title: Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells.
abstract: In diabetes mellitus (DM), high glucose (HG) and advanced glycation end products (AGEs) are involved in bone quality deterioration. Osteocytes produce sclerostin and receptor activator of nuclear factor-кB ligand (RANKL) and regulate osteoblast and osteoclast function. However, whether HG or AGEs directly affect osteocytes and regulate sclerostin and RANKL production is unknown. Here, we examined the effects of HG, AGE2, and AGE3 on the expression of sclerostin and RANKL and on apoptosis in osteocyte-like MLO-Y4-A2 cells. Treatment of the cells with 22 mM glucose, 100 μg/mL either AGE2 or AGE3 significantly increased the expression of sclerostin protein and mRNA; however, both AGEs, but not glucose, significantly decreased the expression of RANKL protein and mRNA. Moreover, treatment of the cells with HG, AGE2, or AGE3 for 72 h induced significant apoptosis. These detrimental effects of HG, AGE2, and AGE3 on sclerostin and RANKL expressions and on apoptosis were antagonized by pretreatment of the cells with 10(-8) M human parathyroid hormone (PTH)-(1-34). Thus, HG and AGEs likely suppress bone formation by increasing sclerostin expression in osteocytes, whereas AGEs suppress bone resorption by decreasing RANKL expression. Together, these processes may cause low bone turnover in DM. In addition, HG and AGEs may cause cortical bone deterioration by inducing osteocyte apoptosis. PTH may effectively treat these pathological processes and improve osteocyte function.
authors.affiliation: Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan. Electronic address: ken1nai@med.shimane-u.ac.jp.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan. Electronic address: yamaguch@med.shimane-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan. Electronic address: ippei.k@med.shimane-u.ac.jp.
authors.forename: Ippei
authors.initials: I
authors.lastname: Kanazawa
authors.affiliation: Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan. Electronic address: sugimoto@med.shimane-u.ac.jp.
authors.forename: Toshitsugu
authors.initials: T
authors.lastname: Sugimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D010011:Osteocytes / Q000166:cytology* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D053245:RANK Ligand / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017127:Glycation End Products, Advanced; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C470125:PTH protein, human; D010281:Parathyroid Hormone; D053245:RANK Ligand; D012333:RNA, Messenger; C486030:Sost protein, mouse; D005947:Glucose
keywords: Advanced glycation end products; Osteocyte; Parathyroid hormone; Receptor activator of nuclear factor-кB ligand; Sclerostin