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A Hypertensive Drug Telmisartan Selectively Activates PPAR Anti‐Diabetic and Pro‐Adipocytic but not Anti‐Osteoblastic Activities in vitro and in vivo
Author(s) -
Petluru Vipula,
Lu Yalin,
Rahman Sima,
LeckaCzerrnik Beata
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb545
Subject(s) - telmisartan , rosiglitazone , osteoblast , endocrinology , medicine , peroxisome proliferator activated receptor , adipocyte , agonist , chemistry , receptor , mesenchymal stem cell , pharmacology , in vitro , adipose tissue , microbiology and biotechnology , biology , biochemistry , blood pressure
Anti‐diabetic drugs Thiazolidinediones (TZDs) improve insulin sensitivity by activating nuclear receptor PPARγ , however prolonged use causes bone loss and increases fracture risk. In marrow Mesenchymal stem cells (MSCs), activation of PPARγ2 with TZD rosiglitazone (R) induces adipocyte and suppresses osteoblast differentiation. The beneficial anti‐diabetic and pro‐adipocytic activities of PPARγ2 can be separated from the unwanted anti‐osteoblastic activity by using selective PPARγ agonists. The anti‐hypertensive drug Telmisartan (TEL) inhibits the activity of Angiotensin II receptor and also acts as a selective PPARγ agonist. Activation of PPARγ with TEL improves insulin resistance and lipid profile. We tested the effect of TEL on MSCs lineage commitment using U33/γ2 cell model of MSCs differentiation under the control of PPARγ2 . TEL (50 μM) did not affect osteoblast phenotype, however it induced adipocyte phenotype. Next, we tested whether TEL may protect against the anti‐OB effect of R. U33/γ2 cells were treated with R alone (1μM) or in combination with TEL (50 μM). As expected, R alone suppressed osteoblast phenotype; however combined treatment with TEL and R did not affect ALP activity or expression of genes. Unlike R‐activated PPARγ2 which suppresses the activity of TGFβ/BMP signaling pathway, TEL did not affect pathway activity and protected from negative effects of R. When administered to hyperglycemic and diabetic Avy/a mice, both drugs had a similar antidiabetic effect. However, administration of R resulted in 60% decrease in trabecular bone mass, whereas TEL did not have any effect on bone. Moreover, when mice received combination of both drugs, TEL prevented bone loss induced by R. Thus, TEL selectively induces PPARγ2 anti‐diabetic activity without affecting osteoblastic phenotype in bone MSCs and in mice. Thus, TEL represents a paradigm of multifunctional drug, which can be used alone or in combination with R, for simultaneous treatment of hypertension and diabetes without adverse effects on bone.