Skip to main content
Top
Published in: BMC Musculoskeletal Disorders 1/2019

Open Access 01-12-2019 | Research article

Non-invasive skin autofluorescence, blood and urine assays of the advanced glycation end product (AGE) pentosidine as an indirect indicator of AGE content in human bone

Authors: Yoshikuni Kida, Mitsuru Saito, Akira Shinohara, Shigeru Soshi, Keishi Marumo

Published in: BMC Musculoskeletal Disorders | Issue 1/2019

Login to get access

Abstract

Background

Bone mineral density (BMD) measurements are widely used to assess fracture risk. However, the finding that some fracture patients had high BMD together with the low contribution of drugs to osteoporosis suggests that bone strength factors other than BMD contribute to bone quality. We evaluated the amount of advanced glycation end products (AGEs) by non-invasive assays of serum and urine as well as by skin autofluorescence to measure the levels of a representative AGE, pentosidine, to investigate whether pentosidine can serve as an indirect indicator of AGEs formation in bone collagen.

Methods

A total of 100 spinal surgery patients without fragility fracture (54 males and 46 females) treated at our hospital were enrolled. The amount of pentosidine in blood, urine, skin and bone (lumbar lamina) samples from these patients was measured. AGE accumulation was assessed by measuring skin autofluorescence. We examined the correlation between pentosidine content in tissues and body fluid, as well as skin AGEs with age, height, body weight, BMI, and estimated glomerular filtration rate (eGFR).

Results

A significant age-related increase in pentosidine levels in tissues was observed, while there was a significant negative correlation between tissue pentosidine and eGFR. The amount of skin pentosidine was significantly and positively correlated with pentosidine content of the bone in those under 50 years of age. Urine pentosidine also correlated positively with bone pentosidine and skin pentosidine, but only in females. The total amount of AGEs in skin did not correlate with bone pentosidine.

