Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Aikawa,Takao; Matsubara,Hidenori; Ugaji,Shuhei; Shirakawa,Junichi; Nagai,Ryoji; Munesue,Seiichi; Harashima,Ai; Yamamoto,Yasuhiko; Tsuchiya,Hiroyuki

doi:10.3892/mmr.2017.6589

Contribution of methylglyoxal to delayed healing of bone injury in diabetes

Authors:
- Takao Aikawa
- Hidenori Matsubara
- Shuhei Ugaji
- Junichi Shirakawa
- Ryoji Nagai
- Seiichi Munesue
- Ai Harashima
- Yasuhiko Yamamoto
- Hiroyuki Tsuchiya
View Affiliations

Affiliations: Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920‑8641, Japan, Laboratory of Food and Regulation Biology, Graduate School of Agriculture, Tokai University, Minamiaso, Aso‑gun, Kumamoto 869‑1404, Japan, Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920‑8640, Japan
Published online on: May 16, 2017 https://doi.org/10.3892/mmr.2017.6589
Pages: 403-409

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end‑products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0‑mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0‑400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non‑diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO‑derived AGEs, Nε‑(carboxymethyl)‑lysine and Nδ‑(5‑hydro‑5‑methyl‑4‑imidazolone‑2‑yl)‑ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose‑dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.

