Klotho:A new therapeutic target in diabetic retinopathy?

Klotho(Kl)is considered an antiaging gene,mainly for the inhibition of the insulin-like growth factor-1 signaling.Kl exists as full-length transmembrane,which acts as co-receptor for fibroblast growth factor receptor,and in soluble forms(sKl).The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state.In diabetic Patients,serum levels of Kl are significantly decreased compared to healthy subjects,and are related to duration of diabetes.In diabetic retinopathy(DR),one of the most common microvascular complications of type 2 diabetes,serum Kl levels are negatively correlated with progression of the disease.A lot of evidences showed that Kl regulates several mechanisms involved in maintaining homeostasis and functions of retinal cells,including phagocytosis,calcium signaling,secretion of vascular endothelial growth factor A(VEGF-A),maintenance of redox status,and melanin biosynthesis.Experimental data have been shown that Kl exerts positive effects on several mechanisms involved in onset and progression of DR.In particular,treatment with Kl:(1)Prevents apoptosis induced by oxidative stress in human retinal endothelial cells and in retinal pigment epithelium(RPE)cells;(2)reduces secretion of VEGF-A by RPE cells;and(3)decreases subretinal fibrosis and preserves autophagic activity.Therefore,Kl may become a novel biomarker and a good candidate for the treatment of DR.

Bisphosphonates and adipogenesis: Evidence for alendronate inhibition of adipocyte differentiation in 3T3-L1 preadipocytes through a vitamin D receptor mediated effect

Background: Adipocyte and osteoblast derive from the same mesenchimal progenitor. Age-related decrease in bone mass is accompanied by an increase in marrow adipose tissue. Vitamin D3 (VD3) inhibits adipogenesis in 3T3-L1 preadipocytes. Recently it has been demonstrated that alendronate (ALN) inhibits adipogenesis while promoting osteoblast differentiation of mesenchimal stem cells. Aim of the Study: To evaluate the role of ALN on adipocyte differentiation in vitro and the potential synergic role of VD3 co-treatment. Procedures: Murine 3T3-L1 and 3T3-F442A preadipocytes were routinely differentiated in presence of ALN and VD3 10-9 - 10-7 M for 7 days and then stained with Oil Red O. The effect of these treatments on mRNA expression of the main molecular markers of adipocyte differentiation (PPARγ and C/EBPα) and VD Receptor (VDR) were analyzed through RT-PCR. Results: Both ALN and VD3 showed a marked anti-adipogenic effect on 3T3-L1 cells. Co-incubation of ALN 10-8 M and VD3 10-9 M displayed no synergic effect on inhibition of adipogenesis. PPARγ mRNA expression was significantly reduced by ALN and VD3. mRNA expression of C/EBPα was reduced only by VD3 treatment. An increase in VDR mRNA expression of 3T3-L1 cells was observed with both ALN and VD3. On the contrary, 3T3-F442A cells, which are in a more advanced adipogenic differentiation stage compared to 3T3-L1, did not express detectable levels of VDR. Interestingly, adipose differentiation of 3T3-F442A was not affected by ALN nor VD3. These results suggest that VDR may represent the molecular target of the anti-adipogenic effect of ALN. Conclusion: VDR plays a critical role in mediating the anti-adipogenic effect of ALN. Further studies to clarify this mechanism are warranted.

Use of MSC in the Treatment of the Congenital Pseudoarthrosis in Children

Congenital pseudoatrhrosis of the tibia is one of the most frustrating conditions encountered in paediatric orthopaedic surgery because of the difficulty in achieving healing;There are different methods of treatment the most commonly used are: External fixator according Ilizarov’s technique, vascularised fibular grafting, bone grafting with intramedullary fixation, Boyd’s double bone grafting and also after several operation go bad and a significant shortening of the leg even the amputation has to be considered [1] [2]. Numerous treatment options have been explored with several degree of success. In this paper we show a combinated surgical technique using autogenous mesenchymal stem cells (MSC) by precursor of osteogenic differensation at the same time as adjuvant to the surgical stabilization by an external fixator or an intramedullary nailing. We used these combined technique in tibia congenital pseudoarthrosis with and without neurofibromatosis in children. In fact Bone Marrow has been shown to contain a population of rare mesenchymal stem cells that are capable of forming bone, cartilage and other connective tissues enhancing bone repair and regeneration.