Abstract
In diabetic patients, the metabolism of excess glucose increases the toxicity of the aldehyde group of sugar. Aldehydes, including glyceraldehyde (GA), react with intracellular proteins to form advanced glycation end-products (AGEs), which deteriorate bone quality and cause osteoporosis. One of the causes of osteoporotic fractures is impaired osteoblast osteogenesis; however, the cytotoxic effects of aldehydes and the subsequent formation of AGEs in osteoblasts have not yet been examined in detail. Therefore, the present study investigated the cytotoxicity of intracellular GA and GA-derived AGEs, named toxic AGEs (TAGE), in the mouse osteoblastic cell line MC3T3-E1. Treatment with GA induced MC3T3-E1 cell death, which was accompanied by TAGE modifications in several intracellular proteins. Furthermore, the downregulated expression of Runx2, a transcription factor essential for osteoblast differentiation, and collagen correlated with the accumulation of TAGE. The GA treatment also reduced the normal protein levels of collagen in cells, suggesting that collagen may be modified by TAGE and form an abnormal structure. Collectively, the present results show for the first time that GA and TAGE exert cytotoxic effects in osteoblasts, inhibit osteoblastic differentiation, and decrease the amount of normal collagen. The suppression of GA production and associated accumulation of TAGE has potential as a novel therapeutic target for osteoporosis under hyperglycemic conditions.
Highlights
Bone is remodeled through continuous resorption by osteoclasts and the replacement of old bone with new bone formed by osteoblasts
We initially performed a cell viability assay using mouse osteoblastic MC3T3-E1 cells treated with GA because cell death in osteoblasts is one of the most important causes of osteoporosis
We examined the composition of toxic AGEs (TAGE)-modified proteins in GA-treated cells using a Western blot analysis with the anti-TAGE antibody
Summary
Bone is remodeled through continuous resorption by osteoclasts and the replacement of old bone with new bone formed by osteoblasts. The cellular intake of glucose and fructose increases under hyperglycemic conditions, and metabolism proceeds with the production of several metabolic intermediates [12] Some of these intermediates are aldehydes, which are electrophilic compounds that induce cytotoxicity [13]. These aldehyde groups, including glyceraldehyde (GA), react with proteins and form AGEs. Previous studies demonstrated that the expression of osteoblastic markers was downregulated in the mouse osteoblast-like cell line MC3T3-E1 cultured under high glucose conditions [14,15], suggesting that the metabolism of excess glucose suppressed osteoblast differentiation. The production of GA and accumulation of TAGE in osteoblasts are expected to have a negative impact on bone function in patients with DM, and an analysis of these factors in osteoblasts may lead to a more detailed understanding of diabetic osteoporosis. We investigated the effects of GA and the associated accumulation on TAGE in MC3T3-E1 cells
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