title: High d(+)glucose concentration inhibits RANKL-induced osteoclastogenesis.
abstract: Diabetes is a chronic disease associated with hyperglycemia and altered bone metabolism that may lead to complications including osteopenia, increased risk of fracture and osteoporosis. Hyperglycemia has been implicated in the pathogenesis of diabetic bone disease; however, the biologic effect of glucose on osteoclastogenesis is unclear. In the present study, we examined the effect of high d(+)glucose (d-Glc) and l(-)glucose (l-Glc; osmotic control) on RANKL-induced osteoclastogenesis using RAW264.7 cells and Bone Marrow Macrophages (BMM) as models. Cells were exposed to sustained high glucose levels to mimic diabetic conditions. Osteoclast formation was analyzed using tartrate resistant acid phosphatase (TRACP) assay, expression of calcitonin receptor (CTR) and cathepsin K mRNAs, and cultures were examined for reactive oxygen species (ROS) using dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, caspase-3 and Nuclear Factor kappaB (NF-kappaB) activity. Cellular function was assessed using a migration assay. Results show, for the first time, that high d-Glc inhibits osteoclast formation, ROS production, caspase-3 activity and migration in response to RANKL through a metabolic pathway. Our findings also suggest that high d-Glc may alter RANKL-induced osteoclast formation by inhibiting redox-sensitive NF-kappaB activity through an anti-oxidative mechanism. This study increases our understanding of the role of glucose in diabetes-associated bone disease. Our data suggest that high glucose levels may alter bone turnover by decreasing osteoclast differentiation and function in diabetes and provide new insight into the biologic effects of glucose on osteoclastogenesis.
authors: Department of Pathology, University of Texas Health Science Center, and South Texas Veteran's Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA. wittrant@uthscsa.edu
authors: Y
authors: Y
authors: Wittrant
authors: Y
authors: Y
authors: Gorin
authors: K
authors: K
authors: Woodruff
authors: D
authors: D
authors: Horn
authors: H E
authors: HE
authors: Abboud
authors: S
authors: S
authors: Mohan
authors: S L
authors: SL
authors: Abboud-Werner
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; D053148:Caspase 3; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14; D005947:Glucose