Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation
Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation
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DOI：
10.1210/en.2004-0735
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Jilka, RL
中科院分区：
文献类型：
--
作者：
Ali, AA;Weinstein, RS;Jilka, RL
由于成骨细胞和骨髓脂肪细胞源自一个常见的间充质祖细胞，因此成年可能发生的成年可能会以成骨细胞为代价，从而导致骨质流失。我们以前的体外研究表明，促脂异酶体增生剂激活的受体同工态γ2的激活抑制了成骨细胞的分化。在这里，我们表明接受罗格列酮28 d的5个月大的瑞士 - 温布斯特小鼠表现出与骨髓脂肪细胞增加相关的骨质流失，成骨细胞与骨质细胞的比率降低，骨形成率的降低以及骨骼形成率的降低以及骨骼的降低。在墙壁宽度中，每个团队成骨细胞形成的骨骼数量。罗格列酮对早期成骨细胞或破骨细胞祖细胞或成骨细胞寿命没有影响，但降低了关键成骨细胞生成的转录因子Runx2和iosterix在骨髓来源的中源性中源性培养物中的表达。这些作用与将双能祖细胞从成骨细胞转移到脂肪细胞谱系以及抑制单位成骨细胞祖细胞的分化。然而，在分化的后期，罗格列酮对成骨细胞没有影响。因此，罗格列酮会减弱成骨细胞分化，从而降低体内骨形成率，从而导致骨质流失。这些发现为最近的证据提供了一种机械解释，即过氧化物酶体增殖物激活的受体同工γ激活是骨骼质量的负调节剂，并表明随着年龄的增长，氧化脂肪酸的产生增加确实可能是年龄相关的骨质疏松症的重要机制。人类。
Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. Our previous in vitro studies indicated that activation of the proadipogenic transcription factor peroxisome proliferator-activated receptor isoform gamma2 with rosiglitazone suppressed osteoblast differentiation. Here, we show that 5-month-old Swiss-Webster mice receiving rosiglitazone for 28 d exhibited bone loss associated with an increase in marrow adipocytes, a decrease in the ratio of osteoblasts to osteoclasts, a reduction in bone formation rate, and a reduction in wall width-an index of the amount of bone formed by each team of osteoblasts. Rosiglitazone had no effect on the number of early osteoblast or osteoclast progenitors, or on osteoblast life span, but decreased the expression of the key osteoblastogenic transcription factors Runx2 and Osterix in cultures of marrow-derived mesenchymal progenitors. These effects were associated with diversion of bipotential progenitors from the osteoblast to the adipocyte lineage, and suppression of the differentiation of monopotential osteoblast progenitors. However, rosiglitazone had no effect on osteoblastic cells at later stages of differentiation. Hence, rosiglitazone attenuates osteoblast differentiation and thereby reduces bone formation rate in vivo, leading to bone loss. These findings provide a mechanistic explanation for the recent evidence that peroxisome proliferator-activated receptor isoform gamma activation is a negative regulator of bone mass and suggest that the increased production of oxidized fatty acids with age may indeed be an important mechanism for age-related osteoporosis in humans.