Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment.
Our previous studies demonstrated that glimepiride enhanced the proliferation and differentiation of osteoblasts and led to activation of the PI3K/Akt pathway. Recent genetic evidence shows that endothelial nitric oxide synthase (eNOS) plays an important role in bone homeostasis. In this study, we further elucidated the roles of eNOS, PI3K and Akt in bone formation by osteoblasts induced by glimepiride in a high glucose microenvironment. We demonstrated that high glucose (16.5 mM) inhibits the osteogenic differentiation potential and proliferation of rat osteoblasts. Glimepiride activated eNOS expression in rat osteoblasts cultured with two different concentrations of glucose. High glucose-induced osteogenic differentiation was significantly enhanced by glimepiride. Down-regulation of PI3K P85 levels by treatment with LY294002 (a PI3K inhibitor) led to suppression of P-eNOS and P-AKT expression levels, which in turn resulted in inhibition of RUNX2, OCN and ALP mRNA expression in osteoblasts induced by glimepiride at both glucose concentrations. ALP activity was partially inhibited by 10 µM LY294002. Taken together, our results demonstrate that glimepiride-induced osteogenic differentiation of osteoblasts occurs via eNOS activation and is dependent on the PI3K/Akt signaling pathway in a high glucose microenvironment.
Department of oral implantology, Beijing Stomatological Hospital of Capital Medical University, Beijing, China.
Pan
P
Ma
Department of Stomatology, Chinese PLA General Hospital and Postgraduate Military Medical School, Beijing, China.
Bin
B
Gu
Clinical Aviation Medicine Center of PLA, Air Force General Hospital, Beijing, China.
Wei
W
Xiong
Department of oral implantology, Beijing Stomatological Hospital of Capital Medical University, Beijing, China.
Baosheng
B
Tan
Department of oral implantology, Beijing Stomatological Hospital of Capital Medical University, Beijing, China.
Wei
W
Geng
Department of oral implantology, Beijing Stomatological Hospital of Capital Medical University, Beijing, China.
Jun
J
Li
Department of Stomatology, Chinese PLA General Hospital and Postgraduate Military Medical School, Beijing, China.
Hongchen
H
Liu
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D000469:Alkaline Phosphatase; D002867:Chromones; D050659:Core Binding Factor Alpha 1 Subunit; D005947:Glucose; D007004:Hypoglycemic Agents; D009025:Morpholines; D052250:Nitric Oxide Synthase Type III; D015675:Osteocalcin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013453:Sulfonylurea Compounds; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C057619:glimepiride