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Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease.

ABSTRACT: Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus, expression of these three proteins was characterized by immunohistochemistry in 32 pediatric and young adult patients with CKD stages 2-5. When compared to normal controls, bone FGF-23 and DMP1 expression were increased in all stages of CKD; significant differences in bone FGF-23 and DMP1 expression were not detected between pre-dialysis CKD and dialysis patients. Bone MEPE expression in CKD did not differ from controls. FGF-23 was expressed in osteocyte cell bodies located at the trabecular periphery. DMP1 was widely expressed in osteocyte cell bodies and dendrites throughout bone. MEPE was also expressed throughout bone, but only in osteocyte cell bodies. Bone FGF-23 expression correlated directly with plasma levels of the protein (r=0.43, p<0.01) and with bone DMP1 expression (r=0.54, p<0.01) and expression of both proteins were inversely related to osteoid accumulation. Bone MEPE expression was inversely related to bone volume. In conclusion, skeletal FGF-23 and DMP1 expression are increased in CKD and are related to skeletal mineralization. The patterns of expression of FGF-23, MEPE, and DMP1 differ markedly in trabecular bone, suggesting that individual osteocytes may have specialized functions. Increases in bone FGF-23 and DMP1 expression suggest that osteocyte function is altered early in the course of CKD.

SUBMITTER: Pereira RC

PROVIDER: S-EPMC2783834 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease.

Pereira Renata C RC Juppner Harald H Azucena-Serrano Carlos E CE Yadin Ora O Salusky Isidro B IB Wesseling-Perry Katherine K

Bone 20090811 6

Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus, expression of these three proteins was characterized by immunohistochemistry in 32 pediatric ...[more]

PMID: 19679205

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Project description:FGF-23 has arisen as an early biomarker of renal dysfunction, but at the onset of chronic kidney disease (CKD), data suggest that FGF-23 may be produced independently of the parathyroid hormone (PTH), 1,25(OH)2 -vitamin D3 signaling axis. Iron status is inversely correlated to the level of circulating FGF-23, and improvement in iron bioavailability within patients correlates with a decrease in FGF-23. Alternately, recent evidence also supports a regulatory role of inflammatory cytokines in the modulation of FGF-23 expression. To determine the identity of the signal from the kidney-inducing upregulation of osteocytic FGF-23 at the onset of CKD, we utilized a mouse model of congenital CKD that fails to properly mature the glomerular capillary tuft. We profiled the sequential presentation of indicators of renal dysfunction, phosphate imbalance, and iron bioavailability and transport to identify the events that initiate osteocytic production of FGF-23 during the onset of CKD. We report here that elevations in circulating intact-FGF-23 coincide with the earliest indicators of renal dysfunction (P14), and precede changes in serum phosphate or iron homeostasis. Serum PTH was also not changed within the first month. Instead, production of the inflammatory protein IL-1β from the kidney and systemic elevation of it in the circulation matched the induction of FGF-23. IL-1β's ability to induce FGF-23 was confirmed on bone chips in culture and within mice in vivo. Furthermore, neutralizing antibody to IL-1β blocked FGF-23 expression in both our congenital model of CKD and a second nephrotoxic serum-mediated model. We conclude that early CKD resembles a situation of primary FGF-23 excess mediated by inflammation. These findings do not preclude that altered mineral availability or anemia can later modulate FGF-23 levels but find that in early CKD they are not the driving stimulus for the initial upregulation of FGF-23. © 2020 American Society for Bone and Mineral Research.

Project description:BACKGROUND AND OBJECTIVES:Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. RESULTS:Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4-5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). CONCLUSIONS:Low FGF-2 levels are independently associated with atheromatosis progression in CKD.

Project description:Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF-23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF-23 being found within the brain, there are no prior studies assessing whether FGF-23 levels are associated with cognitive performance. We measured FGF-23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross-sectional association between patient characteristics and FGF-23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF-23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF-23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF-23 levels. Higher FGF-23 was independently associated with a lower memory score (per doubling of FGF-23, β = -0.08 SD [95% confidence interval, CI: -0.16, -0.01]) and highest quartile vs. lowest quartile (β = -0.42 SD [-0.82, -0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = -0.03 SD [-0.10, 0.04]); however, there was a trend in the quartile analysis (β = -0.28 SD [-0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF-23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF-23 levels in hemodialysis patients may contribute to cognitive impairment.

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Dataset Information

Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease.

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Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease.

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