Abstract
The influence of osteoprotegerin and RANKL as regulators of osteoclastogenesis and bone remodeling in liver disease and in the development of osteoporosis in primary biliary cirrhosis (PBC) is uncertain. Therefore, 68 women with PBC and 20 healthy females were studied by assessing circulating osteoprotegerin and RANKL. Bone mineral density and markers of bone turnover were measured as well. Osteoprotegerin-mRNA expression was also assessed in liver tissue from 16 patients and 5 controls. Osteoprotegerin was higher in PBC than in controls (5.4 ± 0.2 vs. 2.9 ± 0.2 pM/l, P < 0.0001), whilst RANKL was lower in patients than in controls (0.39 ± 0.06 vs. 1.40 ± 0.16 pM/l, P < 0.0001). Osteoprotegerin was more elevated in patients with more advanced disease, as defined by bilirubin above 1.2 mg/dl (6.6 ± 0.6 vs. 5.2 ± 0.2 pM/l, P = 0.02) or by Mayo over 4 (5.9 ± 0.3 vs. 4.8 ± 0.2 pM/l, P = 0.02). Osteoprotegerin and RANKL were unrelated with osteoporosis, and no associations were found with markers of bone remodeling, except for RANKL, which was particularly decreased in patients with low osteocalcin. This marker of bone formation was also higher in patients with elevated circulating osteoprotegerin. Liver osteoprotegerin gene expression was similar in patients and controls, and no correlation was found between liver osteoprotegerin-mRNA and patients’ respective circulating levels. In conclusion, osteoprotegerin and RANKL are abnormal in patients with PBC, regardless of osteoporosis. The elevated circulating osteoprotegerin is associated with the severity of disease, but not with gene expression in the liver.
Similar content being viewed by others
References
Guañabens N, Parés A, Mariñoso L, Brancós MA, Piera C, Serrano S et al (1990) Factors influencing the development of metabolic bone disease in primary biliary cirrhosis. Am J Gastroenterol 85:1356–1361
Leslie WD, Bernstein CN, Leboff MS, The American Gastroenterological Association Clinical Practice Committee (2003) AGA Technical Review on Osteoporosis in Hepatic Disorders. Gastroenterology 125:941–966
Hodgson SF, Dickson ER, Eastell R, Eriksen EF, Bryant SC, Riggs BL (1993) Rates of cancellous bone remodeling and turnover in osteopenia associated with primary biliary cirrhosis. Bone 14:819–827
Guañabens N, Parés A, Ros I, Caballería L, Pons F, Vidal S et al (2005) Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis. J Hepatol 42:573–577
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lûthy R et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319
Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N et al (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139:1329–1337
Koshla S (2001) Minireview: the OPG/RANKL/RANK System. Endocrinology 142:5050–5055
Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D (2004) The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathological bone remodeling. Cytokine Growth Factor Rev 15:49–60
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342
Szalay F, Hegedus D, Lakatos PL, Tornai I, Bajnook E, Dunkel K et al (2003) High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol 38:395–400
Gaudio A, Lasco A, Morabito N, Atteritano M, Vergara C, Catalano A et al (2005) Hepatic osteodystrophy: does the osteoprotegerin/receptor activator of nuclear factor-κB ligand system play a role. J Endocrinol Invest 28:677–682
Moschen AR, Kaser A, Stadlmann S, Millonig G, Kaser S, Mühllechner P et al (2005) The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol 43:973–983
Ludwig J, Dickson ER, McDonald GSA (1978) Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch (Pathol Anat) 379:103–112
WHO Study Group (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 843:1–129
Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A et al (1999) Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 14:518–527
Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R (2002) Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 87:4470–4475
Browner WS, Lui LY, Cummings SR (2001) Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 86:631–637
Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD (2001) Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab 86:3162–3165
Hegedus D, Fernencz V, Lakatos PL, Meszaros S, Lakatos P, Horvath C et al (2002) Decreased bone density, elevated serum osteoprotegerin, and β-Cross-Laps in Wilson disease. J Bone Miner Res 17:1961–1967
Gonzalez-Calvin JL, Mundi JL, Casado FJ, Olivares EG (2004) Bone mineral density and serum levels of estradiol and osteoprotegerin in postmenopausal women with viral cirrhosis. Gastroenterology 126:1225–1226
Fábrega E, Orive A, García-Suárez C, García-Unzueta M, Amado A, Pons-Romero F (2005) Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Liver Int 25:305–310
Monegal A, Guañabens N, Navasa M, Alvarez L, Ozalla D, Peris P et al (2007) Serum osteoprotegerin and its ligand in cirrhotic patients referred for orthotopic liver transplantation: relationship with metabolic bone disease. J Liver Int 27:492–497
García-Valdecasas-Campelo E, González-Reimers E, Santolaria-Fernández F, De la Vega-Prieto MJ, Milena-Abril A, Sánchez-Pérez MJ et al (2006) Serum osteoprotegerin and RANKL levels in chronic alcoholic liver disease. Alcohol Alcohol 41:261–266
Alvarez L, Peris P, Guañabens N, Vidal S, Ros I, Pons F et al (2003) Serum osteoprotegerin and its ligand in Paget’s disease of bone. Relationship to disease activity and effect of treatment with bisphosphonates. Arthritis Rheum 48:824–828
Hofbauer LC, Schoppet M (2004) Clinical implications of the Osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 292:490–495
Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, Matsumura S, Yabushita K, Okano N, Tsuji T (1999) Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol 19:422–427
Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, Harver J, Katz G, Lindor K (2002) Tumor necrosis factor alpha and transforming growth factor beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol 17:196–202
Hofbauer LC, Koshla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15:2–12
Bolon B, Shalhoub V, Kostenuik PJ, Campagnuolo G, Morony S, Boyle WJ et al (2002) Osteoprotegerin, an endogenous antiosteoclast factor for protecting bone in rheumatoid arthritis. Arthritis Rheum 46:3121–3135
Stellon AJ, Webb A, Compston J, Williams R (1987) Low bone turnover state in primary biliary cirrhosis. Hepatology 7:137–147
Schett G, Kiechl S, Redlich K, Oberhollenzer F, Weger S, Egger G et al (2004) Soluble RANKL and risk of nontraumatic fracture. JAMA 291:1108–1113
Acknowledgment
This study was supported in part by grants from the Instituto de Salud Carlos III C03/08 and C03/02 and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Guañabens, N., Enjuanes, A., Alvarez, L. et al. High osteoprotegerin serum levels in primary biliary cirrhosis are associated with disease severity but not with the mRNA gene expression in liver tissue. J Bone Miner Metab 27, 347–354 (2009). https://doi.org/10.1007/s00774-009-0042-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-009-0042-1