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      La diabetes altera el potencial osteogénico de células progenitoras de médula ósea: Efectos del tratamiento con metformina Translated title: Diabetes Decreases the Osteogenic Potential of Bone Marrow Progenitor Cells: Effects of Treatment with Metformin

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          Abstract

          En este trabajo, estudiamos el efecto de una Diabetes inducida por destrucción parcial de la masa de células beta pancreáticas, sobre el compromiso osteogénico de células progenitoras de médula ósea (CPMO), y su modulación por el tratamiento oral con Metformina. Para ello utilizamos ratas Sprague Dawley, divididas en cuatro grupos: controles [C], controles tratadas con Metformina [M], diabéticas [D], y diabéticas tratadas con Metformina [DM]. La inducción de Diabetes se realizó, por inyección intraperitoneal sucesiva de ácido nico-tínico y estreptozotocina. Sobre los cultivos de CPMO se evaluó la actividad específica de Fosfatasa Alcalina (FAL) y la producción de Colágeno tipo 1 (Col-1) en estado basal y en medio de diferenciación osteogénico luego de 15 días. A los 21 días, se evaluaron los depósitos de mineral extracelular. La FAL y el Col-1 de CPMO basales, no mostraron diferencias significativas entre los cuatro grupos experimentales. Al cabo de 15 días, las CPMO de ratas M mostraron un incremento en el Col-1 de 122 % respecto de C; D 30 % respecto de C y DM 68 % respecto de C. La FAL expresó un 171 % para M, 34 % para D; y 125 % para DM todos respecto de C. Luego de 21 días, se observó una disminución en la mineralización de las CPMO de D (65 % respecto del grupo C). El tratamiento con metformina incrementó la mineralización de las CPMO en todos los casos. En conclusión, en nuestro modelo experimental de Diabetes, ésta disminuye el potencial osteogénico de las CPMO, un efecto que es parcialmente revertido por el tratamiento oral con Metformina. Estos hallazgos podrían explicar, al menos en parte, las alteraciones óseas descriptas en el hueso asociadas con la Diabetes. Los autores declaran no poseer conflictos de interés.

          Translated abstract

          Diabetes mellitus is associated with an increased incidence of skeletal abnormalities, resulting in lower bone formation and/or remodeling. Osteopenia, osteoporosis and an increased incidence of non-traumatic fractures has been particularly observed in patients with type 2 diabetes. Recently, we have demonstrated that metformin has in vitro and in vivo osteogenic effects: (a) it stimulates the proliferation, differentiation and mineralization of osteoblasts in culture, and (b) in non-diabetic rats, it increases the repair of minimal bone lesions and improves femoral trabecular bone microarchitecture. In this study, we evaluated in rats the effect of diabetes induction by a partial destruction of pancreatic beta cells, on the osteogenic commitment of bone marrow progenitor cells (BMPC), and the modulation of this effect by orally administered metformin. We used young male Sprague Dawley rats (200 g), divided into four groups: untreated non-diabetic controls [C], non-diabetic rats treated for 2 weeks with metformin administered in drinking water (100 mg/kg/day) [M], untreated diabetic rats [D], and diabetic rats treated for 2 weeks with metformin (100 mg/kg/day) [DM]. Induction of Diabetes was performed one week prior to treatment with metformin, by successive intraperitoneal injections with 75 mg/kg body weight of nicotinic acid and 60 mg/kg body weight of streptozotocin. At the end of all treatments, blood samples were obtained to confirm the development of Diabetes, after which the animals were sacrificed by cervical dislocation under anesthesia. Femora and/or tibiae were dissected, and bone marrow cells were collected by flushing the bone diaphysal canal with Dulbecco's modified essential medium (DMEM) under sterile conditions. Adherent cells were grown to confluence in DMEM-10 % fetal bovine serum (FBS), after which we assessed alkaline phosphatase specific activity (ALP) by an enzymatic kinetic method, and type 1 collagen production (Col-1) by a Sirius Red colorimetric method (basal osteoblastic differentiation of BMPC). Subsequently, BMPC were submitted to an osteogenic induction for 15 days with an osteogenic medium (DMEM-10 % FBS containing ascorbic acid and sodium beta-glycerophosphate), after which ALP and Col-1 were evaluated. Basal ALP activity and type 1 collagen production (BMPC without osteogenic differentiation) showed no significant differences between the four experimental groups. After 15 days of culture in osteogenic medium, BMPC from control rats increased their expression of ALP (5 times compared to baseline) and collagen production (11 times compared to baseline). BMPC from diabetic rats after 15 days culture in osteogenic medium, also showed a significant (although smaller) increase in ALP (2-3 fold over basal activity) and collagen production (4-fold compared to baseline). BMPC obtained from rats treated with metformin (groups M and DM) and submitted to osteogenic induction for 15 days, showed an approximately 2-4-fold increase in both ALP and Col-1 (when compared with groups C and D, respectively). After 21 days of osteogenic induction, a decrease was observed in the mineralization of BMPC obtained from group D (65 % of that for group C). Treatment with metformin increased the mineralizing capacity of BMPC in all cases, including a reversal of the inhibitory effect of Diabetes on this parameter. In conclusion, we have found that our model of Diabetes reduces the osteogenic potential of bone marrow progenitor cells, and that this effect is partially reverted by orally administered metformin. These findings could explain, at least in part, the bone alterations that have been associated with Diabetes mellitus. No financial conflicts of interest exist.

