Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor.
Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor.
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DOI：
10.1016/j.bone.2009.09.009
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发表时间：
2010-02
期刊：
影响因子：
4.1
通讯作者：
Lanske B
中科院分区：
文献类型：
--
作者：
Maeda Y;Schipani E;Densmore MJ;Lanske B
在胎儿期软骨内骨形成过程中，印度刺猬(IHH)对软骨细胞的增殖分化和成骨细胞分化是必不可少的。IHH在出生后软骨细胞中的表达在出生后维持生长板和维持骨小梁方面具有非多余的作用。出生后软骨细胞中IHH的丢失导致生长板融合和骨小梁减少。为了使这种异常的软骨细胞表型正常化，并研究假定的生长板异常的挽救是否足以纠正骨骼中的严重变化，我们在COL2α1-CRER*；IHDLD小鼠通过与COL2α1-CRER*交配；Ihf1/fl小鼠与COL2PTH/PTHrP受体转基因小鼠(Jansen，J)的软骨细胞中表达了固有活性的甲状旁腺素/甲状旁腺素受体(IHH/PTHrP受体)。Col2α1-Cre ER*；Ihhf/f；J小鼠在P0处注射他莫昔芬，产生Col2α1-Cre ER*；Ihhd/d；J小鼠。与已报道的COL2α1-Cre ER*；Ihhd/d小鼠在P7出现异位软骨细胞肥大的生长板表型不同，Col2α1-Cre ER*；Ihhd/d；J双突变体生长板排列整齐，基因表达模式与对照组相似。然而，尽管挽救了异常的软骨细胞分化，但成骨细胞标志物和Wnt信号转导靶点Dkk1在COL2α1-Cre ER*；Ihhd/d；J小鼠的骨领中的表达与对照组相比仍然减少。此外，在COL2α1-Cre ER*；Ihhd/d；J小鼠中，软骨细胞的增殖仍然显著受损，这最终导致了P14时生长板的融合。综上所述，我们已经证明，在软骨细胞中表达Jansen受体能够挽救软骨细胞的异常分化，但不会损害软骨细胞的增殖和出生后软骨细胞中IHH基因缺失的小鼠的骨异常。综上所述，我们的研究结果表明，IHH在出生后软骨内骨发育过程中既有PTHrP依赖的功能，也有非独立的功能。
Indian hedgehog (Ihh) is essential for chondrocyte proliferation/differentiation and osteoblast differentiation during prenatal endochondral bone formation. Ihh expression in postnatal chondrocytes has a non-redundant role in maintaining a growth plate and sustaining trabecular bone after birth. Loss of Ihh in postnatal chondrocytes results in fusion of the growth plate and a decrease in trabecular bone. In order to normalize this abnormal chondrocyte phenotype and to investigate whether a putative rescue of the growth plate anomalies is sufficient to correct the severe alterations in the bone, we expressed a constitutively active PTH/PTHrP receptor, (an Ihh downstream target) in the chondrocytes of Col2α1-Cre ER*; Ihhdld mice by mating Col2α1-Cre ER*; Ihhfl/fl mice with Col2α1-constitutively active PTH/PTHrP receptor transgenic mice (Jansen, J). Col2α1-Cre ER*; Ihhf/f; J mice were then injected with tamoxifen at P0 to generate Col2α1-Cre ER*; Ihhd/d; J mice. In contrast with the previously reported growth plate phenotype of Col2α1-Cre ER*; Ihhd/d mice that displayed ectopic chondrocyte hypertrophy at P7, growth plates of Col2α1-Cre ER*; Ihhd/d; J double mutants were well organized, and exhibited a gene expression pattern similar to the one of control mice. However, expression of osteoblast markers and Dkk1, a Wnt signaling target, remain decreased in the bone collar of Col2α1-Cre ER*; Ihhd/d; J mice when compared to control mice despite the rescue of abnormal chondrocyte differentiation. Moreover, proliferation of chondrocytes was still significantly impaired in Col2α1-Cre ER*; Ihhd/d; J mice, and this eventually led to the fusion of the growth plate at P14. In summary, we have demonstrated that expression of a Jansen receptor in chondrocytes was able to rescue abnormal chondrocyte differentiation but not impaired chondrocyte proliferation and the bone anomalies in mice lacking the Ihh gene in chondrocytes after birth. Taken together, our findings suggest that Ihh has both PTHrP -dependent and –independent functions during postnatal endochondral bone development.
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影响因子：
56.9
作者：
Vortkamp, A;Lee, K;Tabin, CJ
通讯作者：
Tabin, CJ
影响因子：
4.6
作者：
Mak, Kinglun Kingston;Kronenberg, Henry M.;Yang, Yingzi
通讯作者：
Yang, Yingzi
影响因子：
56.9
作者：
Lanske, B;Karaplis, AC;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
56.9
作者：
SCHIPANI, E;KRUSE, K;JUPPNER, H
通讯作者：
JUPPNER, H
DOI：
10.1073/pnas.0608449104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Maeda, Yukiko;Nakamura, Eiichiro;Lanske, Beate
通讯作者：
Lanske, Beate