The Effects Of Fioglitazone On The Adiponectin Of Ovariectomized Rats And Their Relationship To The Bone

PPARγis a subtype of the peroxisome proliferator-activated receptors (PPARs),asa candidate gene affecting bone metabolism, its relative basic andclinicalresearchisless at present, while its synthetic ligand of thiazolidinediones (TZDs) medicine hasbeen widely used in clinic as atreatment for diabetes. In the year of 2006, the negativeeffects of TZD on bone metabolism was officially reported for the first time inlarge clinical studies on diabetic glycemic control - ADOPT study, theymanifested in decline in bone mass of postmenopausal female patients of diabetesand the risk of causing or aggravating osteoporosis, and their specificmechanisms remain to be explored. Adiponectin is a recently discoveredspecific protein secreted by fat cells, it has functionsof anti-inflammatory,improving insulin resistance, glycemic drop, anti-atherosclerosis andregulation of bone metabolism. At present,the research on adiponectin inrespect of improving insulin resistance is already very mature, but that on itsinfluence mechanism in bone metabolism is less, the research on itsrole in postmenopausal osteoporosis and its relationship to PPAR-γis increasingabroad day by day and not reported yet at home.Objective: In this study, by observing the effects of TZDs medicine of pioglitazoneon bone metabolism changes, body fat changes, and bone metabolism relatedindexes of ovariectomized rats，the relationship between this medicine andpostmenopausal osteoporosis and its possible functionary mechanisms were discussed,and then, through research on the effect of pioglitazone on ovariectomizedadiponectin, the functionary mechanisms of adiponectin and its effect on bone werediscussed, so asto provide a theoretical basis for rational clinical medication.Methods: Select 144 healthy female 3-month-old rats as the object of study, dividethem into ovariectomized group and sham-operation group, each group include sixsub-groups including physiological saline group, pioglitazone 4mg/kg·d and20mg/kg·d sub-groups, carry out intragastric administration for the rats and feed themthe medicine, take 6 rats at different time points of 0 weeks, 4 weeks, 8weeks, and 12 weeks respectively for the detection of various indicators, use DPXdual-energy X-ray scanner of bone mineral density to test the animal’s bone masschanges, perform HE staining for decalcified bone slices to observe the morphological changes, measure the blood sugar with blood sugar meter,measure the levels of bloodinsulin, blood estradiol and osteocalcin by radioimmunoassay, usespectrophotometer to measure the changes of fat, calcium, phosphorus, andalkaline phosphatase in the blood, measure the level of PPAR-γ2 using RT-PCR,and measure the levels of adiponectin and bone alkaline phosphatase ofbone marrow supernatant by euzymelinked immunosorbent assay.Results: 1. As the ovariectomized group is compared with thesham-operation group, the body weight, TG, CHO, LDLC, blood ALPFNS,HOMA-IR, BGP, BALP, PPARγ2 and adiponectin all rose, while theE2, HDLC andBMD all dropped, the difference was statistically significant (P <0.01).2．After the intervention of the pioglitazone of different concentrations, the insulin,insulin resistance index, BMD, BGP and BALP of the ovariectomized group andsham-operation group dropped depending on the dosage, while the adiponectin andPPARγ2 rose in the same way, the difference between groups was statisticallysignificant ( P <0.05). The TG, CHO, LDLC and ALP of t heovariectomized group dropped depending on the dosage, the difference betweengroups was statisticallysignificant (P <0.05).3. After the intervention of the pioglitazone, control group of the ovariectomizedgroup BGP and BALP rose with the change of time ,4mg/kg·d and 20mg/kg·d ofthe ovariectomized group BGP and BALP dropped with the change of time;controlgroup, pioglitazone 4mg/kg·d and 20mg/kg·d of the ovariectomized groupPPARγ2 and adiponectin rose with the change of time, while the BMD dropped, thedifference between groups was statistically significant ( P <0.01).4. The adiponectin was positively correlated with PPARγ2（r = 0.718，P＜0.05），positively correlated with BGP and BALP（r = 0.339，r =0.595；P＜0.05），and negatively correlated with BMD（r = -0.946，P＜0.05）. 5. Bone morphologicalchanges: The structure of vertebral trabecular bone of the sham-operation groupwas normal, as compared with this,the vertebral trabecular bone of theovariectomized group became thin, sparsely arranged, partially fractured, and theosteoblast and osteoclast around the trabecular bone proliferated actively. After theintervention of the pioglitazone, the trabecular bones of both the sham-operationand ovariectomized groups were damaged to different extents, while the damage ofthe ovariectomized group was more obvious.Conclusion: 1. Pioglitazone activated the transcriptional activity of PPARγ2, increased the PPARγ2 expression, reduced the levels of the marker genes of BGPand BALP of the osteoblast, and time-dependentlyand dose-dependently reducedthe BMD, these confirmed its adverseeffects on bone metabolism.2. Pioglitazone time-dependently and dose-dependently advancedthe secretion of adiponectin, the level of adiponectin was negativelycorrelated with BMD,it indicates that APN levels may be involved in the TZDs drugscaused decline in bone mass in postmenopausal patients with the occurrence anddevelopment process.