OPG/RANKL/RANK cytokine system in renal osteodystrophy
Abstract
Background: Renal osteodystrophy is one of the most common complications affecting patients with endstage renal disease treated with hemodialysis (HD). The action of calciotropic hormones in renal osteodystrophy is regulated by the OPG/RANKL/RANK system. Its function is modulated by interleukines, calcitriol and parathyroid hormone (PTH).The aim of our study was to confirm that this system is involved in the pathogenesis of renal osteodystrophy and supports the mechanism of PTH action on bone.
Methods: 106 HD patients (mean age 60 years) and 50 healthy volunteers (mean age 64 years) were enrolled in the study. In serum samples of patients and controls we determined concentrations of OPG, RANKL, tartarat resistant acid phosphatase 5b (TRAP 5b), serum Cterminal telopeptide cross-links of type I collagen (CTx), bone specific alkaline phosphatase (BALP), osteocalcin (OC) and parathyroid hormone (PTH). We compared serum measurements of HD patients and controls and assessed the correlation of OPG and RANKL with bone markers. The most frequent OPG promotor gene polymorphisms were also determined. SPSS 12.1 for Windows was used for statistical analysis.
Results: Median OPG concentrations were approximately three times higher in HD patients (0.804 µg/l) than in healthy volunteers (0.272 µg/l). Mean serum RANKL concentrations were 1.66- fold higher in HD patients (1.36 pmol/l) than in controls (0.82 pmol/l). Serum RANKL levels significantly differed between patients with and without calcitriol therapy (p = 0.001). After dividing HD patients into tertiles according to PTH, we observed significantly higher OPG values in the lower and RANKL in the upper tertile (p < 0.001). OPG did not correlate with bone resorption markers. Only weak correlation of bone formation markers with osteocalcin was noted. In contrast to OPG, RANKL correlated well with PTH, OC and CTX. OPG promoter gene polymorphisms (149 T → C, 163 A → G, 950 T → C) do not influence OPG expression and consequently its serum levels.
Conclusions: Our results support the outcomes of in vitro studies of PTH inhibitory action on OPG and PTH stimulatory action on RANKL synthesis. The highest OPG values were observed in the first tertile and RANKL levels in the third PTH tertile. In HD patients with high bone turnover, PTH action leads to disbalance in OPG/RANKL/RANK and consequently to accelerated bone resorption. We proved the role of the OPG/RANKL/RANK system in the pathogenesis of renal osteodystrophy.
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References
Hruska K. New concepts in renal osteodystrophy. Nephrol Dial Transplant 1998; 13: 2755–60.
Disthabanchong S, Gonzales EA. Regulation of bone cell development and function: implications for renal osteodystrophy. J Investig Med 2001; 49: 240–9.
Reichel H, Esser A, Roth HJ, Schmidt-Gayk H. Influence of PTH assay methodology on differential diagnosis of renal bone disease. Nephrol Dial Transplant 2003; 759–68.
Montalban C, Garcia-Unzueta MT, De Francisco AL, Amado JA. Serum interleukin-6 in renal osteodystrophy: Relationship with serum PTH and bone remodeling markers. Horm Metab Res 1999; 31: 14–7.
Haughes FJ, Howells GL. Interleukin-6 inhibits bone formation in vitro. Bone Miner 1993; 21: 28–8.
Coen G, Ballanti P, Calabria S, Fischer MS, Lifrieri F, Di Zazzo G, et al. Osteoprotegerin / osteoprotegerin – ligand (OPG/OPGL) system in renal osteodystrophy (RO). JN 2002; 15: 725–40.
Gonzales EA. The role of cytokines in skeletal remodelling: possible consequence for renal osteodystrophy. Nephrol Dial Transplant 2000; 15: 945–50.
Morony S, Capparelli C, Lee R, Shimamoto G, Boone T, Lacey DL, et al. A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1 beta, TNF-alpha, PTH, PTHrP, and 1.25(OH)2D3. J Bone Miner Res 1999; 14: 1478–85.
Martin KJ, Olgaard K, Coburn JW. Diagnosis, assessment and treatment of bone turnover abnormalities in renal osteodystrophy. Am J Kidney Dis 2004; 43: 558–65.
Innis MA, Gelfand DH, Sninsky N, White TJ. PCR protocol: A quide to methods and applications. San Diego: Academic Press; 1990.
Haas M, Leko-Mohr Z, Roschger P, Kletzmayr J, Schwarz C, Domer Zsontsich T, et al. Osteoprotegerin and parathyroid hormone as markers of high turnover osteodystrophy and decreased bone mineralization in hemodialysis patients. Am J Kidney Dis 2002; 39: 580–6.
Avberšek-Lužnik I, Pečovnik-Balon B, Rus I, Marc J. Increased bone resorption in HD patients: is it caused by elevated RANKL synthesis? Nephrol Dial Transplant 2005; 20: 566–70.
Coen G, Ballanti P, Balducci A, Calabria S, Fischer MS, Jankovic L, et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 2002; 17: 233–8.
Kazama JJ, Shigematsu T, Yano K, Tsuda E, Miura M, Iwasaki Y, et al. Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis 2002; 39: 525–32.
Avberšek-Lužnik I, Malešič I, Rus I, Marc J. Increased levels of osteoprotegerin in hemodialysis patients. Clin Chem Lab Med 2002; 40: 1019–23.
Kazama JJ, Shigematsu T, Yano K, Tsuda E, Miura M, Iwasaki Y, et al. Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis 2002; 39: 525–32.
Malyszko J, Malyszko JS, Wolczynski S, Mysliwiec M. Osteoprotegerin and its Correlations with new markers of bone formation and bone resorption in kidney transplant recipients. Transplant Proc 2003; 35: 2227–9.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang M-S, Lüthy R. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309–19.
Lacey DL, Timms E, Tan H-L, Kelly MJ, Dunstan CR, Burgess T, et al. osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–76.
Hruska KA, Saab G, Chaudhary LR, Quinn CO, Lund RJ, Surendran K. Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy. Seminars in Nephrology 2004; 24: 25–38.
Arko B, Avberšek-Lužnik I, Marc J. Vpliv polimorfizmov v promotorju gena za OPG na njegovo serumsko koncentracijo pri dializnih bolnikih. Farm Vestn 2004; 55: 322–4.
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