View Figures

View References

1	Vestergaard P: Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta- analysis. Osteoporosis Int. 18:427–444. 2007. View Article : Google Scholar
2	Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, Einhorn TA and Graves DT: Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone. 44:357–363. 2009. View Article : Google Scholar : PubMed/NCBI
3	Retzepi M and Donos N: The effect of diabetes mellitus on osseous healing. Clin Oral Implants Res. 21:673–681. 2010. View Article : Google Scholar : PubMed/NCBI
4	Simpson CM, Calori GM and Giannoudis PV: Diabetes and fracture healing: The skeletal effects of diabetic drugs. Expert Opin Drug Saf. 11:215–220. 2012. View Article : Google Scholar : PubMed/NCBI
5	de Liefde II, van der Klift M, de Laet CE, van Daele PL, Hofman A and Pols HA: Bone mineral density and fracture risk in type-2 diabetes mellitus: The Rotterdam study. Osteoporosis Int. 16:1713–1720. 2005. View Article : Google Scholar
6	Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, Leone CW, Morgan EF, Gerstenfeld LC, Einhorn TA and Graves DT: Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res. 22:560–568. 2007. View Article : Google Scholar : PubMed/NCBI
7	Kayal RA, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D, Einhorn TA, Gerstenfeld LC and Graves DT: TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J Bone Miner Res. 25:1604–1615. 2010. View Article : Google Scholar : PubMed/NCBI
8	Loder RT: The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res. 210–216. 1988.PubMed/NCBI
9	Folk JW, Starr AJ and Early JS: Early wound complications of operative treatment of calcaneus fractures: Analysis of 190 fractures. J Orthop Trauma. 13:369–372. 1999. View Article : Google Scholar : PubMed/NCBI
10	Botushanov NP and Orbetzova MM: Bone mineral density and fracture risk in patients with type 1 and type 2 diabetes mellitus. Folia Med (Plovdiv). 51:12–17. 2009.PubMed/NCBI
11	Stolzing A, Sellers D, Llewelyn O and Scutt A: Diabetes induced changes in rat mesenchymal stem cells. Cells Tissues Organs. 191:453–465. 2010. View Article : Google Scholar : PubMed/NCBI
12	Sheweita SA and Khoshhal KI: Calcium metabolism and oxidative stress in bone fractures: Role of antioxidants. Curr Drug Metab. 8:519–525. 2007. View Article : Google Scholar : PubMed/NCBI
13	Sanguineti R, Storace D, Monacelli F, Federici A and Odetti P: Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci. 1126:166–172. 2008. View Article : Google Scholar : PubMed/NCBI
14	Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, Pischon N, Trackman PC, Gerstenfeld L and Graves DT: Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 40:345–353. 2007. View Article : Google Scholar : PubMed/NCBI
15	Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature. 414:813–820. 2001. View Article : Google Scholar : PubMed/NCBI
16	Westwood ME and Thornalley PJ: Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation end product-modified serum albumins. J Protein Chem. 14:359–372. 1995. View Article : Google Scholar : PubMed/NCBI
17	Phillips SA and Thornalley PJ: The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur J Biochem. 212:101–105. 1993. View Article : Google Scholar : PubMed/NCBI
18	Silva Sousa M, Gomes RA, Ferreira AE, Ponces Freire A and Cordeiro C: The glyoxalase pathway: The first hundred years… and beyond. Biochem J. 453:1–15. 2013. View Article : Google Scholar : PubMed/NCBI
19	Thornalley PJ: Pharmacology of methylglyoxal: Formation, modification of proteins and nucleic acids, and enzymatic detoxification-a role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol. 27:565–573. 1996. View Article : Google Scholar : PubMed/NCBI
20	Kalapos MP: Methylglyoxal in living organisms: Chemistry, biochemistry, toxicology and biological implications. Toxicol Lett. 110:145–175. 1999. View Article : Google Scholar : PubMed/NCBI
21	Vander Jagt DL and Hunsaker LA: Methylglyoxal metabolism and diabetic complications: Roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase. Chem Biol Interact. 143–144:341–351. 2003. View Article : Google Scholar
22	Scheijen JL and Schalkwijk CG: Quantification of glyoxal, methylglyoxal and 3-deoxyglucosone in blood and plasma by ultra performance liquid chromatography tandem mass spectrometry: Evaluation of blood specimen. Clin Chem Lab Med. 52:85–91. 2014. View Article : Google Scholar : PubMed/NCBI
23	Yamanaka M, Matsumura T, Ohno R, Fujiwara Y, Shinagawa M, Sugawa H, Hatano K, Shirakawa J, Kinoshita H, Ito K, et al: Non-invasive measurement of skin autofluorescence to evaluate diabetic complications. J Clin Biochem Nutr. 58:135–140. 2016. View Article : Google Scholar : PubMed/NCBI
24	Shirakawa J, Arakawa S, Tagawa T, Gotoh K, Oikawa N, Ohno R, Shinagawa M, Hatano K, Sugawa H, Ichimaru K, et al: Salacia chinensis L. extract ameliorates abnormal glucose metabolism and improves the bone strength and accumulation of AGEs in type 1 diabetic rats. Food Funct. 7:2508–2515. 2016. View Article : Google Scholar : PubMed/NCBI
25	Otsuka E, Yamaguchi A, Hirose S and Hagiwara H: Characterization of osteoblastic differentiation of stromal cell line ST2 that is induced by ascorbic acid. Am J Physiol. 277:C132–C138. 1999.PubMed/NCBI
26	Yamaguchi A, Ishizuya T, Kintou N, Wada Y, Katagiri T, Wozney JM, Rosen V and Yoshiki S: Effects of BMP-2, BMP-4 and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochem Biophys Res Commun. 220:366–371. 1996. View Article : Google Scholar : PubMed/NCBI
27	Suh KS, Choi EM, Rhee SY and Kim YS: Methylglyoxal induces oxidative stress and mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. Free Radic Res. 48:206–217. 2014. View Article : Google Scholar : PubMed/NCBI