Conclusion

In this study, the strong correlation between the pentosidine content in each sample and eGFR may indicate that renal dysfunction with advancing age increases oxidative stress and induces AGEs formation in collagen-containing tissues. The correlation of skin pentosidine concentration and eGFR, with AGEs formation in bone collagen suggests that pentosidine would be a useful indirect index of decreased bone quality. Skin AGEs estimated by autofluorescence in clinical situations may not be suitable as an indirect assessment of bone quality. Because urine pentosidine correlated positively with bone pentosidine and skin pentosidine in females, urine pentosidine may be a candidate for an indirect assessment of bone quality.
Appendix
Available only for authorised users
Literature
1.
go back to reference Saito M, Kida Y, Nishizawa T, Arakawa S, Okabe H, Seki A, Marumo K. Effects of 18-month treatment with bazedoxifene on enzymatic immature and mature cross-links and non-enzymatic advanced glycation end products, mineralization, and trabecular microarchitecture of vertebra in ovariectomized monkeys. Bone. 2015;81:573–80.CrossRef Saito M, Kida Y, Nishizawa T, Arakawa S, Okabe H, Seki A, Marumo K. Effects of 18-month treatment with bazedoxifene on enzymatic immature and mature cross-links and non-enzymatic advanced glycation end products, mineralization, and trabecular microarchitecture of vertebra in ovariectomized monkeys. Bone. 2015;81:573–80.CrossRef
2.
go back to reference Yamamoto M, Sugimoto T. Advanced Glycation end products, diabetes, and bone strength. Curr Osteoporos Rep. 2016;14(6):320–6.CrossRef Yamamoto M, Sugimoto T. Advanced Glycation end products, diabetes, and bone strength. Curr Osteoporos Rep. 2016;14(6):320–6.CrossRef
3.
go back to reference Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195–214.CrossRef Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195–214.CrossRef
4.
go back to reference Nojiri H, Saita Y, Morikawa D, Kobayashi K, Tsuda C, Miyazaki T, Saito M, Marumo K, Yonezawa I, Kaneko K, et al. Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res. 2011;26(11):2682–94.CrossRef Nojiri H, Saita Y, Morikawa D, Kobayashi K, Tsuda C, Miyazaki T, Saito M, Marumo K, Yonezawa I, Kaneko K, et al. Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking. J Bone Miner Res. 2011;26(11):2682–94.CrossRef
5.
go back to reference Saito M, Fujii K, Soshi S, Tanaka T. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int. 2006;17(7):986–95.CrossRef Saito M, Fujii K, Soshi S, Tanaka T. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int. 2006;17(7):986–95.CrossRef
6.
go back to reference Saito M, Marumo K, Soshi S, Kida Y, Ushiku C, Shinohara A. Raloxifene ameliorates detrimental enzymatic and nonenzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int. 2010;21(4):655–66.CrossRef Saito M, Marumo K, Soshi S, Kida Y, Ushiku C, Shinohara A. Raloxifene ameliorates detrimental enzymatic and nonenzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int. 2010;21(4):655–66.CrossRef
7.
go back to reference Saito M, Fujii K, Marumo K. Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int. 2006;79(3):160–8.CrossRef Saito M, Fujii K, Marumo K. Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int. 2006;79(3):160–8.CrossRef
8.
go back to reference Saito M, Marumo K, Kida Y, Ushiku C, Kato S, Takao-Kawabata R, Kuroda T. Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. Osteoporos Int. 2011;22(8):2373–83.CrossRef Saito M, Marumo K, Kida Y, Ushiku C, Kato S, Takao-Kawabata R, Kuroda T. Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. Osteoporos Int. 2011;22(8):2373–83.CrossRef
9.
go back to reference Saito M, Marumo K, Fujii K, Ishioka N. Single-column high-performance liquid chromatographic-fluorescence detection of immature, mature, and senescent cross-links of collagen. Anal Biochem. 1997;253(1):26–32.CrossRef Saito M, Marumo K, Fujii K, Ishioka N. Single-column high-performance liquid chromatographic-fluorescence detection of immature, mature, and senescent cross-links of collagen. Anal Biochem. 1997;253(1):26–32.CrossRef
10.
