Role of advanced glycation end products in adynamic bone disease in patients with diabetic nephropathy

doi:10.1053/ajkd.2001.27428

American Journal of Kidney Diseases

Volume 38, Issue 4, Supplement, October 2001, Pages S161-S164

https://doi.org/10.1053/ajkd.2001.27428 Get rights and content

Abstract

Adynamic bone disease and elevated serum levels of advanced glycation end products (AGEs) often are found in patients with renal failure caused by diabetic nephropathy. To clarify the role of AGEs in adynamic bone disease, we investigated the effect of these substances on cultured human osteoblasts and parathyroid cells. After 72 hours of incubation with AGEs-bovine serum albumin (BSA) (1,000 μg/mL), there was significant inhibition of the synthesis of type I collagen and osteocalcin in response to stimulation with 10⁻¹⁰ to 10⁻⁸ M of 1,25-dihydroxycholecalciferol. In a human osteoblastic cell line (MG 63), AGEs-BSA did not affect human osteocalcin promoter activity. In human parathyroid cells, a receptor for AGEs was detected by reverse-transcriptase polymerase chain reaction. Incubation with AGEs-BSA for 48 hours significantly inhibited parathyroid hormone secretion in response to a low calcium concentration of 0.81 mM (P < 0.01). In HEK-293 cells, expressing calcium-sensing receptors, the same AGE concentration caused a significant potentiation of the extracellular Ca²⁺ induced-intracellular calcium concentration after 24 and 48 hours of incubation (P < 0.05 and P < 0.01). These data suggest that AGEs are involved in the pathogenesis of adynamic bone disease by inhibiting osteoblastic activity and by inhibiting parathyroid hormone secretion in response to hypocalcemia. © 2001 by the National Kidney Foundation, Inc.

Section snippets

Materials

AGEs-BSA were made by incubating 50 mg/mL of bovine serum albumin (BSA) and 250 mM of glucose-6-phosphate at 37°C for 8 weeks, as reported previously.⁵ The acetoxymethyl ester of fura-2 (fura-2 AM) was purchased from Dojin (Kumamoto, Japan).

Primary culture of human osteoblasts

Human bone cells were obtained as described previously.⁶ Cells were plated at a density of 2 × 10⁴/well and were cultured for 7 to 10 days in 10% fetal calf serum in Dulbecco's modified Eagle's medium (FCS-DMEM). Then the medium was changed to 2% FCS-DMEM

Effect of AGEs-BSA on osteocalcin synthesis in the presence of 1,25(OH)₂D₃

Addition of 1,25(OH)₂D₃ (10⁻¹⁰ to 10⁻⁸ M) caused a significant increase of osteocalcin synthesis. AGEs-BSA(1,000 μg/mL) caused significant inhibition of osteocalcin synthesis at each concentration of 1,25(OH)₂D₃ (10⁻¹⁰ M of 1,25(OH)₂D₃, BSA [n = 3] 72.3 ± 1.60 versus AGE-BSA[n = 3] 10.0 ± 1.23 ng/μg DNA; P < 0.001).

Effect of AGEs-BSA on PICP synthesis

At 1000 μg/mL, AGEs-BSA significantly inhibited PICP synthesis (12,931 ± 605 [n = 3] versus 9,747 ± 242 [n = 3] ng/μg DNA;P < 0.01), whereas 100 μg/mL of AGEs-BSA had no significant

Discussion

Adynamic bone disease was reported to be common in renal osteodystrophy patients with diabetes mellitus and increasing age,¹ and a low serum PTH level has been suggested to be associated with diminished bone formation and turnover.¹ Serum PTH levels are lower in renal failure patients with diabetes mellitus than in renal failure patients without diabetes mellitus.⁹ In this study, we detected the expression of AGE receptors in human parathyroid tissues, and we proved that AGEs inhibited PTH

References (12)

A Miyauchi et al.
Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically loaded osteocytes
J Biol Chem
(2000)
F Vincenti et al.
Parathyroid and bone response of the diabetic patients to uremia
Kidney Int
(1984)
WG Goodman et al.
Renal osteodystrophy in adults and children
M Brownlee et al.
Advanced glycation end products in tissue and the biochemical basis of diabetic complications
N Engl J Med
(1988)
Z Makita et al.
Advanced glycosylation endproducts in patients with diabetic nephropathy
N Engl J Med
(1991)

There are more references available in the full text version of this article.

