Abstract
Bone changes related to diabetes have been well stablished, but few strategies have been developed to prevent this growing health problem. In our work, we propose to investigate the effects of calcitriol as well as of a vitamin D analog (paricalcitol) and a calcimimetic (cinacalcet), in fin regeneration and de novo mineralization in a zebrafish model of diabetes. Following exposure of diabetic transgenic Tg(ins:nfsb-mCherry) zebrafish to calcitriol, paricalcitol and cinacalcet, caudal fins were amputated to assess their effects on tissue regeneration. Caudal fin mineralized and regenerated areas were quantified by in vivo alizarin red staining. Quantitative real-time PCR was performed using RNA from the vertebral column. Diabetic fish treated with cinacalcet and paricalcitol presented increased regenerated and mineralized areas when compared with non-treated diabetic group, while no significant increase was observed in non-diabetic fish treated with both drugs. Gene expression analysis showed an up-regulation for runt-related transcription factor 2b (runx2b), bone gamma-carboxyglutamic acid-containing protein (bglap), insulin a (insa) and insulin b (insb) and a trend of increase for sp7 transcription factor (sp7) in diabetic groups treated with cinacalcet and paricalcitol. Expression of insra and vdra was up-regulated in both diabetic and nondiabetic fish treated with cinacalcet. In nondiabetic fish treated with paricalcitol and cinacalcet a similar increase in gene expression could be observed but not so pronounced. The increased mineralization and regeneration in diabetic zebrafish treated with cinacalcet and paricalcitol can be explained by increased osteoblastic differentiation and increased insulin expression indicating pro-osteogenic potential of both drugs.
Highlights
Prevalence of diabetes mellitus worldwide was estimated to be of 135 million in 1995 and is predicted to be of 300 million in the year 2025 1 leading to an increase in patients living with the risk of developing diabetesrelated complications 2
We found that glucose concentrations in the plasma of fish treated with MET were significantly higher than in fish treated with vehicle only, with these differences being highly significant at 90, 120,150 and 180 minutes after IP injection (Figure 1)
This study demonstrated that zebrafish is a suitable model for the study of bone pathologies related to diabetes
Summary
Prevalence of diabetes mellitus worldwide was estimated to be of 135 million in 1995 and is predicted to be of 300 million in the year 2025 1 leading to an increase in patients living with the risk of developing diabetesrelated complications 2. VitD, the vitamin D analog paricalcitol and the calcimimetic cinacalcet have been used for the treatment of SH in CKD patients with beneficial effects in lowering PTH values and in increasing bone mass [7,8]. Later Kojima et al (2003, 2004) 23,24 showed the presence of cells positive for insulin RNA in the liver, adipose tissue and bone marrow in several diabetic mice models, but not in nondiabetic mice. This insulin expressing cells had no impact on reducing hyperglycemia in diabetic mice. Kojima et al demonstrated that beside not having any impact in regulating glucose levels, this Proins/TNF-α-expressing cells had their origin in bone marrow and migrated to several parts of the body, initiating diabetic neuropathy
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