osteoprotegerin and Lupus-Erythematosus--Systemic

Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic arthritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis. Many of the cytokines and growth factors implicated in the inflammatory processes in rheumatic diseases have also been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key osteoclastogenic factor receptor activator of nuclear factor (NF) kappaB ligand (RANKL) and/or its inhibitor osteoprotegerin (OPG). Further elucidation of the mechanisms responsible for inflammation-induced bone loss will potentially lead to the identification of novel therapeutic strategies for the prevention of bone loss in these diseases. In this review, we provide an overview of the cell types, inflammatory mediators, and mechanisms that are implicated in bone loss and new bone formation in inflammatory joint diseases.

Topics: Animals; Arthritis, Juvenile; Arthritis, Rheumatoid; Bone and Bones; Bone Remodeling; Bone Resorption; Carrier Proteins; Cytokines; Glycoproteins; Humans; Inflammation; Lupus Erythematosus, Systemic; Membrane Glycoproteins; Osteoclasts; Osteogenesis; Osteoprotegerin; Parathyroid Hormone-Related Protein; Prostaglandins; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction; Spondylarthropathies

Introduction Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family. It has recently been demonstrated that OPG is produced by a variety of tissues, including the cardiovascular system (heart, arteries, veins), lung, kidney, immune tissues, and bone. The OPG-RANKL signaling pathway is strongly related to vascular calcification. We determined the association of this biomarker with subclinical atherosclerosis in systemic lupus erythematous (SLE). Methods We measured OPG and markers of subclinical atherosclerosis (coronary artery calcium (CAC), carotid intima-media thickness (cIMT) carotid plaque) in 166 SLE patients (91% female, 64% Caucasian, 31% African American, 5% others, mean age 45 years). Subgroups of patients with different levels of OPG level were compared with respect to average levels of CAC, cIMT, and with respect to presence of carotid plaque. Age was adjusted for using multiple regression. Results OPG was highly correlated with age ( p < 0.0001). Individuals with higher levels of OPG tended to have higher measures of CAC, cIMT, and more carotid plaque. However, after adjustment for age, these associations, while still positive, were no longer statistically significant. Conclusion In our study much of the association observed was due to confounding by age, and after adjusting for age, our findings do not rule out the possibility of a null association.

Topics: Adult; Age Factors; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Double-Blind Method; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Osteoprotegerin; Plaque, Atherosclerotic

This study aims to explore effects of osteoprotegerin (OPG) gene polymorphisms and other possible factors on bone mineral density (BMD) in children with systemic lupus erythematosus (SLE).. Osteoprotegerin gene rs2073617 and rs3134069 were evaluated in 74 SLE patients and 100 controls then genotypes, alleles and haplotypes' frequencies were compared between cases and controls and between patients with BMD z-scores above and below -2 evaluated by dual energy X-ray absorptiometry (DEXA). Disease activity was evaluated by SLE disease activity index (SLEDAI).. The patients aged 14.01 ± 2.6 years and included 57 (77%) females and 27 (36%) patients with BMD z-score below -2. Genotypes, alleles, and haplotypes frequencies did not differ between patients and controls (. This is the first study to demonstrate OPG gene influence on BMD in children with SLE. The studied SNPs are not risk for developing SLE but, rs2073617 T allele is a possible predictor for reduced BMD in SLE. Other predictors include long disease duration and high activity supporting that osteoporosis in SLE is multifactorial.

Topics: Adolescent; Alleles; Bone Density; Child; Female; Genotype; Humans; Lupus Erythematosus, Systemic; Male; Osteoporosis; Osteoprotegerin; Polymorphism, Single Nucleotide

To identify the osteoprotegerin (OPG) correlates with antiphospholipid syndrome (APS) parameters.. Our cohort included 40 patients with primary APS disease associated with systemic lupus erythematosus (SLE) (mean age, 43.7 years; 87% female). Data on cardiovascular risk factors and specific clinical events in APS were collected. Then we tested OPG and 10 criteria and noncriteria antiphospholipid antibodies (aPLs) on preserved specimens in all cases.. A total of 26 patients (65%) had high serum OPG levels. Patients with high OPG were mostly overweight. In patients with SLE, the OPG levels were associated with anti-double-stranded DNA (anti-dsDNA) and anti-Sm titers. However, we did not find significant correlations of the OPG with any of the 10 aPLs tested. Also, we found no relationship regarding venous APS events.. In APS, high OPG levels are not linked to serum aPL expression.

