increased along with other proinflammatory mediators and correlated with decreased concentrations of anti-inflammatory molecules.
PubMed: 36672686
DOI: 10.3390/biomedicines11010178 -
Journal of Functional Biomaterials Jan 2023Particle-induced osteolysis is a major cause of aseptic prosthetic loosening. Implant wear particles stimulate tissue macrophages inducing an aseptic inflammatory...
Particle-induced osteolysis is a major cause of aseptic prosthetic loosening. Implant wear particles stimulate tissue macrophages inducing an aseptic inflammatory reaction, which ultimately results in bone loss. Fetuin-A is a key regulator of calcified matrix metabolism and an acute phase protein. We studied the influence of fetuin-A on particle-induced osteolysis in an established mouse model using fetuin-A-deficient mice. Ten fetuin-A-deficient (Ahsg−/−) mice and ten wild-type animals (Ahsg+/+) were assigned to test group receiving ultra-high molecular weight polyethylene (UHMWPE) particle implantation or to control group (sham surgery). After 14 days, bone metabolism parameters RANKL, osteoprotegerin (OPG), osteocalcin (OC), alkaline phosphatase (ALP), calcium, phosphate, and desoxypyridinoline (DPD) were examined. Bone volume was determined by microcomputed tomography (μCT); osteolytic regions and osteoclasts were histomorphometrically analyzed. After particle treatment, bone resorption was significantly increased in Ahsg−/− mice compared with corresponding Ahsg+/+ wild-type mice (p = 0.007). Eroded surface areas in Ahsg−/− mice were significantly increased (p = 0.002) compared with Ahsg+/+ mice, as well as the number of osteoclasts compared with control (p = 0.039). Fetuin-A deficiency revealed increased OPG (p = 0.002), and decreased levels of DPD (p = 0.038), OC (p = 0.036), ALP (p < 0.001), and Ca (p = 0.001) compared with wild-type animals. Under osteolytic conditions in Ahsg−/− mice, OPG was increased (p = 0.013), ALP (p = 0.015) and DPD (p = 0.012) were decreased compared with the Ahsg+/+ group. Osteolytic conditions lead to greater bone loss in fetuin-A-deficient mice compared with wild-type mice. Reduced fetuin-A serum levels may be a risk factor for particle-induced osteolysis while the protective effect of fetuin-A might be a future pathway for prophylaxis and treatment.
PubMed: 36662077
DOI: 10.3390/jfb14010030 -
The Journal of Neuroscience : the... May 2019Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. Here, we present evidence that...
Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. Here, we present evidence that epigenetic modulation underlies VNS-induced improvements in cognition. We show that VNS enhances novelty preference (NP); alters the hippocampal, cortical, and blood epigenetic transcriptomes; and epigenetically modulates neuronal plasticity and stress-response signaling genes in male Sprague Dawley rats. Brain-behavior analysis revealed structure-specific relationships between NP test performance (NPTP) and epigenetic alterations. In the hippocampus, NPTP correlated with decreased histone deacetylase 11 (HDAC11), a transcriptional repressor enriched in CA1 cells important for memory consolidation. In the cortex, the immediate early gene (IEG) ARC was increased in VNS rats and correlated with transcription of plasticity genes and epigenetic regulators, including HDAC3. For rats engaged in NPTP, ARC correlated with performance. Interestingly, blood ARC transcripts decreased in VNS rats performing NPTP, but increased in VNS-only rats. Because DNA double-strand breaks (DSBs) facilitate transcription of IEGs, we investigated phosphorylated H2A.X (γH2A.X), a histone modification known to colocalize with DSBs. In agreement with reduced cortical stress-response transcription factor NF-κB1, chromatin immunoprecipitation revealed reduced γH2A.X in the ARC promoter. Surprisingly, VNS did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. However, TNFRSF11B (osteoprotegerin) correlated with NPTP as well as plasticity, stress-response signaling, and epigenetic regulation transcripts in both hippocampus and cortex. Together, our findings provide the first evidence that VNS induces widespread changes in the cognitive epigenetic landscape and specifically affects epigenetic modulators associated with NPTP, stress-response signaling, memory consolidation, and cortical neural remodeling. Recent studies have implicated vagus nerve stimulation (VNS) in enhanced learning and memory. However, whereas epigenetic modifications are known to play an important role in memory, the particular mechanisms involved in VNS-enhanced cognition are unknown. In this study, we examined brain and behavior changes in VNS and sham rats performing a multiday novelty preference (NP) task. We found that VNS activated specific histone modifications and DNA methylation changes at important stress-response signaling and plasticity genes. Both cortical and hippocampal plasticity changes were predictive of NP test performance. Our results reveal important epigenetic alterations associated with VNS cognitive improvements, as well as new potential pharmacological targets for enhancing cortical and hippocampal plasticity.
Topics: Animals; Calcium Signaling; Cerebral Cortex; Cognition; Epigenesis, Genetic; Exploratory Behavior; Hippocampus; Male; Neuronal Plasticity; Rats, Sprague-Dawley; Stress, Physiological; Transcriptome; Vagus Nerve Stimulation
PubMed: 30804093
DOI: 10.1523/JNEUROSCI.2407-18.2019 -
Journal of Clinical Medicine Apr 2024: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the...