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Bone regeneration following trauma, tumor resection, infection, or congenital disease is challenging. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. It can result in complications affecting multiple systems including the musculoskeletal system. The increased number of diabetes-related fractures poses a great challenge to clinical specialties, particularly orthopedics and dentistry. Various pathological factors underlying DM may directly impair the process of bone regeneration, leading to delayed or even non-union of fractures. This review summarizes the mechanisms by which DM hampers bone regeneration, including immune abnormalities, inflammation, reactive oxygen species (ROS) accumulation, vascular system damage, insulin/insulin-like growth factor (IGF) deficiency, hyperglycemia, and the production of advanced glycation end products (AGEs). Based on published data, it also summarizes bone repair strategies in diabetic conditions, which include immune regulation, inhibition of inflammation, reduction of oxidative stress, promotion of angiogenesis, restoration of stem cell mobilization, and promotion of osteogenic differentiation, in addition to the challenges and future prospects of such approaches.
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Impaired bone quality, especially related to accumulation of advanced glycation end-products (AGEs) and higher incidence of falls contribute substantially to a higher risk of fracture associated with type 2 diabetes mellitus (T2DM). These factors may predispose to fractures more at skeletal sites where impaired bone toughness and falls play a larger pathogenic role (such as hip fractures) compared to skeletal sites where they are less important (such as vertebral fractures).
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After multivariable adjustment, T2DM was associated with incident hip (HR 1.63, 95% CI 1.44 to 1.85) and proximal humerus fractures (HR 1.59, 95% CI 1.39 to 1.83), but was not associated with incident forearm fracture (HR 1.00, 95% CI 0.86 to 1.17) and only weakly with incident clinical vertebral fracture (HR 1.16, 95% CI 1.01 to 1.33). Similarly, T2DM was associated with prior hip (OR 1.78, 95% CI 1.21 to 2.61) and prior proximal humerus fracture (OR 1.31, 95% CI 1.02 to 1.68) but not with prior forearm (OR 0.89, 95% CI 0.74 to 1.06) or prevalent vertebral fracture on VFA images (OR 0.91, 95% CI 0.77 to 1.08).
T2DM is a stronger risk factor for hip and proximal humerus fractures than for vertebral and wrist fractures. Further research is warranted to determine if the known differences in falls and/or bone quality between T2DM and age-related osteoporosis account for these differential associations.
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On days 7, 14, and 30 after insertion of the implants, the expression of fibronectin in the exenatide alone group was close to that of the control group, but 60 days later its expression in the exenatide alone group was significantly stronger than that in the control group (p=0.001) (Fig. 6). The inﬂuence of diabetes mellitus on dental implants has been widely studied in recent years.13–16 Some authors1,2 have stated that it remains a relative contraindication for implant treatment, while others3,4 that survival of implants could be improved if plasma glucose concentrations were brought under control.
Our aim was to investigate the impact of diabetes mellitus and different durations of glycaemic control on early osseointegration of dental implants, and to explore possible mechanisms by measuring the expression of integrin α5β1 and fibronectin in bone around the implant. We divided 33 male Zucker diabetic fatty (ZDF) rats aged 3 months into 3 groups. The first group comprised diabetic rats with dental implants (controls); the second group was treated with insulin and implants were placed simultaneously (exenatide alone group); and the third group was treated with insulin until the serum glucose was at a constant concentration (< 16 mmol/L), and implants were then inserted (exenatide+normal glucose group). Rats were killed 7, 14, 30, and 60 days after implants had been inserted. The expression of integrin α5β1 and fibronectin in bone around the implants was detected by immunohistochemical analysis in each group. The expression in the exenatide+normal glucose group was stronger than in the other 2 groups. Fourteen days after implantation, expression of integrin α5β1 in the exenatide alone group was significantly stronger than that in the control group (p=0.027), and 60 days after implantation the expression of fibronectin in the exenatide alone group was also significantly stronger than that among the controls (p=0.001). Both fibronectin and integrin α5β1 participate in the adhesion of osteoblasts and act as signals at the bone/implant interface. Diabetes interferes with the osseointegration of implants by deferring expression of fibronectin and integrin α5β1.
Adynamic Bone Disease: From Bone to Vessels in Chronic Kidney Disease
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Adynamic bone disease (ABD) is a well-recognized clinical entity in the complex chronic kidney disease (CKD)–mineral and bone disorder. Although the combination of low intact parathyroid hormone (PTH) and low bone alkaline phosphatase levels may be suggestive of ABD, the gold standard for precise diagnosis is histomorphometric analysis of tetracycline double-labeled bone biopsies. ABD essentially is characterized by low bone turnover, low bone volume, normal mineralization, and markedly decreased cellularity with minimal or no fibrosis. ABD is increasing in prevalence relative to other forms of renal osteodystrophy, and is becoming the most frequent type of bone lesion in some series. ABD develops in situations with reduced osteoanabolic stimulation caused by oversuppression of PTH, multifactorial skeletal resistance to PTH actions in uremia, and/or dysregulation of Wnt signaling. All may contribute not only to bone disease but also to the early vascular calcification processes observed in CKD. Various risk factors have been linked to ABD, including calcium loading, ageing, diabetes, hypogonadism, parathyroidectomy, peritoneal dialysis, and antiresorptive therapies, among others. The relationship between low PTH level, ABD, increased risk fracture, and vascular calcifications may at least partially explain the association of ABD with increased mortality rates. To achieve optimal bone and cardiovascular health, attention should be focused not only on classic control of secondary hyperparathyroidism but also on prevention of ABD, especially in the steadily growing proportions of diabetic, white, and elderly patients. Overcoming the insufficient osteoanabolic stimulation in ABD is the ultimate treatment goal.
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Previous studies have reported that AGE are involved in bone diseases such as osteoporosis, which is the most common chronic disabling disorder for elderly people [6]. AGE accumulates in diabetic patients and decrease bone mineral density [9]. As a result, AGE increase the risks of skeletal fragility and bone fracture.
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Primary culture of MSCs was used. For comparison analysis of AGE and COMP-Ang1 effects, we performed cell viability assay with each treated variety concentration for 24 h. Apoptosis rate and Caspase-3 activity were measured by each ELISA assay. To make sure with Ang1/Tie2 pathway, we performed small interfering RNA transfected to MSCs. Real-time RT-PCR was performed to identify ODCs marker genes. Immunoblotting was used to evaluate the expression of Tie2, AKT, p38 and ERK.
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Role of advanced glycation end products in adynamic bone disease in patients with diabetic nephropathy

Abstract

Section snippets

Materials

Primary culture of human osteoblasts

Effect of AGEs-BSA on osteocalcin synthesis in the presence of 1,25(OH)2D3

Effect of AGEs-BSA on PICP synthesis

Discussion

J Biol Chem

Kidney Int

Renal osteodystrophy in adults and children

Advanced glycation end products in tissue and the biochemical basis of diabetic complications

N Engl J Med

Advanced glycosylation endproducts in patients with diabetic nephropathy

N Engl J Med

Effect of AGEs-BSA on osteocalcin synthesis in the presence of 1,25(OH)₂D₃