The Effects Of Pioglitazone On Bone Turnover And Its Related Molecular Mechanism In STZ-induced Diabetic Rats

Objective:Diabetes mellitus (DM) is a metabolic syndrome characterized by hyperglycemia due to an absolute or relative deficiency in insulin secretion. The definite mechanism underlying the development of diabetic osteopenia has not been elucidated. Thiazolidinediones (TZDs) are now widely used in the management of T2DM, and their use may increase in other diseases characterized by insulin resistance,inflammationm,et al.However, several clinical studies have reported that the TZDs currently in clinical use increase the risk of fractures in women with type II diabetes mellitus. Research is needed to better understand the mechanisms of bone loss with TZDs. our investigation aimed at testing the mRNA level of several cytokines and transcription factors related to bone turnover in bone tissues of STZ-induced diabetic rats and PIO-treated diabetic rats. The cytokines and transcription factors include RANKL(receptor activator of nuclear factorκB ligand), OPG (osteoprotegerin),Cbfal(core binding factor 1), OC(osteocalcin). The ratio of RANKL/OPG is essential for the bone resorption process. We also try to demonstrate if it is a possible mechanism involved in PIO-treated diabetic osteopenia by detecting mRNA level of peroxisome proliferators-activated receptor (PPAR)γ2 in bone tissue which can induce adipogenesis over oseoblastogenesis in pluripotent cells and by counting adipocyte number in femur marrow of rats studied.Materials and methods:The DM rat models were established by intravenous injection of STZ(45mg/kg). Then, they were randomly divided into seven groups, including small-dose PIO group (group PL,4mg/kg/d), small- dose PIO combined with glargine group (group PLIn, PIO 4mg/kg/d and glargine 4U//kg/d), large-dose PIO group (group PH,20mg/kg/d), CsA group (group CsA, lmg/kg/d), CsA combined with glargine group(group CsAIn, CsA lmg/kg/d and glargine 4U//kg/d), glargine trentment group(group In, glargine 4U//kg/d) and no-treatment group(group DM). Another group of normal rats(group CON) was also monitored simultaneously. Sixteen weeks later, blood were collected and serum were separated for the measurement of Ca, P and ALP. The left tibia was dissected for bone histomorphometry analysis. Right femur and lumbar vertebrae(L1-L4) were reserved for both BMD and bone biomechanical test. The study of bone tissue mRNA was performed by reverse transcription polymerase chain reaction assays.Results:No significant difference was found in serum Ca, P and ALP level between 7 groups of rats studied. STZ-induced diabetic rats were characterized by extreme hyperglycemia, marked weight loss, polyuria and hypercalciuria. A low-turnover osteopenia was evidenced in this group by decreased BMD (both femur and lumbar vertebrae), impaired bone biomechanics,decreased trabecular volume and thickness and reduced bone label surface and bone formation rate by bone dynamic study. The intervention of low dose PIO didn't affect bone mass, bone turnover rate and biomechanics in STZ-induced DM rats. In STZ-induced DM rats treated with high dose PIO, reduced bone formation rate was noted by decreased BMD, impaired bone biomechanics, decreased trabecular volume, bone activation frequency by bone dynamic study.Conclusion:STZ- induced diabetic rats showed decreased bone mass and biomechanics due to reduced bone formation rate. The intervention of low dose PIO didn't affect bone mass and biomechanics in STZ-induced DM rats. A reduced bone formation rate was found with high dose PIO in the diabetic osteopenia was exacerbated. A low-turnover osteopenia was evidenced in STZ-induced diabetic rats by significant decrease of both osteoclastic and osteoblastic marker mRNA level in tibia. We also proposed another pathway that contribute to diabetic bone loss which involves the selection of of adipogenesis over osteoblastogenesis in diabetic bone tissue. The use of low dose PIO doesn't affect bone- turnover condition in STZ rats. High dose PIO can induce a decreased osteoblastic activity osteopenia in diabetic rats ,but not affect osteoclastic activity. It may induce adipogenesis over oseoblastogenesis in pluripotent cells and by counting adipocyte number in femur marrow of rats studied.