osteoprotegerin and Pulmonary-Disease--Chronic-Obstructive

Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease.

Topics: Adiponectin; Aging; Airway Remodeling; Biomarkers; C-Reactive Protein; Cachexia; Cardiovascular Diseases; CD40 Ligand; Chemokines, CC; Cytokines; Desmosine; Fibrinogen; Humans; Inflammation; Intercellular Adhesion Molecule-1; Isodesmosine; Lung Neoplasms; Matrix Metalloproteinases; Natriuretic Peptide, Brain; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Serum Amyloid A Protein; Severity of Illness Index; Telomere; Uteroglobin

Osteoporosis is a common complication of chronic obstructive pulmonary disease (COPD). Recent clinical and biological researches have increasingly delineated the biomolecular pathways of bone metabolism regulation in COPD. We extended this work by examining the specific association and potential contribution of the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis to the pathogenesis of osteoporosis in advanced COPD. The aim of this study was to assess the relationships of serum OPG, RANKL, and tumor necrosis factor-alpha (TNF-μ) with bone turnover in men with very severe COPD.. Pulmonary function, T-score at the lumbar spine (LS) and femoral neck (FN), serum OPG, RANKL, soluble receptor of tumor necrosis factor-alpha-I and II (sTNFR-I, sTNFR-II), osteocalcin (OC), and β-CrossLaps (βCL) levels were measured in 45 men with very severe stage COPD and 36 male non-COPD volunteers. COPD patients and healthy controls were compared using an independent t-test and Mann-Whitney U-test. The Pearson coefficient was used to assess the relationships between variables.. OPG and OC were lower in male COPD patients than in control subjects whereas RANKL, serum βCL, TNF-μ, and its receptors were higher. OPG directly correlated with forced expiratory volume in 1 s (FEV1) % predicted (r = 0.46, P < 0.005), OC (r = 0.34, P < 0.05), LS (r = 0.56, P < 0.001), and FN T-score (r = 0.47, P < 0.01). In contrast, serum RANKL inversely associated with LS and FN T-score (r = -0.62, P < 0.001 and r = -0.48, P < 0.001) but directly correlated with βCL (r = 0.48, P < 0.001). In addition, OPG was inversely correlated with RANKL (r = -0.39, P < 0.01), TNF-μ (r = -0.56, P < 0.001), and sTNFR-I (r = -0.40, P < 0.01).. Our results suggest that serum OPG and RANKL levels are inversely associated with bone loss in men with advanced stage COPD.

Topics: Bone Density; Cross-Sectional Studies; Humans; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; RANK Ligand; Respiratory Function Tests; Tumor Necrosis Factor-alpha

A disequilibrium of tumor necrosis superfamily (TNF) members, including the serum osteoprotegerin, soluble receptor activator of nuclear factor-κB ligand, soluble TNF-related apoptosis-inducing ligand and TNF-α, was associated with the occurrence of a reduced skeletal mass and osteoporosis in male patients with end-stage chronic obstructive pulmonary disease (COPD). The purpose of this study was to explore the associations between serum biomarkers of tumor necrosis factor (TNF) superfamily and body and bone compositions in end-stage COPD males. Pulmonary function, T-score at the lumbar spine and femoral neck, lean mass, serum osteoprotegerin (OPG), soluble receptor activator of nuclear factor-κB ligand (sRANKL), TNF-α and its receptors (sTNFR-I, sTNFR-II) and soluble TNF-related apoptosis-inducing ligand (sTRAIL) levels were evaluated in 48 male patients with end-stage COPD and 36 healthy male volunteers. OPG was lower in male COPD patients than in control subjects, whereas sRANKL, TNF-α and its receptors were higher. The serum sTRAIL level showed a tendency to increase compared with that of healthy subjects (P = 0.062). Serum OPG showed a positive correlation with bone density. In contrast, serum TNF-α, sRANKL and sTRAIL were inversely associated with pretransplant bone density. We have noted the appearance of statistically significant inverse relationships between lean mass values and TNF-α, sTNFR-I and II and sRANKL levels in male COPD patients. Moreover, there was a negative correlation between sTRAIL levels with airway obstruction (P = 0.005) and hypercapnia (P = 0.042) in advanced COPD patients. Through a multiple linear regression analysis, our study revealed that a disequilibrium of TNF family members was strongly associated with the occurrence of a reduced skeletal mass and osteoporosis. These results provide further evidence that abnormal levels of TNF superfamily molecules may cause not only a decrease in BMD, but also lower muscle mass in end-stage COPD.

