Constitutively active PTH/PTHrP receptor specifically expressed in osteoblasts enhances bone formation induced by bone marrow ablation.
Constitutively active PTH/PTHrP receptor specifically expressed in osteoblasts enhances bone formation induced by bone marrow ablation.
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DOI：
10.1002/jcp.22986
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发表时间：
2012-02
影响因子：
5.6
通讯作者：
Noda, Masaki
中科院分区：
文献类型：
--
作者：
Ono, Noriaki;Nakashima, Kazuhisa;Schipani, Ernestina;Hayata, Tadayoshi;Ezura, Yoichi;Soma, Kunimichi;Kronenberg, Henry M.;Noda, Masaki
骨的维持是由成骨细胞的增殖和骨祖细胞的分化提供的连续的骨形成。甲状旁腺激素（PTH）激活骨形成，但由于成骨细胞谱系中细胞的复杂性，这些成骨细胞在体内是如何被PTH调节的尚不完全清楚。为了阐明分化成骨细胞中PTH信号如何在体内调节骨祖细胞，我们使用col1a1组成型活性PTH/PTHrP受体（caPPR）转基因小鼠进行骨髓消融。这些小鼠通过使用2.3 kb Col1a1启动子在成骨细胞中特异性表达caPPR，在稳态条件下表现出较高的骨小梁体积。相比之下，骨髓消融后，转基因小鼠骨髓腔中从骨表面募集的基质细胞广泛增殖，而野生型小鼠增殖有限。野生型小鼠的新生骨形成仅限于消融区，而转基因小鼠的整个骨髓腔，不仅包括消融区，还包括消融区外，都充满了新生骨。转基因小鼠消融后骨密度显著增高。在成骨培养基中培养的转基因小鼠骨髓细胞碱性磷酸酶阳性区明显增加。此外，转基因小鼠骨髓细胞骨髓消融后，wnt信号分子LRP5、Wnt7b、Wnt10b mRNA表达上调。这些结果表明，分化成骨细胞中PTH/PTHrP受体的组成性激活可增强骨髓消融诱导的骨祖细胞募集、增殖和分化。
Bone is maintained by continuous bone formation by osteoblasts provided by proliferation and differentiation of osteoprogenitors. Parathyroid hormone (PTH) activates bone formation, but because of the complexity of cells in the osteoblast lineage, how these osteoprogenitors are regulated by PTH in vivo is incompletely understood. To elucidate how signals by PTH in differentiated osteoblasts regulate osteoprogenitors in vivo, we conducted bone marrow ablation using Col1a1-constitutively active PTH/PTHrP receptor (caPPR) transgenic mice. These mice express caPPR specifically in osteoblasts by using 2.3 kb Col1a1 promoter and showed higher trabecular bone volume under steady-state conditions. In contrast, after bone marrow ablation, stromal cells recruited from bone surface extensively proliferated in the marrow cavity in transgenic mice, compared to limited proliferation in wild-type mice. Whereas de novo bone formation was restricted to the ablated area in wild-type mice, the entire marrow cavity, including not only ablated area but also outside the ablated area, was filled with newly formed bone in transgenic mice. Bone mineral density was significantly increased after ablation in transgenic mice. Bone marrow cell culture in osteogenic medium revealed that alkaline phosphatase-positive area was markedly increased in the cells obtained from transgenic mice. Furthermore, mRNA expression of Wnt-signaling molecules such as LRP5, Wnt7b, and Wnt10b were upregulated after marrow ablation in bone marrow cells of transgenic mice. These results indicate that constitutive activation of PTH/PTHrP receptor in differentiated osteoblasts enhances bone marrow ablation-induced recruitment, proliferation, and differentiation of osteoprogenitors.
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影响因子：
4
作者：
Liu, F;Malaval, L;Aubin, JE
通讯作者：
Aubin, JE
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
4.8
作者：
Qin, L;Li, X;Partridge, NC
通讯作者：
Partridge, NC
影响因子：
46.9
作者：
Adams, Gregor B.;Martin, Roderick P.;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
64.5
作者：
Komori, T;Yagi, H;Kishimoto, T
通讯作者：
Kishimoto, T