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Bone Abstracts (2014) 3 PP109 | DOI: 10.1530/boneabs.3.PP109

Cell biology: osteoblasts and bone formation

Advanced glycation end products inhibit the mineralization of marrow stromal cells by binding the receptor for AGEs and increasing TGF-β expression and secretion

Toru Yamaguchi, Masakazu Notsu, Kyoko Okazaki, Ken-ichiro Tanaka, Noriko Ogawa, Ippei Kanazawa & Toshitsugu Sugimoto


Internal Medicine 1, Shimane University Faculty of Medicine, Izumo-shi, Shimane, Japan.

We and others have recently showed that patients with type 2 diabetes mellitus (T2DM) have a higher risk for fracture, although they have normal or slightly higher bone mineral density (BMD). These findings suggest that bone fragility in T2DM, which is not defined by BMD, may contribute to fracture risk. Hyperglycemia accelerates the formation of advanced glycation end products (AGEs) and causes diabetic complications. AGEs including pentosidine are also known to cause bone fragility due to quality deterioration in diabetic patients. We found that AGEs suppressed mineralization of mouse stromal ST2 cells by inhibiting their differentiation with reduced expressions of osteocalcin (OCN) and osterix (OSX) mRNA in the cells. It is known that TGF-β is especially abundant in bone, and that enhancement of its signals deteriorates bone quality in animal experiments. However, it is still unclear whether or not TGF-β signal is involved in the AGEs-induced suppression of osteoblastic bone formation. In this study, we made AGE3 by incubating BSA with glycolaldehyde, and examined the roles of TGF-β in the suppression of mineralization of ST2 cells induced by AGE3. Treatments of the cells with AGE3 (200 μg/ml) significantly inhibited mineralization by 71.2% on experimental day 21 (P<0.001). Simultaneously, AGE3 significantly increased the mRNA expression and protein level of TGF-β by RT-PCR and ELISA of whole cell lysates, respectively, on days 3, 5, and 7 (P<0.001). Transfection of siRNA of the receptor for AGEs (RAGE) significantly inhibited the AGE3-induced increase in TGF-β protein level (P<0.001), and recovered mineralization in the cells (P<0.05). Moreover, treatments of TGF-β type I receptor kinase inhibitors (2.5 uM SD208 and 3.0 uM SB431542) significantly antagonized the AGE3-induced suppression in OCN and OSX mRNA expressions (P<0.05), and recovered mineralization completely. Similar results were also obtained in human primary mesenchymal stem cells differentiated into osteoblasts. These findings indicate that the AGEs-RAGE pathway inhibits the mineralization of marrow stromal cells by increasing TGF-β expression and secretion, suggesting that TGF-β action stimulated by AGEs adversely affects bone in the process of diabetic complications.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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