go back to reference Vaculik J, Braun M, Dungl P, Pavelka K, Stepan JJ. Serum and bone pentosidine in patients with low impact hip fractures and in patients with advanced osteoarthritis. BMC Musculoskelet Disord. 2016;17:308.CrossRef Vaculik J, Braun M, Dungl P, Pavelka K, Stepan JJ. Serum and bone pentosidine in patients with low impact hip fractures and in patients with advanced osteoarthritis. BMC Musculoskelet Disord. 2016;17:308.CrossRef
11.
go back to reference Choi DH, Lee SM, Lim SA, Choi YS. Feasibility of serum Pentosidine level as a potential risk factor for osteoporotic vertebral compression fracture. Asian Spine J. 2018;12(6):992–7.CrossRef Choi DH, Lee SM, Lim SA, Choi YS. Feasibility of serum Pentosidine level as a potential risk factor for osteoporotic vertebral compression fracture. Asian Spine J. 2018;12(6):992–7.CrossRef
12.
go back to reference Shiraki M, Urano T, Kuroda T, Saito M, Tanaka S, Miyao-Koshizuka M, Inoue S. The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. J Bone Miner Metab. 2008;26(6):595–602.CrossRef Shiraki M, Urano T, Kuroda T, Saito M, Tanaka S, Miyao-Koshizuka M, Inoue S. The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. J Bone Miner Metab. 2008;26(6):595–602.CrossRef
13.
go back to reference Shiraki M, Kuroda T, Tanaka S, Saito M, Fukunaga M, Nakamura T. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab. 2008;26(1):93–100.CrossRef Shiraki M, Kuroda T, Tanaka S, Saito M, Fukunaga M, Nakamura T. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab. 2008;26(1):93–100.CrossRef
14.
go back to reference Tanaka S, Kuroda T, Saito M, Shiraki M. Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res. 2011;26(11):2778–84.CrossRef Tanaka S, Kuroda T, Saito M, Shiraki M. Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res. 2011;26(11):2778–84.CrossRef
15.
go back to reference Kageyama Y, Takahashi M, Nagafusa T, Torikai E, Nagano A. Methotrexate reduces the levels of pentosidine and 8-hydroxy-deoxy guanosine in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(5):398–402.CrossRef Kageyama Y, Takahashi M, Nagafusa T, Torikai E, Nagano A. Methotrexate reduces the levels of pentosidine and 8-hydroxy-deoxy guanosine in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(5):398–402.CrossRef
16.
go back to reference Kheniser KG, Polanco Santos CM, Kashyap SR. The effects of diabetes therapy on bone: a clinical perspective. J Diabetes Complicat. 2018;32(7):713–9.CrossRef Kheniser KG, Polanco Santos CM, Kashyap SR. The effects of diabetes therapy on bone: a clinical perspective. J Diabetes Complicat. 2018;32(7):713–9.CrossRef
17.
go back to reference Sanaka T, Funaki T, Tanaka T, Hoshi S, Niwayama J, Taitoh T, Nishimura H, Higuchi C. Plasma pentosidine levels measured by a newly developed method using ELISA in patients with chronic renal failure. Nephron. 2002;91(1):64–73.CrossRef Sanaka T, Funaki T, Tanaka T, Hoshi S, Niwayama J, Taitoh T, Nishimura H, Higuchi C. Plasma pentosidine levels measured by a newly developed method using ELISA in patients with chronic renal failure. Nephron. 2002;91(1):64–73.CrossRef
18.
go back to reference Yoshihara K, Nakamura K, Kanai M, Nagayama Y, Takahashi S, Saito N, Nagata M. Determination of urinary and serum pentosidine and its application to elder patients. Biol Pharm Bull. 1998;21(10):1005–8.CrossRef Yoshihara K, Nakamura K, Kanai M, Nagayama Y, Takahashi S, Saito N, Nagata M. Determination of urinary and serum pentosidine and its application to elder patients. Biol Pharm Bull. 1998;21(10):1005–8.CrossRef
19.
go back to reference Meerwaldt R, Lutgers HL, Links TP, Graaff R, Baynes JW, Gans RO, Smit AJ. Skin autofluorescence is a strong predictor of cardiac mortality in diabetes. Diabetes Care. 2007;30(1):107–12.CrossRef Meerwaldt R, Lutgers HL, Links TP, Graaff R, Baynes JW, Gans RO, Smit AJ. Skin autofluorescence is a strong predictor of cardiac mortality in diabetes. Diabetes Care. 2007;30(1):107–12.CrossRef
20.
go back to reference Meerwaldt R, Links T, Graaff R, Thorpe SR, Baynes JW, Hartog J, Gans R, Smit A. Simple noninvasive measurement of skin autofluorescence. Ann N Y Acad Sci. 2005;1043:290–8.CrossRef Meerwaldt R, Links T, Graaff R, Thorpe SR, Baynes JW, Hartog J, Gans R, Smit A. Simple noninvasive measurement of skin autofluorescence. Ann N Y Acad Sci. 2005;1043:290–8.CrossRef
21.