Topics: Adult; Antiphospholipid Syndrome; Autoantibodies; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Osteoprotegerin; Risk Factors

Predictors of bone mineral density (BMD) loss are additional tools in the management of osteoporosis in premenopausal women with systemic lupus erythematosus (SLE). This study provides original evidence that N-terminal propeptide of type 1 collagen (P1NP), the most specific bone formation marker, is a predictor of BMD loss in this group of women.. SLE is associated with a high risk of low bone mass/fractures but this risk is still controversial in premenopausal women. Our aim was to determine the 1 year incidence of BMD loss in premenopausal SLE women and the value of bone turnover markers as predictors of this complication.. This study enrolled a convenience sample of 63 premenopausal SLE patients. BMD was evaluated by dual X-ray absorptiometry at lumbar spine and hip at baseline and after 12 months. BMD changes above the least significant change were considered significant. Serum levels of P1NP and CTX (electrochemiluminescence), OPG, and RANKL (ELISA) were determined at baseline.. Mean age was 31.1±6.8 years, and disease duration was 5.25±3.8 years. 36.5 % of patients presented BMD loss and 17.5 % BMD gain at lumbar spine and/or hip. Patients were divided in three groups: BMD loss (BL), no BMD change (NC), and BMD gain (BG). Patients with BL and NC received similar cumulative/mean/maximum glucocorticoid doses during the study, but patients with BG received lower doses (p<0.05). Baseline P1NP levels were different in the groups (BL: 36.95±23.37 vs. NC: 54.63±30.82 vs. BG: 84.09±43.85 ng/mL; p=0.031 BL vs. NC, p<0.001 BL vs. BG, and p=0.039 NC vs. BG). There was no difference in CTX, OPG, or RANKL levels. After multivariate analysis, P1NP remained as an independent risk factor for BMD loss (p<0.03).. This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of BMD loss over 12 months in premenopausal SLE patients.

Topics: Absorptiometry, Photon; Adult; Biomarkers; Bone Density; Bone Remodeling; Collagen Type I; Female; Follow-Up Studies; Hip; Humans; Lumbar Vertebrae; Lupus Erythematosus, Systemic; Middle Aged; Osteoprotegerin; Peptide Fragments; Peptides; Procollagen; RANK Ligand; Young Adult

Premenopausal women with systemic lupus erythematosus (SLE) have a higher prevalence of low bone mineral density and vertebral fractures. Multiple genetic loci for osteoporotic fracture were identified in recent genome-wide association studies. This study provides a novel data demonstrating that receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) polymorphisms likely plays an important role in the bone remodeling process in SLE premenopausal women.. The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) of the RANKL, RANK, and OPG genes in premenopausal SLE patients and their association with sRANKL and OPG serum levels, vertebral fractures, and bone mineral density (BMD).. A total of 211 premenopausal SLE patients (American College of Rheumatology (ACR) criteria) and 154 healthy controls were enrolled. SNPs of RANKL 290A>G (rs2277438), OPG 1181G>C (rs2073618), 245T>G (rs3134069), 163A>G (rs3102735), and RANK A>G (rs3018362) were obtained by real-time PCR. sRANKL/OPG serum levels were determined by ELISA. BMD and vertebral fractures were evaluated by dual-energy X-ray absorptiometry (DXA).. SLE patients and controls had similar frequencies of the RANKL 290 G allele (p = 0.94), OPG 1181 C allele (p = 0.85), OPG 245 G allele (p = 0.85), OPG 163 G allele (p = 0.78), and RANK G allele (p = 0.87). Further analysis of the SLE patients revealed that the frequency of the RANKL 290 G allele was lower in patients with fractures than that in patients without fractures (28.1 vs 46.9%, p = 0.01). In addition, the frequency of the OPG 245 G allele was higher in patients with low BMD than that in patients with normal BMD (31.4 vs 18.1%, p = 0.04). No association of OPG 1181 G>C, OPG 163 A>G, and RANK A>G SNPs with BMD/fractures was found. Additionally, no association was observed between RANKL/OPG/RANK SNPs and sRANKL/OPG serum levels.. Our study provides novel data demonstrating that RANKL/OPG genetic variations appear to play a role in bone remodeling, particularly in its major complication, fracture, in premenopausal patients with SLE.