Topics: Aged; Biomarkers; Bone and Bones; Bone Density; Humans; Lung Transplantation; Male; Middle Aged; Muscle, Skeletal; Osteoporosis; Osteoprotegerin; Prevalence; Pulmonary Disease, Chronic Obstructive; RANK Ligand; Tumor Necrosis Factor-alpha

Osteoprotegerin (OPG), a potent inhibitor of osteoclastogenesis, decreases bone resorption and has protective effects on bone mineral density (BMD). Recently we have shown that the adipose-tissue derived OPG relates to BMD in patients with chronic obstructive pulmonary disease (COPD), a condition associated with increased risk of osteoporosis.. Here we aimed to investigate the potential of circulatory OPG to reflect hip BMD in patients with COPD.. In 56 subjects with COPD [age, 61.7 ± 6.7 years; forced expiratory volume in 1 s (FEV1), 53.6 ± 19.2% predicted], total femur BMD was assessed by dual energy X-ray absorptiometry, serum OPG and β-crosslaps, a marker of increased bone resorption, by commercially available assays.. From patients with normal hip BMD (n = 32, T-score 0.1 ± 0.8) to those with osteopenia (n = 14, T-score -1.6 ± 0.4) and osteoporosis (n = 10, T-score -3.4 ± 0.7) serum OPG levels significantly increased (6.6 ± 1.8 versus 7.2 ± 2.9 and versus 8.6 ± 1.5 pmol/l, p = 0.036). In addition, hip T-scores were directly related to FEV1, and inversely to β-crosslaps (R = 0.40, p = 0.002; R = 0.38, p = 0.01, respectively). In multivariate analysis, OPG independently predicted hip T-scores after adjustments for age, gender, FEV1, and β-crosslaps (p = 0.011, adjusted R(2) = 0.354). Area under receiver operator curve for OPG as a discriminator of osteoporosis was 0.787 (95% CI, 0.653-0.921) (p = 0.005).. Present results suggest that osteoporosis of the hip is associated with increased circulatory levels of OPG in patients with COPD. OPG might serve as a biomarker of this COPD-related comorbidity.

Topics: Aged; Biomarkers; Body Composition; Bone Density; Cross-Sectional Studies; Female; Forced Expiratory Volume; Hip Joint; Humans; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; RANK Ligand; Respiratory Function Tests

Previous studies have shown that matrix metalloproteinase-9 (MMP-9) and its cognate inhibitor TIMP-1, inflammatory cytokine TNF-α, and the OPG/RANK/RANKL system may each play individual roles in the pathogenesis of osteoporosis in patients with COPD. In the present study, we investigated the interrelationships of these factors in male COPD patients with and without osteoporosis. The serum levels of MMP-9, MMP-9/TIMP-1 ratio, TNF-α, RANKL, OPG, and the RANKL/OPG ratio were higher in COPD patients with osteoporosis than in individuals with normal or low bone mineral density (BMD) (N = 30, all P < 0.05 or < 0.01). The lung function FEV1%Pre and the BMD of the lumbar spine and femoral neck were found to be negatively correlated with MMP-9 serum level (r = -0.36, P < 0.05, r = -0.58, P < 0.001, and r = -0.62, P < 0.01, respectively), RANKL serum level (r = -0.21, P < 0.05, and r = -0.25, P < 0.05, and r = -0.26, P < 0.05, respectively), and RANKL/OPG ratio (r = -0.23, P < 0.05, r = -0.33, P < 0.05, and r = -0.38, P < 0.05, respectively). However, they had no correlation with TIMP-1, TNF-α, OPG, or RANK. The MMP-9 serum level was found to be positively correlated with TNF-α level (r = 0.35, P < 0.05) and RANKL/OPG ratio (r = 0.27, P < 0.05) but not associated with RANKL. These results suggest that MMP-9, TNF-α, and the OPG/RANK/RANKL system may be closely interrelated and may play interactive roles in pathogenesis of osteoporosis in COPD.

Topics: Aged; Body Mass Index; Bone Density; Case-Control Studies; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

COPD is characterized by chronic airflow limitation and inflammation of the respiratory tract. Several inflammatory biomarkers have been evaluated in COPD but are poorly related to disease severity and progression. Osteoprotegerin (OPG) is a glycoprotein mediator that is expressed in the lung and macrophages, so we have studied its concentration in induced sputum and macrophages of patients with COPD.. OPG was measured by enzyme-linked immunosorbent assay in induced sputum of patients with COPD and control subjects.. OPG concentrations in induced sputum of patients with COPD (18.7 ± 18.6 ng/mL, n = 39) were significantly higher than those of healthy smokers (8.1 ± 5.6 ng/mL, n = 15), healthy nonsmokers (3.5 ± 3.8 ng/mL, n = 14), or patients with asthma (8.0 ± 5.4 ng/mL, n = 18). Sputum OPG levels in COPD negatively correlated with FEV(1) and positively correlated with residual volume to total lung capacity ratio (RV/TLC) (r = 0.55, P < .05), transfer factor of the lung for carbon monoxide (r = -0.53, P < .05), and carbon monoxide transfer coefficient (r = -0.61, P < .01). By contrast, sputum IL-8 concentrations were related to disease severity but not to RV/TLC or gas diffusion. Airway macrophages and neutrophils were positive for OPG by immunocytochemistry in sputum and peripheral lung tissue. OPG induced matrix metalloproteinase-9 release from sputum macrophages in vitro.. Sputum OPG may be a useful biomarker to monitor parenchymal destruction in COPD.

