Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure

doi:10.1053/ajkd.2002.31402

American Journal of Kidney Diseases

Volume 39, Issue 3, March 2002, Pages 525-532

Presented in part at the 32nd Annual Meeting of the American Society of Nephrology, Miami Beach, FL, November 1-8, 1999. Published in abstract form (J Am Soc Nephrol 10:599A, 1999).

https://doi.org/10.1053/ajkd.2002.31402 Get rights and content

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 × 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 × 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 × 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. © 2002 by the National Kidney Foundation, Inc.

Section snippets

Serum samples

For the pilot study, serum samples were obtained from chronic dialysis patients at facilities affiliated with Niigata University (Niigata, Japan) and Kobe University (Kobe, Japan; n = 162; 108 men, 54 women; age, 55.71 ± 28.45 years) and age- and sex-matched healthy volunteers (n = 212; 130 men, 82 women; age, 53.45 ± 26.87 years) with creatinine levels less than 1.0 mg/dL and no abnormal urinalysis findings.

For the main study, serum samples were obtained from 46 predialysis patients (26 men,

Results

In healthy controls, serum OCIF levels were similar (0.945 ± 0.263 ng/mL) to those reported previously¹⁶ and increased in an age-dependent manner (OCIF = 0.226 + 0.020 × age; r² = 0.529; P < 0.0001). Age-dependent increases in serum OCIF levels also were observed in age- and sex-matched dialysis patients (OCIF = 0.121 + 0.051 × age; r² = 0.126; P < 0.0001), as well as healthy controls. However, OCIF levels in dialysis patients were higher than those of healthy controls for all ages (Fig

Discussion

The calcemic action of PTH is blocked in uremic patients, referred to as increased skeletal resistance to PTH.¹ Bone histomorphometric studies have shown that parameters associated with osteoclastic bone resorption generally were suppressed compared with values estimated from serum PTH levels in healthy controls.3, 17, 18, 19, 20, 21 Because increased skeletal resistance to PTH was first recognized in the early 1970s, it has been regarded as one of the major mechanisms of pathogenesis of

Acknowledgements

The authors thank Dr Takeshi Kurosawa, Sumiyoshi Clinic Hospital, Mito, Japan, for cooperation in serum sampling from chronic dialysis patients. We also thank members of the ROD-21 Clinical Research Group for thoughtful discussions.

