Osteoporosis is defined as a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Osteoporosis is well known increasing with age. The number and size of marrow adipocytes increase in a linear manner with age. Early histomorphometric observations suggested that the consequence of the adipose replacement of the marrow functional cell population was a cause of osteoporosis. The replacement of functional cells in the marrow by fat cells is common in several pathological study of osteoporosis. All these evidences clearly demonstrate the reciprocal relationship between osteoblast and adipocyte differentiation. The trans-differentiation of osteoblast to adipocyte is an important mechanism of pathogenesis of osteoporosis. Several reports have indicated that the long-term use of steroids could induce osteonecrosis and osteoporosis. Using a mouse pluripotent mesenchymal cell, D1, as a model, we have demonstrated that dexamethasone, a glucocorticoid, can induce adipogenesis.
Peroxisome proliferator-activated receptors-£^ (PPAR£^) plays a critical role in glucose and lipid metabolism, macrophage function, and adipogenesis. It is a nuclear hormone receptor, activated through ligand binding, which results in allosteric changes in receptor conformation, recruitment of coactivators, assembly of a transcriptional complex, there regulates gene expression. Thiazolidinedione (TZD) is one of the agonist of PPAR£^ receptor which has been a medication for diabetic mellitus for years. Treatment with TZDs leads to selective accumulation of subcutaneous adipose tissue. We examined whether adipogenesis induction in D1 cells is initiated by activation of peroxisome proliferator-activated receptor-£^. The results revealed that pioglitazone induces adipogenesis in D1 cells in dosedependent manner and decreases alkaline phosphatase activity in D1 cells.
Interestingly, this adipogenesis was not blocked by bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor-£^ antagonist. A peroxisome proliferator-activated receptor-£^-mediated reporter gene assay showed no response to pioglitazone. We then asked whether dexamethasone-induced adipogenesis can be repressed by mifepristone (RU486), an antagonist of glucocorticoid receptor. The results disclosed that mifepristone cannot counteract dexamethasone-induced adipogenesis, and mifepristone itself induced adipogenesis in D1 cells. Moreover, glucocorticoid receptor-mediated reporter gene assay was not responsive to dexamethasone or mifepristone. We concluded that the adipogenesis induced by pioglitazone and dexamethasone in D1 cells may not occur via a peroxisome proliferator-activated receptor-£^ and glucocorticoid receptor pathway.
These results suggested that the adipogenesis induced by glucocorticoids and pioglitazone is directed by a multiple cell signaling pathway. Finally, data from microarray analysis confirmed this adipogenesis pathway, as several adipogenesis-related genes are highly provoked by DEX. We found that the expressions of several adipogenesis-related genes are highly provoked by this agent.
Our studies suggest that the adipocyte conversion of bone marrow stromal cells may be the mechanism of bone loss caused by pioglitazone. Considering its widespread clinical use, the detrimental skeletal effects of pioglitazone should be closely monitored.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0213108-000403 |
| Date | 13 February 2008 |
| Creators | Hung, Shao-Hung |
| Contributors | Jiin-Tsuey Cheng, none, none, none, none, David Chao |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0213108-000403 |
| Rights | unrestricted, Copyright information available at source archive |
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