Topics: Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Macrophages, Alveolar; Male; Middle Aged; Osteoprotegerin; Prognosis; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Severity of Illness Index; Sputum

The role of fat-bone interactions in the pathogenesis of osteoporosis in chronic obstructive pulmonary disease (COPD) is poorly understood. Our aim was to investigate expressions of leptin and osteoprotegerin (OPG) in the adipose tissue, and their relationships to osteoporosis in patients with COPD.. In 39 patients with stable COPD, bone mineral density (BMD) and body composition was assessed by Dual Energy X-Ray Absorptiometry. Serum leptin was determined by the enzyme-linked immunosorbent assay, and bone turnover markers osteocalcin and β-crosslaps by the electrochemiluminiscence immunoassays. Subcutaneous adipose tissue samples were analyzed using real-time PCR.. Twenty-one patients without, and 18 with osteoporosis were enrolled (35 men; age 62.2 ± 7.3years). Compared to patients without osteoporosis, those with the disease had significantly lower serum levels and adipose tissue expressions of leptin, in association with increased serum β-crosslaps (p=0.028, p=0.034, p=0.022, respectively). Log adipose tissue leptin was inversely related to serum β-crosslaps (p=0.015), and directly to serum leptin (p<0.001) and to the total, femoral, and lumbar BMD and T-score (p<0.02 for all relationships). Adipose tissue OPG expression was related to all variables of bone density except for lumbar BMD and T-score (p<0.05 for all relationships). Log adipose tissue leptin and OPG expressions predicted femoral T-score independently of age, gender and pulmonary function (p<0.001, adjusted R(2)=0.383; p=0.008, adjusted R(2)=0.301, respectively). Introducing body mass (or fat mass) index into these models eliminated independent predictive value of leptin and OPG expressions.. Our results suggest that adipose tissue leptin and OPG expressions are related to osteoporosis in patients with COPD, and appear to act as mediators between fat mass and BMD.

Topics: Adipose Tissue; Biomarkers; Bone Density; Bone Remodeling; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests

Osteoporosis is one of the systemic features of COPD. A correlation between the emphysema phenotype of COPD and reduced bone mineral density (BMD) is suggested by some studies, however, the mechanisms underlying this relationship are unclear. Experimental studies indicate that IL-1β, IL-6 and TNF-α may play important roles in the etiology of both osteoporosis and emphysema. The OPG/RANK/RANKL system is an important regulator of bone metabolism, and participates in the development of post-menopausal osteoporosis. Whether the OPG/RANK/RANKL pathway is involved in the pathogenesis of osteoporosis in COPD has not been studied.. Eighty male patients (current or former smokers) completed a chest CT scan, pulmonary function test, dual x-ray absorptiometry measurements and questionnaires. Among these subjects, thirty patients with normal BMD and thirty patients with low BMD were selected randomly for measurement of IL-1β, IL-6, TNF-α (flow cytometry) and OPG/RANK/RANKL (ELISA). Twenty age-matched healthy volunteers were recruited as controls.. Among these eighty patients, thirty-six had normal BMD and forty-four had low BMD. Age, BMI and CAT score showed significant differences between these two COPD groups (p < 0.05). The low-attenuation area (LAA%) in the lungs of COPD patients was negatively correlated with lumbar vertebral BMD (r = 0.741; p < 0.0001). Forward logistic regression analysis showed that only LAA% (p = 0.005) and BMI (p = 0.009) were selected as explanatory variables. The level of IL-1β was significantly higher in the COPD patients as compared to the normal controls (p < 0.05), but the difference between the two COPD groups did not reach significance. The levels of IL-6 and TNF-α among the three groups were significantly different (p < 0.05). The level of RANKL and the RANKL/OPG ratio were significantly higher in COPD patients with low BMD compared to those with normal BMD and the normal controls (p < 0.05), and correlated negatively with lumbar vertebral BMD, but positively with LAA%.. Radiographic emphysema is correlated with low BMD in current and former smokers with COPD. IL-1β, IL-6, TNF-α, and the osteoporosis-related protein system OPG/RANK/RANKL may have some synergetic effects on emphysema and bone loss in COPD.

