title: Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure.
abstract: Skeletal resistance to parathyroid hormone (PTH) is one of the major abnormalities underlying bone diseases in uremia, the mechanism of which has not yet been fully elucidated. Osteoclastogenesis inhibitory factor (OCIF), or osteoprotegerin, is a natural decoy receptor for osteoclast differentiation factor (ODF), produced by osteoblasts in response to PTH. To elucidate the kinetics and roles of OCIF in chronic renal failure, serum OCIF levels were measured in 46 predialysis patients and 21 dialysis patients by means of enzyme-linked immunosorbent assay (ELISA). Serum OCIF levels in predialysis patients increased as renal function declined (OCIF = 1.178 + 0.233 x creatinine; r2 = 0.413; P < 0.0001). Twenty-four-hour creatinine clearance and 1/OCIF in predialysis patients showed a clear positive correlation and a straight line regression (1/OCIF = 0.443 + 0.004 x creatinine clearance; r2 = 0.425; P < 0.0001). In dialysis patients, serum OCIF levels were significantly elevated (5.18 +/- 1.48 ng/mL) to a level that would inhibit 50% osteoclast formation in vitro. These findings suggest that OCIF accumulates in serum of patients with renal dysfunction. Because serum levels of OCIF with the ability to bind ODF in vitro (active OCIF) correlated well with those of OCIF detected by standard ELISA (active OCIF = 0.251 + 0.877 x OCIF; r2 = 0.829; P < 0.0001), OCIF accumulated in serum may be a candidate uremic toxin responsible for the skeletal resistance to PTH seen in chronic renal failure. Further studies with serum parameters and bone histological evaluation are needed to assess this possibility.
authors.affiliation: Niigata University Medical School, Niigata, Japan.
authors.forename: Junichiro J
authors.initials: JJ
authors.lastname: Kazama
authors.forename: Takashi
authors.initials: T
authors.lastname: Shigematsu
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yano
authors.forename: Eisuke
authors.initials: E
authors.lastname: Tsuda
authors.forename: Masakazu
authors.initials: M
authors.lastname: Miura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Yoshindo
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001681:Biological Assay; D001862:Bone Resorption; D002352:Carrier Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000503:physiopathology* / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D012044:Regression Analysis; D006435:Renal Dialysis
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human