: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor family involved in processes in many inflammatory states. OPG concentration is enhanced in the majority of chronic kidney disease (CKD) patients and those undergoing renal replacement therapy. The aim of the study was to assess the relation of OPG and chronic inflammation in peritoneal dialysis (PD) patients and to evaluate whether OPG concentrations in plasma and dialysate were related to plasma and dialysate levels of proinflammatory mediators (interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), interleukin 33 (IL-33) and interleukin 1 receptor-like 1IL-1RL1 (IL-1RL1, sST2)). : The study included 37 patients of the Peritoneal Dialysis Center, Department of Nephrology, Transplantology and Internal Medicine, Szczecin, Poland, 4-6 weeks after the onset of peritoneal dialysis therapy. During a peritoneal equilibration test, plasma (at 2 h) and dialysate (at 4 h) OPG, IL-33, 1IL-1RL1 (sST2), IL-6 and hsCRP concentrations were determined. : Plasma concentration of OPG did not correlate with dialysate OPG level ( = 0.04, = 0.8). There was a strong positive correlation between plasma OPG concentrations and plasma IL-1RL1 (sST2) ( = 0.41; = 0.01), plasma IL-6 ( = 0.38; = 0.01) and plasma hsCRP ( = 0.35; = 0.02). Dialysate OPG concentrations were positively associated with dialysate IL-1RL1 (sST2) ( = 0.37; = 0.02) and dialysate IL-6 levels ( = 0.44; = 0.005). Multivariate analysis showed that higher IL-1RL1 (sST2) ( = +0.38, = 0.006), higher plasma hsCRP ( = +0.32, = 0.02) and older age ( = +0.35, = 0.01) were independent determinants of higher plasma OPG concentration and that higher concentrations of dialysate IL-6 ( = +0.37, = 0.02) were independent determinants of higher dialysate OPG concentration. : Both plasma and dialysate OPG levels are associated with the severity of systemic and local inflammation illustrated by the plasma and dialysate concentrations of IL-1RL1 (sST2), hsCRP and IL-6, suggesting that OPG might have a pivotal role in explaining the milieu of systemic and intraperitoneal inflammation.
PubMed: 38673616
DOI: 10.3390/jcm13082345 -
Experimental and Therapeutic Medicine Aug 2022The present study explored the potential role of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand...
The present study explored the potential role of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) in promoting vascular calcification by periodontitis. Thirty-six male Wistar rats were randomly assigned to four groups to establish animal models as follows: the sham group (group C), vascular calcification group (group VDN), periodontitis group (group CP), and test group (group CP+VDN). After eight weeks, all the rats were sacrificed. The periodontal and vascular calcification indices were detected. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were used to quantify OPG/RANK/RANKL expression in vascular tissue and serum. Protein expression analyses revealed the expression of OPG and RANKL in the vascular tissues of the four groups. The expression of OPG in group C was the highest, which was similar to group CP+VDN, and the expression of OPG in groups CP and VDN were lower. However, the expression of RANKL was inversely correlated with OPG, and the ratio of RANKL/OPG was also higher in groups CP and VDN than that in groups C and CP+VDN. In conclusion, OPG/RANK/RANKL may play an essential role in the promotion of vascular calcification by periodontitis. However, the expression levels of OPG and RANKL were not simply superimposed when periodontitis and vascular calcification co-existed.
PubMed: 35813311
DOI: 10.3892/etm.2022.11439 -
Cell Proliferation Jan 2020miR-21 can promote osteoblast differentiation of periodontal ligament stem cells. However, the effect of miR-21 on bone remodelling in the midpalatal suture is unclear....
OBJECTIVES
miR-21 can promote osteoblast differentiation of periodontal ligament stem cells. However, the effect of miR-21 on bone remodelling in the midpalatal suture is unclear. This study aimed to elucidate the effects of miR-21 on the midpalatal suture bone remodelling by expanding the palatal sutures.
MATERIALS AND METHODS
miR-21 deficient (miR-21 ) and wild-type (WT) mice were used to establish animal models by expanding the palatal sutures. Micro-CT, haematoxylin-eosin (HE) staining, tartrate-resistant acid phosphatase (TRAP) staining, fluorescence labelling and immunohistochemistry were used to investigate the function of miR-21 in midpalatal suture bone remodelling. Besides, bone mesenchymal stem cells (BMSCs) derived from both miR-21 and WT mice were cultured. The MTT, CCK8, EdU analysis, transwell and wound healing test were used to assess the effects of miR-21 on the characteristics of cells.
RESULTS
The expression of ALP was suppressed in miR-21 mice after expansion except 28 days. The expression of Ocn in WT mice was much higher than that of miR-21 mice. Besides, with mechanical force, miR-21 deficiency downregulated the expression of Opg, upregulated the expression of Rankl, and induced more osteoclasts as TRAP staining showed. After injecting agomir-21 to miR-21 mice, the expression of Alp, Ocn and Opg/Rankl were rescued. In vitro, the experiments suggested that miR-21 deficiency reduced proliferation and migration ability of BMSCs.
CONCLUSIONS
The results showed that miR-21 deficiency reduced the rate of bone formation and prolonged the process of bone formation. miR-21 regulated the bone resorption and osteoclastogenesis by affecting the cell abilities of proliferation and migration.
Topics: Animals; Bone Marrow Cells; Bone Remodeling; Cell Differentiation; Cell Proliferation; Cranial Sutures; Gene Expression Regulation; Mesenchymal Stem Cells; Mice; Mice, Knockout; MicroRNAs; Osteoprotegerin; Palate; RANK Ligand; Stress, Mechanical; Tartrate-Resistant Acid Phosphatase
PubMed: 31713930
DOI: 10.1111/cpr.12697