Influence Of Pioglitazone On IL-1β、IL-6、TNF-a In Ovaries Rats And Experimental Study On The Relation Of Them With Bone Metabolism

The incidence of Osteoporosis (OP) has increased obviously with the aging ofsociety ,69400000 people over the age of 50 suffering from OP in our country,andOP in postmenopausal women (postmenopausal osteoporosis ,PMOP) account for1/3,which will bring bone pain and fracture for patients and heavy burden for socialand family.Therefore,it has become an urgent need to study the mechanism ofPMOP .The bone is continuously being remodeled following two opposite andcoordinated processes.Under normal conditions, specialized cells called osteoclaststransiently break down old bone (resorption process) at multiple sites as other cellsknown as osteoblasts are replacing it with new tissue (bone formation);otherwise,when the bone remodeling is imbalanced,it can lead to many metabolicbone diseases,such as OP,bone sclerosis,rickets.OP results in bone excessive loss andbone tissue microstructure damage.It is known OP could be divided into high andlow conversion type according to the conversion rate,and previous study showed thatPMOP belong to high conversion type.Peroxisome proliferators-activated receptor (PPARγ) is a group of ligandactivated transcription factor,widely exist in the human body,belonging to the nuclearreceptor superfamily. The view that the effect of PPARγ2 on the differentiation ofbone marrow stem cells and bone metabolism is reported differently by theresearch .Research shows that thiazolidine two ketone (TZDs)–as the synthetic ligandof PPARγ2,such as rosiglitazone,pioglitazone,can reduce insulin resistance in diabetestreatment,also increase the incidence rate of PMOP. Howerer, there is little researchabout the effect of PPARγon bone metabolism and bone turnover of PMOP at homeand abroad.For postmenopausal women with body fat increased ,fat cells and bonemarrow mononuclear cells secrete more Interleukin 1 beta (IL-1β), Interleukin 6(IL-6),tumor necrosis factor alpha (TNF-α), which may be a reason for triggering aglycolipid metabolism disorder and insulin resistance.As OC strongest factor , IL-1β、IL-6、TNF-a, can accelerate bone resorption,become a resson forPMOP.Pioglitazone–activated PPARγ2 can reduce insulin resistance through inhibition of IL-1β、IL-6、TNF-a,which may also indirectly inhibit OC activity .Thepurpose of our study is to observe the effect of pioglitazone on bone formationmarkers and cytokine levels of ovariectomized rats,to provide new ideas for exploringthe mechamism of PMOP.Objective:To observe the effect of pioglitazone on fat ,bone density andhistomorphomertry,expression of bone formation marker bone alkaline phosphatase(BALP),osteocalcin (OCN) and OC stimulating factor IL-1β、IL-6、TNF-a andmRNA expression of PPARγ2 of ovariectomized and sham operation rats,andinvestigate the possible mechanism of postmenopausal bone mass changes caused byTZDs.Methods:The PMOP rat models were established by removal of ovaries,the ratswere randomly assigned to ovariectomized group, ovariectomized added low dose ofpioglitazone (4mg/kg�'d) and high dose of pioglitazone (20mg/kg�'d) group,shamoperation group, sham operation added low dose of pioglitazone (4mg/kg�'d) andhigh dose of pioglitazone (20mg/kg�'d) group.Then all rats were killed bybloodletting of abdominal artery at different time,to examine the contence of serumlipids,Ca,P,Insulin,E2and the activites of bone formation makers BALP,OCN, IL-1β、IL-6、TNF-a and mRNA expression of PPARγ2 of bone marrow supernatant,and bonedensity and histomorphometry.Results:1 Compared with the sham operation group,body weight,TG,CHO,LDL-C,ALP,FNS,HOMA-IR,OCN,BALP, PPARγ2,IL-1β,IL-6、TNF-a were increased,butHDL-C, E2were decreased for ovariectomized rats.Statistical significance was foundin interclass comparison (P＜0.01).2 The result showed that pioglitazone up-regulated the mRNA expression ofPPARγ2,and increased the level of OCN, IL-1β、IL-6、TNF-a for ovariectomized ratsin a time and dose–dependent manner, Statistical significance was found in interclasscomparison (P＜0.01);while it increased the level of BALP for ovariectmized rats in atime–dependent manner,statistical significance was found in interclass comparison (P＜0.01).3 The high dose of pioglitazone decreased bone mineral density significantly ina time-dependent manner. statistical significance was found in interclass comparison(P＜0.01).4 The result also showed that bone trabeculars had been thinning,fracture and the number of them had reduced for ovariectmized rats,but for sham operation ratsthere were no changes.With the intervention of pioglitazone, bone trabeculars weredamaged from all the groups,but they were more serious from ovariectomized groups.Conclusions:1 Body weight,blood lipid,insulin and insulin resistance index wereincreased;IL-1β、IL-6、TNF-a secretion promoted OC differentiation,proliferationand accelerated bone resorption.2 Pioglitazone activated the transcription activity and promoted the expressionof PPARγ2, reduced the level of BALP and OCN and suppressed bone formation;while inhibited IL-1β、IL-6、TNF-a expression,decreased high conversion rate ofPMOP.Howere,it may increase the risk of PMOP.