Marrow adipocytes and osteoblasts differentiate from common mesenchymal progenitors in a mutually exclusive manner, and diversion of these progenitors toward adipocytes in old age has been proposed to account for the decline in osteoblasts and the development of involutional osteoporosis. This idea has been supported by evidence that thiazolidinedione (TZD)‐induced activation of PPARγ, the transcription factor required for adipocyte differentiation, increases marrow fat and causes bone loss. We functionally tested this hypothesis using C57BL/6J mice with conditional deletion of PPARγ from early mesenchymal progenitors targeted by the Prx1‐Cre transgene. Using a longitudinal littermate‐controlled study design, we observed that PPARγ is indispensable for TZD‐induced increase in marrow adipocytes in 6‐month‐old male mice, and age‐associated increase in marrow adipocytes in 22‐month‐old female mice. In contrast, PPARγ is dispensable for the loss of cortical and trabecular bone caused by TZD or old age. Instead, PPARγ restrains age‐dependent development of cortical porosity. These findings do not support the long‐standing hypothesis that increased marrow adipocyte differentiation contributes to bone loss in old age but reveal a novel role of mesenchymal cell PPARγ in the maintenance of cortical integrity.

中文翻译：

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增加的骨髓脂肪生成不会导致雌性小鼠的年龄依赖性附肢骨丢失

骨髓脂肪细胞和成骨细胞以相互排斥的方式与常见的间充质祖细胞分化，并且已经提出将这些祖细胞转移到老年脂肪细胞以解释成骨细胞的减少和退化性骨质疏松症的发展。这一观点得到了证据的支持，即噻唑烷二酮 (TZD) 诱导的 PPARγ（脂肪细胞分化所需的转录因子）激活会增加骨髓脂肪并导致骨质流失。我们使用 C57BL/6J 小鼠在功能上测试了这一假设，该小鼠条件性地从 Prx1-Cre 转基因靶向的早期间充质祖细胞中删除了 PPARγ。使用纵向同窝对照研究设计，我们观察到 PPARγ 对于 TZD 诱导的 6 个月大雄性小鼠骨髓脂肪细胞增加是必不可少的，22 个月大的雌性小鼠骨髓脂肪细胞与年龄相关的增加。相比之下，PPARγ对于由TZD或老年引起的皮质骨和骨小梁缺失是可有可无的。相反，PPARγ 抑制了皮质孔隙度的年龄依赖性发展。这些发现不支持长期存在的假设，即骨髓脂肪细胞分化增加会导致老年骨质流失，但揭示了间充质细胞 PPARγ 在维持皮质完整性中的新作用。