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Plasma OPG concentrations in type 2 diabetic patients without microvascular complications or with both DMa and microalbuminuria (MA). Data are means^S.E. *P , 0.05 vs no complications.
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Context 1
... patients had microalbuminuria (average UAE 33.5 £/4 1.4 mg/min); all of these also had DMa. In these seven subjects, displaying both microvascular complications, plasma OPG was significantly higher (3.61^ 0.36 ng/l) than in the NGT (2.54^0.16 ng/l, P , 0.01), IGT (2.82^0.21 ng/l, P , 0.05), and no retinopathy groups (2.83^0.20 ng/l, P , 0.05) (Fig. 2). Diabetic patients with (n ¼ 7) and without (n ¼ 33) macrovascular disease had similar plasma OPG (3.1^0.58 vs 3.0^1.0 ng/l, not ...
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Citations
... The treatment with a high glucose medium plus AGEs produced a significant increase in OPG expression in the hOB cultures from the OP and T2DM groups. High OPG levels have been linked with macrovascular and microvascular damage in DM patients [28, 29] . Furthermore , a strong increase in OPG expression might cause a decrease in the bone remodelling cycle and contribute towards the vascular calcification that is so often found in diabetic patients [30]. ...
... Previous studies have pointed out that there is an imbalance in the RANKL/OPG ratio in the diabetic disease [6, 7, 9, 27]. To the best of our knowledge, no previous studies have been performed in hOB cultures from diabetic patients, although high OPG and low RANKL serum levels have been reported in patients with type 1 and type 2 diabetes [28, 29] . In this study, we simulated the metabolic conditions of poorly controlled T2DM patients, such as hyperglycaemia and high AGEs, in the hOB cultures. ...
Background
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporotic fracture. Several factors have been identified as being potentially responsible for this risk, such as alterations in bone remodelling that may have been induced by changes in circulating glucose or/and by the presence of non-oxidative end products of glycosylation (AGEs). The aim of this study is to assess whether such variations generate a change in the gene expression related to the differentiation and osteoblast activity (OPG, RANKL, RUNX2, OSTERIX, and AGE receptor) in primary cultures of human osteoblast-like cells (hOB). Methods
We recruited 32 patients; 10 patients had osteoporotic hip fractures (OP group), 12 patients had osteoporotic hip fractures with T2DM (T2DM group), and 10 patients had hip osteoarthritis (OA group) with no osteoporotic fractures and no T2DM. The gene expression was analyzed in hOB cultures treated with physiological glucose concentration (4.5 mM) as control, high glucose (25 mM), and high glucose plus AGEs (2 μg/ml) for 24 h. ResultsThe hOB cultures from patients with hip fractures presented slower proliferation. Additionally, the hOB cultures from the T2DM group were the most negatively affected with respect to RUNX2 and OSX gene expression when treated solely with high glucose or with high glucose plus AGEs. Moreover, high levels of glucose induced a major decrease in the RANKL/OPG ratio when comparing the OP and the T2DM groups to the OA group. Conclusions
Our data indicates an altered bone remodelling rate in the T2DM group, which may, at least partially, explain the reduced bone strength and increased incidence of non-traumatic fractures in diabetic patients.
... Baseline blood samples for determination of biomarkers were collected in EDTA tubes, centrifuged, and plasma was stored at − 80 °C until analysis. Plasma OPG was measured by a sandwich ELISA using commercially available antibodies (R&D Systems, Minneapolis, MN, USA), as previously described (Knudsen et al., 2003). In brief, mouse anti-human OPG (R&D Systems) was used as capture antibody and biotinylated goat anti-human OPG (R&D Systems) for detection. ...
... It prevents osteoclast activation and bone resorption, and participates in immune regulation and cell survival. High plasma osteoprotegerin values have been linked to diabetic microvascular disease [43] . Plasma osteoprotegerin has been identified as an independent predictor of coronary artery disease in asymptomatic microalbuminuric Type 2 diabetic patients [44][45][46]. ...
Background:
We tested minocycline as an anti-proteinuric adjunct to renin-angiotensin-aldosterone system inhibitors (RAASi) in diabetic nephropathy (DN) and measured urinary biomarkers to evaluate minocycline's biological effects.
Methods:
Design: Prospective, single center, randomized, placebo-controlled, intention-to-treat pilot trial. Inclusion. Type 2 diabetes/DN; Baseline creatinine clearance > 30 mL/min; proteinuria ≥ 1.0 g/day; Age ≥30 years; BP <150/95 mm Hg; intolerant of/at maximum RAASi dose. Protocol. 3-wk screening; Baseline randomization; Urine and blood measures at months 1, 2, 4, and Month 6 study completion. Urine interleukin-6 (IL-6) and osteoprotegerin were measured in a subset. Primary outcome. Natural log of urine protein/creatinine (ln U P:Cr) ratio at Month 6 vs Baseline.