Topics: Aged; Cytokines; Emphysema; Female; Humans; Male; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Systemic Inflammatory Response Syndrome

Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls. 409 COPD patients and 231 healthy subjects, aged 40-75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of >10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA. After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p<0.05), and higher levels of CRP (p<0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p<0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p<0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p<0.05). The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Case-Control Studies; Chemokine CXCL16; Chemokines, CXC; Cohort Studies; Female; Humans; Inflammation; Male; Middle Aged; Monocyte Chemoattractant Proteins; Osteoprotegerin; Peptides; Pulmonary Disease, Chronic Obstructive; Receptors, Scavenger; Receptors, Tumor Necrosis Factor, Type I

Previous studies suggest a relationship between systemic inflammation and body composition in chronic obstructive pulmonary disease (COPD). We examined the relationships between body composition (fat free mass index (FFMI) kg·m(-2) and fat mass index (FMI) kg·m(-2)) and three plasma inflammatory markers C-reactive Protein (CRP), soluble tumour necrosis factor receptor 1 (sTNF-R1) and osteoprotegerin (OPG) in 409 stable COPD patients (aged 40-75 yrs, Global Initiative for Obstructive Chronic Lung Disease (GOLD) categories II-IV, 249 male) from the Bergen COPD Cohort Study in Norway. FFMI and FMI were measured by bioelectrical impedance. Plasma CRP (μg·mL(-1)), sTNF-R1 (pg·mL(-1)) and OPG (ng·mL(-1)) were determined by enzyme immunoassays. Correlations and Kruskal-Wallis tests were used for bivariate analyses. Linear regression models were fitted for each of the three markers, CRP, sTNF-R1 and OPG, with FFMI and FMI as explanatory variables including sex, age, smoking habits, GOLD category, hypoxaemia, Charlson Comorbidity Index and inhaled steroid use as potential confounders. CRP and sTNF-R1 levels correlated positively with both FFMI and FMI. The adjusted regression coefficients for an increase in logCRP per unit increase in FFMI was 1.23 (1.14-1.33) kg·m(-2) and 24.9 (11.8-38.1) kg·m(-2) for sTNF-R1. Higher FMI was associated with a lower OPG, with adjusted regression coefficient -0.14 (-0.23- -0.04), whereas FFMI was unrelated to OPG. In conclusion, COPD patients with low FFMI had lower not higher plasma levels of CRP and sTNF-R1, whereas higher fat mass was associated with higher CRP and sTNF-R1 and lower OPG.

Topics: Adult; Aged; Biomarkers; Body Composition; C-Reactive Protein; Cachexia; Cross-Sectional Studies; Female; Humans; Inflammation; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Receptors, Tumor Necrosis Factor, Type I

to study a relationship between the serum level of osteoprotegerin (OPG), the markers of bone metabolism, tumor necrosis factor-alpha (TNF-alpha), and bone mineral density (BMD) in patients with chronic obstructive pulmonary disease (COPD).. Fifty-five patients aged 44 to 58 years who had COPD were examined. BMD in the lumbar spine (L(II)-L(IV)) and left femoral neck (FN) was estimated by dual-energy X-ray absorptiometry (DXA) on Lunar Prodigy Densitometer (USA). The serum levels of OPG, BCrossLaps (BCL), and TNF-alpha were measured. A control group comprised 25 healthy non-smoking gender- and age-matched volunteers.. Osteopenic syndrome (T-test < -1SD) was recorded in 43 (78%) of the 55 examined patients with COPD. In 29 (52%) of them, T-test was lower in two zones towards osteoporosis in 14 (25%) towards osteopenia. In patients with COPD, TNF-alpha concentrations were significantly higher than that in the control group. At the same time, TNF-alpha levels correlated positively with the bone resorption marker BCL (r = 0.52; p = 0.042) and negatively with OPG (r = 0.56; p = 0.003). A direct correlation was established between serum OPG concentrations and BMD in both L(II)-L(IV) and FN (r = 0.56; p < 0.01 and r = 0.47; p < 0.05, respectively). The patients with COPD were found to have lower BMD, elevated TNF-alpha concentrations, an increased bone resorption marker, and lower serum OPG levels. The associations between the levels of OPG, TNF-alpha, and BMD suggest that these markers are implicated in the pathogenesis of osteopenic syndrome in COPD.

Topics: Absorptiometry, Photon; Adult; Bone Density; Case-Control Studies; Femur Neck; Humans; Middle Aged; Osteoporosis; Osteoprotegerin; Pulmonary Disease, Chronic Obstructive; Spine; Tumor Necrosis Factor-alpha