Topics: Adolescent; Adult; Anthropometry; Bone Density; Female; Genetic Predisposition to Disease; Humans; Lupus Erythematosus, Systemic; Osteoporosis; Osteoprotegerin; Polymorphism, Single Nucleotide; Premenopause; RANK Ligand; Spinal Fractures; Young Adult

Patients with systemic lupus erythematosus (SLE) have increased risk for cardiovascular disease. Previous studies disclosed the association of serum osteoprotegerin (OPG) with the presence of symptomatic atherosclerosis in the general population and several disease conditions. We thus investigated the association between serum OPG levels and subclinical atherosclerosis in premenopausal SLE patients.. Serum OPG levels and carotid artery intima-media thickness (IMT) were measured in 181 premenopausal SLE patients and age-matched 85 control subjects. Traditional cardiovascular risk factors and SLE-related factors were analyzed.. Patients with SLE had significantly increased serum OPG levels (1086 versus 517 pg/ml, p < 0.001) and carotid IMT (0.63 versus 0.45 mm, p < 0.001) compared with control subjects. Carotid IMT significantly increased across the quartiles of OPG. Logistic regression analysis revealed that compared to the lowest OPG quartile, the odds ratio (OR, 95% confidence interval) for increased carotid IMT in quartile 2, 3, and 4 was 1.126 (1.013-1.801), 1.562 (1.268-2.799), and 4.460 (1.126-7.128), respectively, after multiple adjustments (p for trend across quartiles < 0.001). These associations remained significant after further adjustment for inflammatory parameters. Interestingly, serum monocyte chemotactic protein-1 (MCP-1) levels were positively correlated with serum OPG levels (γ = 0.332, p < 0.001). Parallel analysis showed that serum MCP-1 was also an independent predictor of carotid IMT incrassation, but this association was lost when serum OPG was included in the model.. Serum OPG levels were increased and correlated with serum MCP-1 levels in premenopausal SLE patients. Increased serum OPG was independently associated with subclinical atherosclerosis in these patients.

Topics: Adult; Asymptomatic Diseases; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Chemokine CCL2; Chi-Square Distribution; Female; Humans; Logistic Models; Lupus Erythematosus, Systemic; Odds Ratio; Osteoprotegerin; Predictive Value of Tests; Premenopause; Republic of Korea; Risk Factors; Up-Regulation

Elevated serum osteoprotegerin (OPG) levels represent an independent risk factor for atherosclerotic disease, although the underlying mechanism is not clear. The aim of this study was to investigate the association of serum OPG levels and circulating endothelial progenitor cell (EPC) numbers, and to explore the effect of OPG on EPC apoptosis and its underlying mechanisms.. Flow cytometry was used to enumerate EPCs in the peripheral blood of 91 patients with systemic lupus erythematosus (SLE). Cultured EPCs, isolated from peripheral blood, were challenged with OPG, and apoptosis was evaluated by TUNEL staining. Expression of apoptosis-related proteins was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Reactive oxygen species (ROS) were detected by flow cytometry, and the expression of NADPH oxidase (NOX) and MAP kinases (MAPK) was measured by qPCR and Western blotting.. The serum OPG level was independently associated with reduced numbers of EPCs in patients with SLE. In vitro treatment with OPG significantly induced apoptosis of EPCs; this effect was mediated by syndecan 4. OPG-induced apoptosis was abolished by the ROS scavenger N-acetylcysteine and the NOX inhibitor diphenyleniodonium. OPG increased ROS production through activation of NOX-2 and NOX-4 and triggered phosphorylation of ERK-1/2 and p38 MAPK. Quenching of ROS by knockdown of NOX-2 or NOX-4 transcripts inhibited phosphorylation of ERK-1/2 and p38 MAPK. Moreover, inhibitors of ERK-1/2 and p38 MAPK decreased ROS production and subsequent EPC apoptosis, indicating a feed-forward loop between NOX and MAPK to amplify ROS production related to apoptosis.. Elevated OPG levels increase apoptosis of EPCs by induction of oxidative stress.