Results:
30 patients completed the study. The 15% decline in U P: Cr in minocycline patients (6 month P:Cr ÷ Baseline P:Cr, 0.85 vs. 0.92) was not significant (p = 0.27). Creatinine clearance did not differ in the 2 groups. Urine IL-6:Cr (p = 0.03) and osteoprotegerin/Cr (p = 0.046) decrements were significant. Minocycline modified the relationship between urine IL-6 and proteinuria, suggesting a protective biological effect.
Conclusions:
Although the decline in U P:Cr in minocycline patients was not statistically significant, the significant differences in urine IL-6 and osteoprotegerin suggest that minocycline may confer cytoprotection in patients with DN, providing a rationale for further study.
Trial registration:
Clinicaltrials.gov NCT01779089.
... Several groups have reported that OPG levels are elevated in patients with type 1 and type 2 DM, as reviewed in [6]. Nevertheless, beside the positive relationship between OPG and type 2 DM, which has been known since 2001 [117], in diabetic patients there is also a strong association between circulating levels of OPG and micro-and macrovascular complications [118, 119]. Here, OPG is associated with cardiovascular events [119, 120] and the presence and severity of silent myocardial ischemia [121][122][123][124] , as well as with the risk of developing endstage renal disease [125]. ...
Cardiovascular diseases (CVD) remain the major cause of death and premature disability in Western societies. Assessing the risk of CVD is an important aspect in clinical decision-making. Among the growing number of molecules that are studied for their potential utility as CVD biomarkers, a lot of attention has been focused on osteoprotegerin (OPG) and its ligands, which are receptor activator of nuclear factor
κ
B ligand (RANKL) and TNF-related apoptosis-inducing ligand. Based on the existing literature and on our experience in this field, here we review what the possible roles of OPG and TRAIL in CVD are and their potential utility as CVD biomarkers.
... Even after the exclusion of diabetic patients with a history of micro-or macrovascular disease, OPG levels remained significantly higher in diabetes [42] and in poorly controlled diabetic patients, serum OPG levels are higher than in well-controlled diabetic patients [46]. Moreover, OPG levels were increased in plasma from type 2 diabetic patients with microvascular complications [47, 48]. Furthermore, the association of OPG and diabetic nephropathy was also studied and OPG serum levels were significantly elevated in patients with microalbuminuria and macroalbuminuria as compared with patients with normoalbuminuria. ...
Osteoprotegerin (OPG), a glycoprotein traditionally implicated in bone remodelling, has been recently related to cardiovascular disease (CVD). Human studies show a positive relationship between circulating OPG, vascular damage, and CVD, and as such OPG has emerged as a potential biomarker for CVD. This review focuses on the relationship between circulating OPG and different endocrine cardiometabolic alterations such as type 1 and 2 diabetes. The association of OPG with diabetic complications (neuropathy, nephropathy, or retinopathy) as well as with atherosclerosis, coronary artery calcification, morbidity, and mortality is pointed out. Moreover, OPG modulation by different treatments is also established. Besides, other associated diseases such as obesity, hypertension, and metabolic syndrome, which are known cardiovascular risk factors, are also considered.
... Noteworthy , a positive correlation between fructosamine and serum OPG was found in a group of elderly women with diabetes, but not in the non-diabetic controls (Browner et al. 2001 ). In agreement with this, a significant correlation between HbA 1c and OPG was shown in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) (Knudsen et al. 2003; Rasmussen et al. 2006). Also, children with T1D had higher OPG levels than healthy age, sex and BMI matched children (Galluzzi et al. 2005), and OPG was significantly correlated with HbA 1c . ...
... These results correlated with the findings by Jorsal et al., showing that increased OPG levels predicted the severity of diabetic nephropathy, and that OPG is an independent marker of mortality (Jorsal et al. 2008). Similarly, Knudsen et al. reported increased OPG levels in T2D patients with microvascular complications compared to T2D patients without complications (Knudsen et al. 2003). Anard and co-workers reported that elevatedFigure 1 Increasing OPG levels associate with the severity of the cardiovascular disease. ...
Osteoprotegerin (OPG) is a glycoprotein involved in bone metabolisms and with a regulatory role in immune, skeletal and vascular systems. Recently, circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease, as well as in the healthy population. Furthermore, OPG has been implicated in various inflammations and linked to diabetes and poor glycaemic control. This review focuses on the relations between circulating OPG levels and cardiovascular complications, with special emphasis on diabetic patients. OPG levels were observed to increase concurrently with the severity of diabetic complications, that is, with the highest circulating OPG levels observed in diabetic patients dying from CVD. Although the clinical prognostic use of OPG may seem far away, OPG does look promising as a biomarker in order to help the cardiologist to a better risk-stratification of the patients.
