Relationship between osteoporosis and adipose tissue leptin and osteoprotegerin in patients with chronic obstructive pulmonary disease
Research highlights
► Osteoporosis is related to reduced leptin expression in adipose tissue (AT) in COPD. ► AT leptin expression correlates with bone mineral density (BMD) and β-crosslaps. ► AT osteoprotegerin (OPG) expression correlates with BDM and β-crosslaps. ► AT leptin and OPG predicted BMD independently of age, gender and lung function. ► Adjustments for adiposity eliminated independent predictive value of leptin and OPG.
Introduction
Chronic obstructive pulmonary disease (COPD), one of the most prevalent diseases worldwide, is characterized by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly cigarette smoke [1]. Nevertheless, the pathological mechanisms and clinical manifestations of COPD are not restricted only to pulmonary inflammation and airway remodeling [2]. In contrast, over the last decade, the recognition of COPD as a systemic disease developed. The best recognized systemic manifestations of COPD include systemic inflammation, cardiovascular comorbidities, osteoporosis, cachexia and muscle dysfunction, and anemia [3]. Chronic comorbidities adversely affect health outcomes in patients with COPD, including mortality.
Osteoporosis, a systemic skeletal disease characterized by low bone mineral density (BMD) and microarchitectural deterioration, is highly prevalent in patients with COPD: a recent meta-analysis of 13 studies in patients with COPD indicated the overall mean prevalence of osteoporosis of 35.1% (range 9–69%) [4]. Nevertheless, osteoporosis remains underdiagnosed and undertreated in these patients, and the underlying mechanisms remain poorly understood [5]. Proposed mechanisms that likely contribute to increased risk of low BMD in COPD include systemic inflammation, decreased physical activity owing to dyspnea, and/or other factors leading to proteolysis, reduced bone formation and increased bone resorption [6], [7]. The recently evolved novel concept of fat–bone interactions suggests that adipose tissue might profoundly affect bone formation and/or resorption [8]. A number of mechanisms for the fat–bone relationship exist, and include the contribution of adipose tissue mass to skeletal loading, the effects of fat mass on the secretion of bone active hormones from the pancreatic beta cells (including insulin and amylin), and the secretion of bone active hormones from adipocytes. Indeed, adipokines such as leptin have recently emerged as mediators of the protective effects of fat on bone tissue [9], [10].
Leptin enhances differentiation of bone marrow cells into osteoblasts, favors osteoblast activity by increasing the synthesis of new mineralized matrix and enhancement of chondrocyte maturation, and reduces osteoclast formation [11]. In addition, leptin stimulates the osteoprotegerin (OPG)-receptor activator of nuclear factor κB (RANK) pathway [12]. OPG, an anti-inflammatory protein derived from osteoblasts, inhibits osteoclastogenesis by acting as a decoy receptor to competitively inhibit RANK ligand (RANKL), and thus prevents the interaction of RANKL with its receptor RANK resulting in decreased bone resorption [13], [14]. Several studies identified positive relationships between serum leptin and bone mass in healthy individuals [15], [16], [17], [18], and in patients with mental anorexia [19] or renal osteodystrophy [20]. Moreover, OPG gene polymorphisms were related to the risk of osteoporosis [21], and the presence of autoantibodies against OPG was associated with high-turnover osteoporosis [22]. In patients with COPD, reductions in circulatory levels of leptin and OPG were recently reported [23], [24], nevertheless, potential relationships between adipose tissue leptin and OPG expressions and osteoporosis remained unexplored. Therefore, the purpose of the present study was to investigate expressions of leptin and OPG in the adipose tissue, and their relationships to osteoporosis in patients with COPD.
Section snippets
Subjects
Patients with diagnosis of COPD according to the American Thoracic Society/European Respiratory Society guidelines, free from exacerbation for ≥ 8 weeks were recruited from two out-patient clinics affiliated with the university hospital setting. The study inclusion criteria required the patients to be clinically stable, performing regular mild physical activity, and receiving an adequate and balanced diet. Exclusion criteria were use of systemic corticosteroids, treatment with long-term home
Patients
Thirty-nine patients with COPD (35 men and 4 women) were enrolled. They were generally late middle-aged (mean age 62.2 ± 7.3 years) with a mean 35.5 ± 25.7 pack years history of smoking. Patients were divided into two groups: the first was formed by 21 (53.8%) patients without, and the second by 18 (46.2%) patients with osteoporosis. Table 1 displays demographic data and body composition parameters in the two groups. The groups did not differ in any of the demographic characteristics. Nevertheless,
Discussion
The present study provides a novel observation on the role of adipose tissue in osteoporosis in patients with COPD. Our data demonstrate that COPD patients with osteoporosis have lower adipose tissue leptin expressions and lower serum leptin levels, in association with increased β-crosslaps compared to those with normal bone density. Adipose tissue leptin and OPG expressions correlated with the both, BMD variables and serum β-crosslaps levels. In addition, in multivariate analyses, leptin and
Acknowledgments
This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0122-06, VEGA 1/0348/09 and VEGA 1/0227/11 of the Ministry of Education, Slovakia. The authors wish to express their gratitude to Drs. Maria Pobehova and Stefan Toth who referred patients to the study from their out-patient clinics; to Mrs. Dana Lalkovicova, the head nurse at the Pulmonary Function Laboratory, and to Mrs. Miroslava Pavuckova, the research nurse who assisted in adipose tissue
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