Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.
Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.
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骨髓脂肪形成增加不会导致雌性小鼠年龄依赖性的阑尾骨质流失。
DOI：
10.1111/acel.13247
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发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Jilka RL
中科院分区：
文献类型：
--
作者：
Almeida M;Kim HN;Han L;Zhou D;Thostenson J;Porter RM;Ambrogini E;Manolagas SC;Jilka RL
骨髓脂肪细胞和成骨细胞以相互排斥的方式从共同的间充质祖细胞分化，并且这些祖细胞在老年时转向脂肪细胞已经被提出来解释成骨细胞的下降和退化性骨质疏松症的发展。噻唑烷二酮（TZD）诱导的PPARγ（脂肪细胞分化所需的转录因子）激活增加骨髓脂肪并导致骨质流失的证据支持了这一观点。我们使用C57 BL/6 J小鼠对这一假设进行了功能性检验，这些小鼠从Prx 1 ‐Cre转基因靶向的早期间充质祖细胞中条件性缺失了PPARγ。使用纵向同窝对照研究设计，我们观察到，PPARγ对于6月龄雄性小鼠中TZD诱导的骨髓脂肪细胞增加和22月龄雌性小鼠中骨髓脂肪细胞的年龄相关增加是不可或缺的。相比之下，过氧化物酶体增殖物激活物受体γ与TZD或老年引起的皮质骨和松质骨丢失无关。相反，过氧化物酶体增殖物激活受体γ抑制了年龄依赖性的皮质骨孔隙度的发展。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。间充质祖细胞向脂肪细胞而不是成骨细胞的转移被认为是骨骼衰老的原因。我们使用间充质祖细胞中有条件缺失PPARγ的小鼠，表明PPARγ减少了皮质骨面积，但对于PPARγ刺激物（TZD）或老年引起的骨丢失来说是不必要的。引人注目的是，PPARγ的缺失加剧了皮质孔隙的发展，但随着年龄的增长减轻了骨关节炎。
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. Diversion of mesenchymal progenitors toward adipocytes instead of osteoblasts has been proposed to account for skeletal aging. Using mice with conditional deletion of PPARγ in mesenchymal progenitors, we show that PPARγ decreases cortical bone area but is dispensable for the loss of bone caused by PPARγ stimulators (TZD) or old age. Strikingly, deletion of PPARγ exacerbates the development of cortical porosity but attenuates osteoarthritis with aging.
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影响因子：
82.9
作者：
Farr JN;Xu M;Weivoda MM;Monroe DG;Fraser DG;Onken JL;Negley BA;Sfeir JG;Ogrodnik MB;Hachfeld CM;LeBrasseur NK;Drake MT;Pignolo RJ;Pirtskhalava T;Tchkonia T;Oursler MJ;Kirkland JL;Khosla S
通讯作者：
Khosla S
影响因子：
4.8
作者：
Ali, AA;Weinstein, RS;Jilka, RL
通讯作者：
Jilka, RL
影响因子：
4.8
作者：
Almeida, Maria;Ambrogini, Elena;Jilka, Robert L.
通讯作者：
Jilka, Robert L.
影响因子：
15.9
作者：
Akune, T;Ohba, S;Kawaguchi, H
通讯作者：
Kawaguchi, H
DOI：
10.1093/gerona/glw064
发表时间：
2016-07-01
影响因子：
5.1
作者：
Apelo, Sebastian I. Arriola;Pumper, Cassidy P.;Lamming, Dudley W.
通讯作者：
Lamming, Dudley W.