osteoprotegerin and Liver-Diseases

The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated.. The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression.. CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice.. Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.

Topics: Animals; Bone and Bones; Bone Density Conservation Agents; Bone Diseases, Metabolic; Bone Remodeling; Bone Resorption; Carbon Tetrachloride; Core Binding Factor Alpha 1 Subunit; Diphosphonates; Disease Models, Animal; Liver Cirrhosis; Liver Diseases; Male; Mice, Inbred C57BL; Osteoprotegerin; Pamidronate; Phosphorus; RANK Ligand; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography

Osteopenia and osteoporosis are common complications of chronic liver disease (CLD). Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) regulate osteoclastogenesis and bone remodelling, and are involved in several inflammatory diseases. This study investigated the activation state of the RANKL/OPG system and its association with bone loss in CLD.. Serum levels of OPG and sRANKL were determined in 193 patients with CLD and 56 age- and gender-matched healthy controls. Cellular sources of OPG and RANKL were determined immunohistochemically. Dual-energy x-ray absorptiometry was performed to determine bone mineral density (BMD) of lumbar spine and femoral neck.. sRANKL serum levels were significantly elevated in non-cirrhotic, but not cirrhotic patients compared to healthy controls. OPG serum levels were elevated 1.6-fold in non-cirrhotic and 2.8-fold in cirrhotic CLD patients. RANKL+ cells were mainly confined to portal fields, while OPG was broadly expressed. In the cirrhotic subgroup (87 patients) we observed a significantly higher OPG/sRANKL ratio in patients with osteopenia or osteoporosis of the lumbar spine and femoral neck region (T-score < -1) compared to those with normal BMD (T-score > or = -1).. CLD is associated with alterations in RANKL/OPG serum levels, which could modulate bone loss in CLD.

Topics: Adult; Aged; Aged, 80 and over; Bone Density; Bone Diseases, Metabolic; Carrier Proteins; Chronic Disease; Female; Glycoproteins; Humans; Liver Cirrhosis; Liver Diseases; Male; Membrane Glycoproteins; Middle Aged; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease (CLD). Recently, two new cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Therefore, the aim of our study was to evaluate bone metabolism, bone mineral density (BMD) and OPG/RANKL system in 65 male patients with CLD and in 65 healthy controls. Our patients showed lower BMD values than controls both at lumbar and femoral levels. Moreover, they had an unbalanced bone turnover with an increased resorption phase, as shown by high levels of urinary deoxypyridinoline and a decreased formation phase, as shown by the slightly, but significant, low levels of bone-alkaline phosphatase. Patients showed lower plasma levels of free-testosterone than controls and higher - although not significantly so - plasma levels of 17 beta-estradiol. Furthermore, patients with CLD had higher levels of sex hormone-binding globulin and OPG, and lower levels of 25-hydroxyvitamin D (25-HOD) and IGF-I than the control group, while RANKL levels were similar in the two groups. In conclusion, our data do not confirm the hypothesis that the OPG/RANKL system could exert a key role in the pathogenesis of hepatic osteodystrophy, but rather that the observed increase in OPG levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Amino Acids; Bone Density; Bone Diseases, Metabolic; Carrier Proteins; Chronic Disease; Estradiol; Glycoproteins; Humans; Insulin-Like Growth Factor I; Liver Diseases; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Hormone-Binding Globulin; Testosterone; Vitamin D