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          Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk.

          We studied the association between fractures and type 1 and type 2 diabetes mellitus. In this case-control study, all subjects diagnosed with a fracture (n=124,655) in Denmark served as cases, and for each case three control subjects (n=373,962) matched for sex and age were retrieved from the general population. Type 1 and type 2 diabetes were associated with an increased risk (1) of any fracture (odds ratio [OR]=1.3, 95% CI: 1.2-1.5 for type 1 diabetes and 1.2, 95% CI: 1.1-1.3 for type 2 diabetes after adjustment for confounders) and (2) of hip fractures (OR=1.7, 95% CI: 1.3-2.2 for type 1 diabetes, and 1.4, 95% CI: 1.2-1.6 for type 2 diabetes). Furthermore, type 2 diabetes was associated with a significant increase in forearm fractures (OR=1.2, 95% CI: 1.0-1.5), and type 1 diabetes was associated with an increased risk of spine fractures (OR=2.5, 95% CI: 1.3-4.6), whereas type 2 diabetes was not. Use of metformin and sulphonylureas was associated with a significantly decreased risk of any fracture, whereas a non-significant trend towards decreased risk of any fracture was associated with the use of insulin. Except for a decrease in hip fractures with use of sulphonylureas, no change in fracture risk in the hip, spine or forearm was associated with the use of insulin or oral antidiabetic drugs. Type 1 and type 2 diabetes are associated with an increased risk of any fracture and hip fractures. The use of drugs to control diabetes may reduce the association between diabetes and fractures.
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            A role for advanced glycation end products in diminished bone healing in type 1 diabetes.

            The effect of type 1 diabetes on bone healing and bone formation in standardized craniotomy defects created in BALB/cByJ mice was determined. The hypothesis that advanced glycation end products (AGEs) contribute to diminished bone healing in diabetes was evaluated by assessing for the presence of the receptor for advanced glycation end products (RAGE) by immunohistochemistry in healing craniotomy defects in diabetic animals. The effect of local application of a known RAGE protein ligand, N(epsilon)-(carboxymethyl)lysine (CML)-mouse serum albumin (MSA), on craniotomy defect healing in normal animals was then assessed and compared to the effects of control MSA. Finally, evidence in support of the expression of RAGE mRNA and protein in osteoblastic cells was obtained. The results indicated that craniotomy defects in diabetic animals healed approximately 40% of the degree to which they healed in nondiabetic animals (P < 0.05). RAGE was expressed at higher levels in healing bone tissues in diabetic compared to control animals. Further studies in nondiabetic animals indicated that bone healing was reduced by 63 and 42% in lesions treated with 900 and 90 micro g CML-MSA, respectively, compared to in animals treated with MSA alone (P < 0.05). Evidence for the expression of RAGE was obtained in mouse and rat osteoblastic cultures. These results support the contribution of AGEs to diminished bone healing in type 1 diabetes, possibly mediated by RAGE.
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              Lilly Lecture 1993. Glycation and diabetic complications.

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                Author and article information

                Journal
                raem
                Revista argentina de endocrinología y metabolismo
                Rev. argent. endocrinol. metab.
                Sociedad Argentina de Endocrinología y Metabolismo (Ciudad Autónoma de Buenos Aires, , Argentina )
                1851-3034
                June 2012
                : 49
                : 2
                Article
                S1851-30342012000200003 S1851-3034(12)04900200003
                e179c04f-8db2-42f6-96fe-12566a956667

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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                Células progenitoras de médula ósea,Metformin,Bone,Bone marrow progenitor cells,Diabetes mellitus,Metformina,Hueso

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