title: Strontium ranelate prevents the deleterious action of advanced glycation endproducts on osteoblastic cells via calcium channel activation.
abstract: Accumulation of advanced glycation endproducts (AGEs) in bone tissue occurs in ageing and in Diabetes mellitus, and is partly responsible for the increased risk of low-stress bone fractures observed in these conditions. In this study we evaluated whether the anti-osteoporotic agent strontium ranelate can prevent the deleterious effects of AGEs on bone cells, and possible mechanisms of action involved. Using mouse MC3T3E1 osteoblastic cells in culture we evaluated the effects of 0.1mM strontium ranelate and/or 100 μg/ml AGEs-modified bovine serum albumin (AGEs-BSA) on cell proliferation, osteogenic differentiation and pro-inflammatory cytokine production. We found that AGEs-BSA alone decreased osteoblastic proliferation and differentiation (P<0.01) while increasing IL-1β and TNFα production (P<0.01). On its own, strontium ranelate induced opposite effects: an increase in osteoblast proliferation and differentiation (P<0.01) and a decrease in cytokine secretion (P<0.01). Additionally, strontium ranelate prevented the inhibitory and pro-inflammatory actions of AGEs-BSA on osteoblastic cells (P<0.01). These effects of strontium ranelate were blocked by co-incubation with either the MAPK inhibitor PD98059, or the calcium channel blocker nifedipine. We also evaluated by Western blotting the activation status of ERK (a MAPK) and b-catenin. Activation of both signaling pathways was decreased by AGEs treatment, and this inhibitory effect was prevented if AGEs were co-incubated with strontium ranelate (P<0.01). On its own, strontium ranelate increased both pERK and activated b-catenin levels. In conclusion, this study demonstrates that strontium ranelate can prevent the deleterious in vitro actions of AGEs on osteoblastic cells in culture by mechanisms that involve calcium channel, MAPK and b-catenin activation.
authors.affiliation: Laboratorio de Investigación en Osteopatías y Metabolismo Mineral, Facultad de Ciencias Exactas, Universidad Nacional de La Plata. 47 y 115, (1900) La Plata, Argentina.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Fernández
authors.forename: María Silvina
authors.initials: MS
authors.lastname: Molinuevo
authors.forename: Claudia
authors.initials: C
authors.lastname: Sedlinsky
authors.forename: León
authors.initials: L
authors.lastname: Schurman
authors.forename: Ana María
authors.initials: AM
authors.lastname: Cortizo
authors.forename: Antonio Desmond
authors.initials: AD
authors.lastname: McCarthy
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D024042:Collagen Type I; D017127:Glycation End Products, Advanced; D053583:Interleukin-1beta; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C081587:strontium ranelate; D048049:Extracellular Signal-Regulated MAP Kinases; D000469:Alkaline Phosphatase; D009543:Nifedipine