Topics: Apoptosis; Cells, Cultured; Endothelial Cells; Female; Flow Cytometry; Gene Silencing; Humans; Lupus Erythematosus, Systemic; Male; Mitogen-Activated Protein Kinase Kinases; NADPH Oxidases; Osteoprotegerin; Oxidative Stress; Reactive Oxygen Species; Recombinant Proteins; RNA, Small Interfering; Stem Cells; Transfection

This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance.. In 73 SLE patients, and in 23 healthy volunteers, urinary levels of TWEAK, OPG, MCP-1, and IL-8 levels were measured. Disease activity was assessed by total SLE disease activity index, and renal activity by renal activity index (rSLEDAI), and both were correlated with urinary biomarkers. Sensitivity, specificity, and predictive values of individual biomarkers to predict lupus nephritis were also calculated.. Significantly higher levels of urinary biomarkers were observed in SLE patients with lupus nephritis (LN) compared with those without LN (TWEAK, p < 0.001; MCP-1, p < 0.001; OPG, p < 0.001; IL-8, p < 0.032). Other significantly higher levels were observed in SLE patients with LN compared with control subjects (TWEAK, MCP-1, OPG, and IL-8 p < 0.001). Positive correlations were observed between rSLEDAI and TWEAK (r = 0.612 and p < 0.001), MCP-1 (r = 0.635 and p < 0.001), and OPG (r = 0.505 and p < 0.001).. Urinary levels of TWEAK, OPG, and MCP-1 positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis while IL-8 was not significantly associated with global or rSLEDAI.

Topics: Adult; Biomarkers; Case-Control Studies; Cohort Studies; Cytokine TWEAK; Disease Progression; Female; Humans; Interleukin-8; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Membrane Cofactor Protein; Molecular Targeted Therapy; Osteoprotegerin; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Tumor Necrosis Factors

Systemic lupus erythematosus (SLE) patients have lower bone mineral density and increased fracture risk when compared with healthy individuals, due to distinct factors and mechanisms. Bone remodeling is a tightly orchestrated process dependent on several factors, including the balance between receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG). Our aim was to assess serum OPG and soluble RANKL (sRANKL) levels as well as sRANKL/OPG ratio in female SLE patients and compare it with female controls.. We have evaluated 103 SLE patients and 114 healthy controls, all Caucasian females. All participants underwent a clinical and laboratory evaluation. sRANKL and OPG were quantified in serum by ELISA based methods. sRANKL, OPG and sRANKL/OPG ratio levels were compared between SLE patients and age, sex and race matched healthy controls. For SLE patients, a multivariate analysis was performed, to find the possible predictors of the changes in sRANKL, OPG and sRANKL/OPG ratio levels.. Although sRANKL levels did not differ between the two groups, serum OPG was lower in SLE patients (P < 0.001). This led to an increased sRANKL/OPG ratio (P = 0.010) in the patients' group.The multivariate analysis was performed considering age and other clinical and laboratorial potential confounders for these variations in the SLE patients group. We have showed that age (P = 0.001) and levels of anti-Sm antibodies (P = 0.016) were independent predictors of sRANKL/OPG ratio variations in SLE patients. No relationship with therapy or disease activity measured by SLEDAI2K was found.. These results are suggestive of increased osteoclastic stimuli driven by the SLE disease mechanisms.

Topics: Adult; Biomarkers; Female; Humans; Lupus Erythematosus, Systemic; Middle Aged; Osteoprotegerin; Predictive Value of Tests; RANK Ligand; snRNP Core Proteins; Up-Regulation; Young Adult

