Over the last few decades obesity has reached epidemic proportions in children as well as in adults. Obesity is associated with increased risk of insulin resistance, dyslipidemia, elevated blood pressure, and inflammation, all features of metabolic syndrome (MetS), which is linked to an increased risk of type 2 diabetes, cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD). NAFLD implies infiltration of hepatocytes with lipids, with a spectrum ranging from simple steatosis to steatohepatitis (NASH), progressive to cirrhosis. NAFLD is presently considered a hepatic manifestation of the MetS, with a key role in the pathogenetic mechanisms of cardiometabolic complications.
Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily, which can function as a decoy receptor by binding to receptor activator of NF- kB (RANK) ligand (RANKL) and competitively inhibiting the interaction between RANKL and RANK. The OPG/RANK/RANKL axis, a key regulatory system in bone homeostasis, also participate in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as insulin resistance, hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Clinical data have showed that serum OPG levels are associated with hypertension and left ventricular hypertrophy in the general population, with vascular calcification and endothelial dysfunction in subjects with and without diabetes, with severity of liver damage in patients with chronic hepatitis C. In addition, plasma sRANKL level as well as OPG gene polymorphism, especially for rs2073617 T>C and rs2073618 G>C polymorphisms, have been closely related to an increased risk of CVD. In view of these findings, there is significant interest in developing OPG/RANK/RANKL as biomarkers and probably therapeutic targets for cardiovascular and metabolic diseases.
As outlined in the previous sections, there is emerging evidence that RANKL/RANK/OPG system, traditionally associated with bone remodeling, participate in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Increased plasma OPG level is an important symbol of RANKL/RANK/OPG system activation. Clinical data have showed that serum OPG levels are associated with hypertension and left ventricular hypertrophy in the general population, with vascular calcification and endothelial dysfunction in subjects with and without diabetes, with onset as well as progression of diabetes mellitus, with a decline in glomerular filtration rate and a significantly higher risk of progression to end-stage renal disease, with severity of liver damage in patients with chronic hepatitis C. In addition, plasma sRANKL level as well as OPG gene polymorphism, especially for rs2073617 T>C and rs2073618 G>C polymorphisms, have been closely related to an increased risk of CVD. In view of these findings, there is significant interest in developing OPG and RANKL as biomarkers and probably therapeutic targets for cardiovascular and metabolic diseases. However, no data are available in children regarding a possible association of circulating OPG, RANKL, and RANK as well genetic polymorphisms of OPG with obesity-related cardiometabolic complications.
To this end, a relatively large sample of overweight/obese children and adolescents will undergo a comprehensive and complete analysis of metabolic and cardiovascular abnormalities using newly available facilities, an approach that has not been used so far.
Expected results:
1) We expect to clarify the association of circulating OPG, RANKL, and RANK and genetic polymorphisms of OPG with NAFLD and cardiometabolic comorbidities in obese children and adolescents; and
2) We expect to define the role of these molecules as a tool to identify patients at high risk of NAFLD progression and cardiometabolic complications including prediabetes/diabetes, decreased renal function, subclinical atherosclerosis, and cardiac structural and functional abnormalities.
Recognition of these complications in the young may be important, because treatment to reverse the process is most likely to be effective earlier in the diseases.
Preliminary results (presented at ESPGHAN 50th Annual Meeting of the European Society for Paediatric Gastroenterology,Hepatology and Nutrition, Prague, 10-13 May, 2017) provide evidence that OPG/RANKL ratio is independently associated with indices of left ventricular hypertrophy in male overweight/obese children and adolescents.
We are now evaluating the preliminary results obtained from gene polymorphism.