28	McLellan AC, Thornalley PJ, Benn J and Sonksen PH: Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin Sci (Lond). 87:21–29. 1994. View Article : Google Scholar : PubMed/NCBI
29	Lapolla A, Reitano R, Seraglia R, Sartore G, Ragazzi E and Traldi P: Evaluation of advanced glycation end products and carbonyl compounds in patients with different conditions of oxidative stress. Mol Nutr Food Res. 49:685–690. 2005. View Article : Google Scholar : PubMed/NCBI
30	Chaplen FW, Fahl WE and Cameron DC: Evidence of high levels of methylglyoxal in cultured Chinese hamster ovary cells. Proc Natl Acad Sci USA. 95:5533–5538. 1998. View Article : Google Scholar : PubMed/NCBI
31	Webb-Robertson BJ, Lowry DF, Jarman KH, Harbo SJ, Meng QR, Fuciarelli AF, Pounds JG and Lee KM: A study of spectral integration and normalization in NMR-based metabonomic analyses. J Pharm Biomed Anal. 39:830–836. 2005. View Article : Google Scholar : PubMed/NCBI
32	Chan WH, Wu HJ and Shiao NH: Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J Cell Biochem. 100:1056–1069. 2007. View Article : Google Scholar : PubMed/NCBI
33	Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC and Einhorn TA: Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res. 87:107–118. 2008. View Article : Google Scholar : PubMed/NCBI
34	Gerstenfeld LC, Wronski TJ, Hollinger JO and Einhorn TA: Application of histomorphometric methods to the study of bone repair. J Bone Miner Res. 20:1715–1722. 2005. View Article : Google Scholar : PubMed/NCBI
35	Shin L and Peterson DA: Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes. Stem Cells Transl Med. 1:125–135. 2012. View Article : Google Scholar : PubMed/NCBI
36	Follak N, Kloting I and Merk H: Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats. Diabetes Metab Res Rev. 21:288–296. 2005. View Article : Google Scholar : PubMed/NCBI
37	Kawaguchi H, Kurokawa T, Hanada K, Hiyama Y, Tamura M, Ogata E and Matsumoto T: Stimulation of fracture repair by recombination human basic fibroblast growth factor in normal and streptozotocin-diabetic rats. Endocrinology. 135:774–781. 1994. View Article : Google Scholar : PubMed/NCBI
38	Bahney CS, Hu DP, Miclau T III and Marcucio RS: The multifaceted role of the vasculature in endochondral fracture repair. Front Endocrinol (Lausanne). 6:42015.PubMed/NCBI
39	Liao YF, Chen LL, Zeng TS, Li YM, Fan Y, Hu LJ and Ling Yue: Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes. Vasc Med. 15:279–285. 2010. View Article : Google Scholar : PubMed/NCBI
40	Okazaki K, Yamaguchi T, Tanaka K, Notsu M, Ogawa N, Yano S and Sugimoto T: Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif Tissu Int. 91:286–296. 2012. View Article : Google Scholar
41	Xue J, Ray R, Singer D, Böhme D, Burz DS, Rai V, Hoffmann R and Shekhtman A: The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry. 53:3327–3335. 2014. View Article : Google Scholar : PubMed/NCBI
42	Voziyan PA and Hudson BG: Pyridoxamine as a multifunctional pharmaceutical: Targeting pathogenic glycation and oxidative damage. Cell Mol Life Sci. 62:1671–1681. 2005. View Article : Google Scholar : PubMed/NCBI
43	Degenhardt TP, Alderson NL, Arrington DD, Beattie RJ, Basgen JM, Steffes MW, Thorpe SR and Baynes JW: Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 61:939–950. 2002. View Article : Google Scholar : PubMed/NCBI
44	Zhu P, Lin H, Sun C, Lin F, Yu H, Zhuo X, Zhou C and Deng Z: Synergistic effects of telmisartan and pyridoxamine on early renal damage in spontaneously hypertensive rats. Mol Med Rep. 5:655–662. 2012.PubMed/NCBI
45	Waanders F, van den Berg E, Nagai R, van Veen I, Navis G and van Goor H: Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats. Nephrol Dial Transplant. 23:518–524. 2008. View Article : Google Scholar : PubMed/NCBI
46	Alderson NL, Chachich ME, Youssef NN, Beattie RJ, Nachtigal M, Thorpe SR and Baynes JW: The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int. 63:2123–2133. 2003. View Article : Google Scholar : PubMed/NCBI
47	Tanimoto M, Gohda T, Kaneko S, Hagiwara S, Murakoshi M, Aoki T, Yamada K, Ito T, Matsumoto M, Horikoshi S and Tomino Y: Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice. Metabolism. 56:160–167. 2007. View Article : Google Scholar : PubMed/NCBI
48	Williams ME, Bolton WK, Khalifah RG, Degenhardt TP, Schotzinger RJ and McGill JB: Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol. 27:605–614. 2007. View Article : Google Scholar : PubMed/NCBI
49	Lewis EJ, Greene T, Spitalewiz S, Blumenthal S, Berl T, Hunsicker LG, Pohl MA, Rohde RD, Raz I, Yerushalmy Y, et al: Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephrol. 23:131–136. 2012. View Article : Google Scholar : PubMed/NCBI
50	Garg S, Syngle A and Vohra K: Efficacy and tolerability of advanced glycation end-products inhibitor in osteoarthritis: A randomized, double-blind, placebo-controlled study. Clin J Pain. 29:717–724. 2013. View Article : Google Scholar : PubMed/NCBI
51	Nagaraj RH, Sarkar P, Mally A, Biemel KM, Lederer MO and Padayatti PS: Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: Characterization of a major product from the reaction of pyridoxamine and methylglyoxal. Arch Biochem Biophys. 402:110–119. 2002. View Article : Google Scholar : PubMed/NCBI
52	Ruggiero-Lopez D, Lecomte M, Moinet G, Patereau G, Lagarde M and Wiernsperger N: Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. Biochem Pharmacol. 58:1765–1773. 1999. View Article : Google Scholar : PubMed/NCBI
53	Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 352:854–865. 1998. View Article : Google Scholar : PubMed/NCBI
54	Kender Z, Fleming T, Kopf S, Torzsa P, Grolmusz V, Herzig S, Schleicher E, Rácz K, Reismann P and Nawroth PP: Effect of metformin on methylglyoxal metabolism in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes. 122:316–319. 2014. View Article : Google Scholar : PubMed/NCBI