... DR is thought to be caused by oxidative stress, advanced glycation end-products (AGEs), inflammatory mediators, and endothelial cell death [3]. A member of the tumor necrosis factor (TNF) receptor superfamily glycoprotein osteoprotegerin (OPG), first identified in 1997, acts as an important regulatory molecule in the vasculature [4, 5]. It is expressed in the endothelial and smooth muscle cells, and it is modulated by proinflammatory cytokines and hormones, like insulin and TNF-í µí»¼ [6, 7]. ...
... There have been several studies examining the associations between OPG polymorphisms and bone diseases [9– 12], atherosclerosis131415, and macrovascular complications of diabetes16171819. On the contrary, not many studies have been performed to investigate the association between polymorphisms in the OPG gene and the risk for microvascular complications in type 2 diabetes [4, 6, 20, 21]. Therefore, the purpose of the present study was to examine whether there is a link between the rs2073618 (c.9C>G, G1181C) and rs3134069 (g.119964988A>C, T245G) polymorphisms of the OPG gene and DR in type 2 diabetic patients and to evaluate whether the combined effects of these gene variations influence the risk for DR. ...
... Elevated serum concentrations of OPG are found in a range of cardiovascular pathologies, suggesting the potential value of OPG as a biomarker of vascular risk and prognosis [30]. Also, in a study on diabetic people, a strong association was observed between circulating OPG and microvascular complications [4, 21, 31]. It is suggested that insulin resistance and inflammatory cytokines might mediate upregulation of the OPG release observed in humans and may reflect the endothelial dysfunction in subjects with diabetes [32]. ...
Recent studies indicate that osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. Also, a strong association was observed between circulation OPG and microvascular complication. By considering the possible role of OPG in diabetic retinopathy (DR) we examined two of the most studied polymorphisms of the OPG genes rs2073618 (located in exon I) and rs3134069 (located in the promoter region) and their relation to DR in Slovenian patients with type 2 diabetes. Logistic regression analysis demonstrated that the carriers of the CC genotype had a 2.2 higher risk for DR than those with either the CG genotype or the GG genotype (codominant model for rs2073618). Furthermore, the combined effect of single nucleotide polymorphisms (SNPs) rs2073618 and rs3134069 on the DR was stronger than that of each SNP alone. The odds ratio (OR) for individuals with CC genotype (rs2073618) and AA genotype (rs3134069) compared with carriers of CG/GG (rs2073618) + AA (rs3134069) was 2.54 (95% CI = 1.26-5.13, P = 0.01). To conclude, these results indicate that SNPs in the OPG gene may be implicated in the pathogenesis of DR.
... Однако данное наблюдение нуждается в дальнейшем изучении и подтверждении. Стоит отметить, что особенно высокий уровень остеопротегерина наблюдался в крови у СД диабета , такие как ретинопатия и микроальбуминурия [38], что, вероятно, является отражением генерализованной эндотелиальной дисфункции, лишь частично опосредованной повышением активности системы RANKL/осте- опротегерин. В то время как наличие прямой связи между повышением уровня остеопротегерина и присутствующими микрососудистыми осложнениями вызывает сомнение, имеются убедительные данные о влиянии дистальной симметричной полинейропатии на кальцификацию артериальной стенки. ...
Arterial media calcification is a common finding in diabetes mellitus (DM) and is associated with distal symmetric neuropathy. Arterial calcification also emerges as a complication of chronic kidney disease and is considered to be a risk factor for cardiovascular and general morbidity. "Calcification" is actually not an accurate term, because morphologic alterations also include bone tissue formation or "ossification". Both processes are complex and exist in tight connection with bone homeostasis. Connection between distal symmetric neuropathy and arterial calcification suggests that neuropathy may be an independent risk factor for cardiovascular morbidity.
... Raised anti-dsDNA levels are associated with active disease, suggesting that patients with active SLE might be more exposed to the effect of RANKL/RANK interaction as a consequence of diminished OPG levels. We have also found a positive association between serum OPG levels and diabetes mellitus, which is in accordance with previous results [18,19]. Gannagé-Yared and colleagues found an inverse correlation between OPG and triglycerides levels, in a nondiabetic , elderly Lebanese male population [20]. ...
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.
... Low expression of OPG leads to osteoporosis and vascular calcification, whereas high expression of OPG leads to osteopetrosis [73,93,101]. Clinically, high serum levels of OPG is thought to be a compensatory increase in response to progressive atherosclerosis (it is thought that OPG may lessen vascular calcification), and thus the levels of OPG is considered to be a marker of atherosclerosis or risk factors for atherosclerotic disease [93,101102103. ...
Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.
