Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21.
Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21.
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DOI：
10.1371/journal.pone.0061372
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Almeida EA
中科院分区：
文献类型：
--
作者：
Blaber EA;Dvorochkin N;Lee C;Alwood JS;Yousuf R;Pianetta P;Globus RK;Burns BP;Almeida EA
骨是一种动态重塑的组织，需要重力介导的机械刺激来维持矿物质含量和结构。骨中的稳态通过破骨细胞、成骨细胞和骨细胞的活性和信号传导以及它们的干细胞祖细胞的增殖和分化的平衡而发生。微重力和卸载已知会导致破骨细胞介导的骨吸收;然而，我们假设骨细胞性骨溶解和成骨过程中的细胞周期阻滞也可能导致空间骨丢失。为了测试这种可能性，我们将16周龄的雌性C57 BL/6 J小鼠（n = 8）在STS-131航天飞机使命中暴露于微重力下15天。 通过µCT对骨盆的分析显示骨体积分数（BV/TV）降低6.29%，骨厚度降低11.91%。TRAP阳性破骨细胞覆盖的松质骨表面在微重力下也增加了170%（p = 0.004），表明破骨细胞骨变性。 高分辨率X线nanoCT研究显示了腔隙性骨质溶解的迹象，包括横截面积（+17%，p = 0.022）、周长（+14%，p = 0.008）和小管直径（+6%，p = 0.037）增加。 通过RT-qPCR测量的骨中基质金属蛋白酶（MMP）1、3和10的表达在微重力下也上调（分别为+12.94、+2.98和+16.85倍，p<0.01），MMP 10定位于骨细胞，与骨细胞性骨质溶解的诱导一致。此外，CDKN 1a/p21在骨中的表达增加了3.31倍（p<0.01），并且定位于成骨细胞，可能在组织再生期间抑制细胞周期以及赋予这些细胞凋亡抗性。最后，凋亡诱导剂Trp 53下调了-1.54倍（p<0.01），可能与CDKN 1a/p21的静止期生存促进功能有关。总之，我们的研究结果确定了小鼠骨骼的骨盆和股骨区域作为微重力下快速骨丢失的活性部位，并表明这种丢失不仅限于骨细胞降解。因此，本研究为微重力诱导的骨细胞性骨溶解和CDKN 1a/p21介导的成骨细胞周期阻滞提供了新的证据。
Bone is a dynamically remodeled tissue that requires gravity-mediated mechanical stimulation for maintenance of mineral content and structure. Homeostasis in bone occurs through a balance in the activities and signaling of osteoclasts, osteoblasts, and osteocytes, as well as proliferation and differentiation of their stem cell progenitors. Microgravity and unloading are known to cause osteoclast-mediated bone resorption; however, we hypothesize that osteocytic osteolysis, and cell cycle arrest during osteogenesis may also contribute to bone loss in space. To test this possibility, we exposed 16-week-old female C57BL/6J mice (n = 8) to microgravity for 15-days on the STS-131 space shuttle mission. Analysis of the pelvis by µCT shows decreases in bone volume fraction (BV/TV) of 6.29%, and bone thickness of 11.91%. TRAP-positive osteoclast-covered trabecular bone surfaces also increased in microgravity by 170% (p = 0.004), indicating osteoclastic bone degeneration. High-resolution X-ray nanoCT studies revealed signs of lacunar osteolysis, including increases in cross-sectional area (+17%, p = 0.022), perimeter (+14%, p = 0.008), and canalicular diameter (+6%, p = 0.037). Expression of matrix metalloproteinases (MMP) 1, 3, and 10 in bone, as measured by RT-qPCR, was also up-regulated in microgravity (+12.94, +2.98 and +16.85 fold respectively, p<0.01), with MMP10 localized to osteocytes, and consistent with induction of osteocytic osteolysis. Furthermore, expression of CDKN1a/p21 in bone increased 3.31 fold (p<0.01), and was localized to osteoblasts, possibly inhibiting the cell cycle during tissue regeneration as well as conferring apoptosis resistance to these cells. Finally the apoptosis inducer Trp53 was down-regulated by −1.54 fold (p<0.01), possibly associated with the quiescent survival-promoting function of CDKN1a/p21. In conclusion, our findings identify the pelvic and femoral region of the mouse skeleton as an active site of rapid bone loss in microgravity, and indicate that this loss is not limited to osteoclastic degradation. Therefore, this study offers new evidence for microgravity-induced osteocytic osteolysis, and CDKN1a/p21-mediated osteogenic cell cycle arrest.
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影响因子：
50.3
作者：
Barbash, Olena;Zamfirova, Petia;Lin, Douglas I.;Chen, Xiangmei;Yang, Ke;Nakagawa, Hiroshi;Lu, Fengmin;Rustgi, Anil K.;Diehl, J. Alan
通讯作者：
Diehl, J. Alan
DOI：
10.1083/jcb.200610046
发表时间：
2007-02-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ge C;Xiao G;Jiang D;Franceschi RT
通讯作者：
Franceschi RT
影响因子：
56.9
作者：
HALEVY, O;NOVITCH, BG;LASSAR, AB
通讯作者：
LASSAR, AB
影响因子：
3.3
作者：
Baecker, N;Tomic, A;Heer, M
通讯作者：
Heer, M
影响因子：
3.3
作者：
CAIOZZO, VJ;BAKER, MJ;BALDWIN, KM
通讯作者：
BALDWIN, KM