go back to reference Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, Thorpe SR, Baynes JW, Gans ROB, Smit AJ. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004;47(7):1324–30.CrossRef Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, Thorpe SR, Baynes JW, Gans ROB, Smit AJ. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia. 2004;47(7):1324–30.CrossRef
22.
go back to reference Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, Federici A. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005;1043:710–7.CrossRef Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, Federici A. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005;1043:710–7.CrossRef
23.
go back to reference Sell DR, Monnier VM. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest. 1990;85(2):380–4.CrossRef Sell DR, Monnier VM. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest. 1990;85(2):380–4.CrossRef
24.
go back to reference Nyman JS, Roy A, Tyler JH, Acuna RL, Gayle HJ, Wang X. Age-related factors affecting the postyield energy dissipation of human cortical bone. J Orthop Res. 2007;25(5):646–55.CrossRef Nyman JS, Roy A, Tyler JH, Acuna RL, Gayle HJ, Wang X. Age-related factors affecting the postyield energy dissipation of human cortical bone. J Orthop Res. 2007;25(5):646–55.CrossRef
25.
go back to reference Hernandez CJ, Tang SY, Baumbach BM, Hwu PB, Sakkee AN, van der Ham F, DeGroot J, Bank RA, Keaveny TM. Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. Bone. 2005;37(6):825–32.CrossRef Hernandez CJ, Tang SY, Baumbach BM, Hwu PB, Sakkee AN, van der Ham F, DeGroot J, Bank RA, Keaveny TM. Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. Bone. 2005;37(6):825–32.CrossRef
26.
go back to reference Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31(1):1–7.CrossRef Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31(1):1–7.CrossRef
27.
go back to reference Maasen K, van Greevenbroek MMJ, Scheijen J, van der Kallen CJH, Stehouwer CDA, Schalkwijk CG. High dietary glycemic load is associated with higher concentrations of urinary advanced glycation endproducts: the cohort on diabetes and atherosclerosis Maastricht (CODAM) study. Am J Clin Nutr. 2019;110(2):358–66.CrossRef Maasen K, van Greevenbroek MMJ, Scheijen J, van der Kallen CJH, Stehouwer CDA, Schalkwijk CG. High dietary glycemic load is associated with higher concentrations of urinary advanced glycation endproducts: the cohort on diabetes and atherosclerosis Maastricht (CODAM) study. Am J Clin Nutr. 2019;110(2):358–66.CrossRef
28.
go back to reference Mitome J, Yamamoto H, Saito M, Yokoyama K, Marumo K, Hosoya T. Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Calcif Tissue Int. 2011;88(6):521–9.CrossRef Mitome J, Yamamoto H, Saito M, Yokoyama K, Marumo K, Hosoya T. Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Calcif Tissue Int. 2011;88(6):521–9.CrossRef
29.
go back to reference Shiraki M, Kuroda T, Shiraki Y, Tanaka S, Higuchi T, Saito M. Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment. J Bone Miner Metab. 2011;29(1):62–70.CrossRef Shiraki M, Kuroda T, Shiraki Y, Tanaka S, Higuchi T, Saito M. Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment. J Bone Miner Metab. 2011;29(1):62–70.CrossRef
30.
go back to reference Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. 2006;17(10):1514–23.CrossRef Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. 2006;17(10):1514–23.CrossRef
31.
go back to reference Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. 2006;17(3):319–36.CrossRef Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Osteoporos Int. 2006;17(3):319–36.CrossRef
32.
go back to reference Saito M, Grynpas MD, Burr DB, Allen MR, Smith SY, Doyle N, Amizuka N, Hasegawa T, Kida Y, Marumo K, et al. Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone. Bone. 2015;73:8–15.CrossRef Saito M, Grynpas MD, Burr DB, Allen MR, Smith SY, Doyle N, Amizuka N, Hasegawa T, Kida Y, Marumo K, et al. Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone. Bone. 2015;73:8–15.CrossRef
Metadata
Title
Non-invasive skin autofluorescence, blood and urine assays of the advanced glycation end product (AGE) pentosidine as an indirect indicator of AGE content in human bone
Authors
Yoshikuni Kida
Mitsuru Saito
Akira Shinohara
Shigeru Soshi
Keishi Marumo
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2019
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-019-3011-4

Other articles of this Issue 1/2019

BMC Musculoskeletal Disorders 1/2019 Go to the issue