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These cytokines and growth factors activate (myo)fibroblasts and promote interstitial fibrosis (X.-M. Meng, Nikolic-Paterson, & Lan, 2014). High serum OPG levels were observed in patients with chronic kidney disease receiving haemodialysis (Kazama et al., 2002). Furthermore, elevated serum OPG was found to predict decline of kidney function in elderly women (Lewis et al., 2014).
Fibrosis is defined by excessive formation and accumulation of extracellular matrix proteins, produced by myofibroblasts, that supersedes normal wound healing responses to injury and results in progressive architectural remodelling. Fibrosis is often detected in advanced disease stages when an organ is already severely damaged and can no longer function properly. Therefore, there is an urgent need for reliable and easily detectable markers to identify and monitor fibrosis onset and progression as early as possible; this will greatly facilitate the development of novel therapeutic strategies. Osteoprotegerin (OPG), a well-known regulator of bone extracellular matrix and most studied for its role in regulating bone mass, is expressed in various organs and functions as a decoy for receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Recently, OPG has been linked to fibrosis and fibrogenesis, and has been included in a panel of markers to diagnose liver fibrosis. Multiple studies now suggest that OPG may be a general biomarker suitable for detection of fibrosis and/or monitoring the impact of fibrosis treatment. This review summarizes our current understanding of the role of OPG in fibrosis and will discuss its potential as a biomarker and/or novel therapeutic target for fibrosis.
Hyporesponsiveness or resistance to the action of parathyroid hormone in chronic kidney disease
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Secondary hyperparathyroidism (SHPT) is an integral component of the chronic kidney disease-mineral and bone disorder (CKD-MBD). Many factors have been associated with the development and progression of SHPT but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will not only review the scientific timeline but also some of the molecular mechanisms behind. Moreover, the presence of resistance to the biological action of PTH is not unique in CKD since resistance to other hormones has also been described (“uremia as a receptor disease”). This hyporesponsiveness carries out important clinical implications since it explains, at least partially, not only the progressive nature of the pathogenesis of CKD-related PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, we underline the importance of PTH control in all CKD stages, but not aiming to completely normalize PTH levels since a certain degree of SHPT may represent an adaptive clinical response. Future studies at the molecular level, i.e. on uremia or the recent description of the calcium-sensing receptor as a phosphate sensor, may become of great value beyond their significance to explain just the hyporesponsiveness to PTH in CKD.
El hiperparatiroidismo secundario (HPS) es uno de los componentes integrales de las alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (ERC) o complejo CKD-MBD («Chronic Kidney Disease-Mineral Bone Disorder»). Se ha demostrado que en el desarrollo y progresión del HPS intervienen muchos factores, estrechamente interrelacionados, pero la presencia e importancia de hiporrespuesta (o resistencia) a la acción de la hormona paratiroidea (PTH) es poco comprendida. En esta revisión analizaremos sus antecedentes, factores que intervienen, así como alguno de los mecanismos moleculares que podrían explicarla. La presencia de resistencia a la acción biológica de la PTH no es única en la ERC ya que también se presenta para otras hormonas, habiéndose incluso usado el término de “uremia como una enfermedad de receptores”. Esta hiporrespuesta a la PTH tiene importantes implicaciones clínicas, dado que no sólo permite explicar parte de la patogenia progresiva de la hipersecreción de PTH e hiperplasia paratiroidea, sino también la creciente prevalencia de enfermedad ósea adinámica en la población con ERC. De este modo, subrayamos la importancia de controlar, sin normalizar completamente, los niveles de PTH en los distintos estadios de ERC dado que un cierto incremento de sus niveles supone inicialmente una adaptación clínica. Futuros estudios a nivel molecular sobre la uremia o la reciente descripción del efecto directo del fosfato sobre la actividad del receptor sensor de calcio como sensor de fosfato, podrían resultar valiosos incluso más allá de explicar la hiporrespuesta a la PTH en la ERC.
Osteoprotegerin Assessment Improves Prediction of Mortality in Stroke Patients
2019, Journal of Stroke and Cerebrovascular Diseases
Background: Elevated circulating osteoprotegerin (OPG) level is associated with an increased risk of hospitalization for ischemic stroke and coronary artery disease. The aim of the present study was to analyze whether OPG assessment may improve the prediction of mortality in patients with stroke. Patients and Methods: Serum OPG, fetuin A, 25-OH-D₃, intact parathyroid hormone levels were assessed in serum samples which were left over after routine tests in a hospital laboratory. This assessment was conducted in 240 consecutive patients with acute ischemic stroke, admitted within 24hours after the onset of symptoms to the Stroke Unit. Mortality data were obtained from the local registry office. Results: The mean OPG serum level was 14.6 ± 6.0pmol/L (range: 3.7-43.4). There were no significant differences in the OPG values between men and women (13.9 ± 5.0 versus 15.1 ± 6.7 pmol/L; P = .12). Therefore, tertiles were calculated for the whole group. During the follow-up, 85 (35.4%) patients died and 92 (38.3%) died or had recurrent stroke. OPG level appeared a significant predictors of death and composite end-point (death/recurrent stroke), in addition to the well-established once (age, atrial fibrillation, diabetes RANKIN at admission and discharge, severity of stroke). In multivariable stepwise backward analyses, the OPG level persisted as a significant and independent predictor of death (hazard ratio [HR] = 1.084 (95% confidence intervals: 1.036-1.134)] and composite and point (HR = 1.082 [1.037-1.129]). Conclusions: OPG level may be considered as a predictor of mortality in stroke patients.
Effect of uremic toxin-indoxyl sulfate on the skeletal system
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Citation Excerpt :
Therefore, IS could increase the cellular oxidative stress that may be a common disorder in the causal pathway between CKD and PTH hyporesponsiveness [39]. Osteoprotegerin (OPG), a decoy receptor of the osteoclast differentiation factor, has been reported to be considerably elevated in advanced CKD than in subjects with a normal kidney function [33, 40, 41]. Accumulation of serum OPG might block the actions of PTH on the bone [4].
Chronic kidney disease-mineral bone disorders (CKD-MBD) exhibit abnormalities in the circulating mineral levels, vitamin D metabolism, and parathyroid function that contribute to the formation of a bone lesion. The uremic toxin, indoxyl sulfate (IS), accumulates in the blood in cases of renal failure and leads to bone loss. The bone and renal responses to the action of the parathyroid hormone (PTH) are progressively decreased in CKD in spite of increasing PTH levels, a condition commonly called PTH resistance. There is a high prevalence of low bone turnover or adynamic bone disease in the early stages of CKD. This could be due to the inhibition of bone turnover, such as in PTH resistance, reduced active vitamin D levels, diabetes, aluminum, and, increased IS. With an increase in IS, there is a decrease in the osteoblast Wnt/b-catenin signaling and increase in the expression of Wnt signaling inhibitors, such as sclerostin and Dickkopf-1 (DKK1). Thus, a majority of early CKD patients exhibit deterioration of bone quality owing to the action of IS, this scenario could be termed uremic osteoporosis. However, this mechanism is complicated and not fully understood. With progressive deterioration in the renal function, IS accumulates along with persistent PTH secretion, potentially leading to high-turnover bone disease because high serum PTH levels have the ability of overriding peripheral PTH resistance and other inhibitory factors of bone formation. Finally, it leads to deterioration in bone quantity with prominent bone resorption in end stage renal disease. Uremic toxins adsorbents may decelerate oxidative stress and improve bone health in CKD patients. This review article focuses on IS and bone loss in CKD patients.
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^*: For the ROD-21 Clinical Research Group, Japan.

^**: Supported in part by a program project grant from the Ministry of Health, Japan (M.F.) and a Special Grant for Medical Research from the Ministry of Post and Telecommunications, Japan (M.F.).

^*: Address reprint requests to Masafumi Fukagawa, MD, PhD, Associate Professor and Chief, Division of Nephrology and Dialysis Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected]

^**: 0272-6386/02/3903-0009$35.00/0

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Original InvestigationsIncreased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure*,**,*,**

Abstract

Section snippets

Serum samples

Results

Discussion

Acknowledgements

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Cell

Cell

Kidney Int

Kidney Int

Kidney Int

Am J Kidney Dis

Bone

Biochem Biophys Res Commun

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Am J Kidney Dis

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects

Ann Intern Med

Renal osteodystrophy

N Engl J Med

Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia

J Clin Endocrinol Metab

Original Investigations
Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure*,**,*,**