This study aims to explore the potential role of circulating Dickkopf-1 (Dkk-1) and osteoprotegerin (OPG) in evaluating erosive arthritis in systemic lupus erythematosus (SLE).. Serum Dkk-1 and OPG levels were examined in 130 SLE patients including eight with erosive arthritis, 100 rheumatoid arthritis (RA) patients and 50 healthy individuals by ELISA. Comparison of serum Dkk-1 levels with presence of anti-cyclic citrullinated peptides (CCP) antibodies in evaluating erosive arthritis in SLE was carried out. Associations of Dkk-1 and OPG levels with results of clinical examination were also noted.. Dkk-1 levels were significantly increased in eight SLE patients with erosive arthritis, compared to 58 SLE patients with non-erosive arthritis, 64 SLE patients without arthritis, and healthy controls, while similar with RA. In contrast, no significant changes of OPG levels were found except for higher levels in RA. No differences were found in Dkk-1 levels of SLE patients with erosive arthritis subdivided according to presence or absence of anti-CCP antibodies. Moreover, higher levels of Dkk-1 were identified in anti-CCP positive SLE patients with erosive arthritis compared to those with non-erosive arthritis or without arthritis. However, no significant correlations between Dkk-1 and OPG levels or between Dkk-1 levels and other laboratory and clinical manifestations were observed.. High levels of circulating Dkk-1 were associated with bone erosion in patients with SLE, even when anti-CCP antibodies were absent.

Topics: Adolescent; Adult; Aged; Antibodies, Antinuclear; Biomarkers; Bone Resorption; Disease Progression; Female; Humans; Intercellular Signaling Peptides and Proteins; Lupus Erythematosus, Systemic; Male; Middle Aged; Osteoarthritis; Osteoprotegerin

Patients with antiphospholipid syndrome (APS) have an increased risk for the development of thrombotic complications. Recent studies indicate that osteoprotegerin (OPG) acts as an important molecule in the development of vascular diseases. The aim of the present study was to examine the association between serum OPG levels and APS manifestations in patients with SLE. Seventy-nine patients with SLE and ninety-two healthy controls, matched for age and sex, were included in this study. Serum levels of OPG, monocyte chemoattractant protein(MCP)-1 and soluble E-selectin were determined by ELISA. At the time of serum sampling, various clinical and laboratory parameters were assessed. We found that serum levels of OPG were significantly higher in patients with SLE than in healthy controls (1236 +/- 82 vs 967 +/- 37 pg/mL, P = 0.003). Particularly, serum OPG levels were significantly higher in SLE patients with APS than those without (1615 +/- 191 vs 1171 +/- 91 pg/mL, P = 0.006). Serum OPG levels correlated with titres of IgG anti-cardiolipin antibody (P = 0.026) and anti-beta(2)-glycoprotein I antibody (P < 0.001). Moreover, serum OPG also correlated with serum levels of sE-selectin (P = 0.002), which is an endothelial cell activation marker, and MCP-1 (P = 0.003), a well known chemokine implicated in thrombogenesis. Collectively, serum OPG levels were increased in SLE patients with APS and correlated with titres of antiphospholipid antibodies, suggesting that OPG might be linked to the development of APS.

Topics: Adult; Antibodies, Antiphospholipid; Case-Control Studies; Chemokine CCL2; E-Selectin; Female; Humans; Lupus Erythematosus, Systemic; Male; Osteoprotegerin

The objective of this study was to determine potential relationship between the levels of serum TNF-related apoptosis inducing ligand (TRAIL) and osteoprotegerin (OPG) and clinical markers in systemic lupus erythematosus (SLE) patients. Forty SLE patients with inactive disease were enrolled in this study. For comparison, 20 Sjögren's syndrome (SS) patients and 30 normal controls were also analysed. Serum levels of TRAIL and OPG were determined by ELISA. Serum TRAIL and OPG concentrations in SLE patients were significantly (P < 0.05) higher than those in healthy volunteers. Of note, serum TRAIL but not OPG was significantly (P < 0.05) higher in the SLE patient subset characterized by the presence of anti-SSA/SSB antibodies. The relationship between high levels of TRAIL and SSA/SSB antibodies was further supported by the analysis of SS patients characterized by SSA/SSB antibodies positivity, in which TRAIL levels resulted comparable to the subgroup of anti-SSA/SSB positive SLE patients. The presence of SSA/SSB antibodies, targeting a specific subset of SLE and SS patients, is related to increased serum levels of TRAIL but not of OPG.

Topics: Adult; Apoptosis; Autoantibodies; Autoantigens; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Osteoprotegerin; Peptide Fragments; Prospective Studies; Severity of Illness Index; TNF-Related Apoptosis-Inducing Ligand