Lin Tzu-Hung, Yang Rong-Sen, Tang Chih-Hsin, Lin Chih-Peng, Fu Wen-Mei
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Bone. 2007 Oct;41(4):562-74. doi: 10.1016/j.bone.2007.06.017. Epub 2007 Jul 4.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, is considered as an anti-osteoblastic factor associated with adiposity and the elderly osteoporosis due to a defect in osteoblastogenesis. We have found that oral administration of PPARgamma activator rosiglitazone decreased tibia BMD and serum ALP but left serum calcium and osteoclast marker C-terminal telopeptide unaffected. In addition, we examined the inhibitory mechanisms of PPARgamma on the bone formation by using PPARgamma activators ciglitazone and 15-deoxy-Delta(12,14)-prostaglandin-J2 (15d-PGJ2). Our data indicated that PPARgamma ligands decreased both mineralized bone nodules and alkaline phosphatase (ALP) activities in cultured primary osteoblasts. Reverse transcription polymerase chain reaction (RT-PCR) showed that the expression of bone morphogenetic protein-2 (BMP-2) and osteocalcin (OCN) was inhibited by ciglitizone and 15d-PGJ2. Furthermore, PPARgamma ligands inhibited NF-kappaB associated downstream COX-2 and iNOS osteogenic signaling. The ultrasound (US)-induced elevation of COX-2 and iNOS expression and nitric oxide (NO) production were attenuated in the presence of PPARgamma ligands. Furthermore, local administration of PPARgamma ligands into the metaphysis of rat tibia decreased the bone volume in secondary spongiosa. These results suggest that the activation of PPARgamma inhibits osteoblastic differentiation and the expression of several anabolic mediators involved in bone formation. These data may reflect osteoporosis and less bone formation in the aging people and patients treated with thiazolidinediones.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种配体激活的转录因子，由于成骨细胞生成缺陷，它被认为是一种与肥胖和老年骨质疏松相关的抗成骨细胞因子。我们发现口服PPARγ激活剂罗格列酮可降低胫骨骨密度和血清碱性磷酸酶（ALP），但血清钙和破骨细胞标志物C端肽不受影响。此外，我们使用PPARγ激活剂环格列酮和15-脱氧-Δ（12,14）-前列腺素-J2（15d-PGJ2）研究了PPARγ对骨形成的抑制机制。我们的数据表明，PPARγ配体可降低原代培养成骨细胞中的矿化骨结节和碱性磷酸酶（ALP）活性。逆转录聚合酶链反应（RT-PCR）显示，环格列酮和15d-PGJ2可抑制骨形态发生蛋白-2（BMP-2）和骨钙素（OCN）的表达。此外，PPARγ配体抑制与核因子κB相关的下游环氧化酶-2（COX-2）和成骨信号诱导型一氧化氮合酶（iNOS）。在存在PPARγ配体的情况下，超声（US）诱导的COX-2和iNOS表达及一氧化氮（NO）生成的升高受到抑制。此外，将PPARγ配体局部注射到大鼠胫骨干骺端可减少次级海绵骨的骨体积。这些结果表明，PPARγ的激活抑制成骨细胞分化以及参与骨形成的几种合成代谢介质的表达。这些数据可能反映了衰老人群和接受噻唑烷二酮治疗的患者中的骨质疏松和骨形成减少。
