Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone
Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone
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DOI：
10.1210/en.2005-0333
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发表时间：
2005-11-01
期刊：
影响因子：
4.8
通讯作者：
McCauley, LK
中科院分区：
文献类型：
--
作者：
Koh, AJ;Demiralp, B;McCauley, LK
PTH是一种用于治疗骨质疏松症的合成代谢剂，但其作用机制尚不清楚。这项研究阐明了小鼠骨骼生长过程中 PTH 合成代谢作用的靶细胞和机制。 c-fos 消融的小鼠骨质疏松，缺乏对 PTH 的合成代谢反应。在本研究中，与 +/+ 相比，c-fos -/- 小鼠细胞中 PTH 调节的成骨细胞分化或增殖在体外没有改变；因此，进一步研究了破骨细胞的影响。一种新颖的移植模型被用来挽救 c-fos 消融的骨硬化缺陷。将c-fos -/- 和-/- 小鼠的椎体（小泡）植入无胸腺宿主中，并挽救c-fos -/- 破骨细胞缺陷。无论囊泡基因型如何，对携带囊泡的小鼠进行 PTH 治疗都会增加骨髓中 5-溴-2'-脱氧尿苷 (BrdU) 的阳性率，并增加骨面积。为了抑制破骨细胞前体向野生型囊泡的募集，基质衍生因子 1 信号传导被阻断，从而削弱了 PTH 合成代谢反应。用护骨素治疗小鼠以抑制破骨细胞分化也能阻断 PTH 的合成代谢作用。相比之下，使用具有晚期破骨细胞分化缺陷的c-src突变小鼠并没有阻碍合成代谢作用，这表明关键靶细胞存在于骨髓中的中间分化破骨细胞群中。这些结果表明，成骨细胞中的 c-fos 对于 PTH 作用并不重要，但破骨细胞谱系的细胞是 PTH 合成代谢作用的中间靶标。
PTH is an anabolic agent used to treat osteoporosis, but its mechanisms of action are unclear. This study elucidated target cells and mechanisms for anabolic actions of PTH in mice during bone growth. Mice with c-fos ablation are osteopetrotic and lack an anabolic response to PTH. In this study, there were no alterations in PTH-regulated osteoblast differentiation or proliferation in vitro in cells from c-fos -/- mice compared with +/+; hence, the impact of osteoclastic cells was further investigated. A novel transplant model was used to rescue the osteopetrotic defect of c-fos ablation. Vertebral bodies (vossicles) from c- fos -/- and -/- mice were implanted into athymic hosts, and the c- fos -/- osteoclast defect was rescued. PTH treatment to vossicle-bearing mice increased 5-bromo-2 '-deoxyuridine ( BrdU) positivity in the bone marrow and increased bone area regardless of the vossicle genotype. To inhibit recruitment of osteoclast precursors to wildtype vossicles, stromal derived factor-1 signaling was blocked, which blunted the PTH anabolic response. Treating mice with osteoprotegerin to inhibit osteoclast differentiation also blocked the anabolic action of PTH. In contrast, using c-src mutant mice with a late osteoclast differentiation defect did not hinder the anabolic action, suggesting key target cells reside in the intermediately differentiated osteoclast population in the bone marrow. These results indicate that c-fos in osteoblasts is not critical for PTH action but that cells of the osteoclast lineage are intermediate targets for the anabolic action of PTH.