Maeda Yukiko, Nakamura Eiichiro, Nguyen Minh-Thanh, Suva Larry J, Swain Frances L, Razzaque Mohammed S, Mackem Susan, Lanske Beate
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6382-7. doi: 10.1073/pnas.0608449104. Epub 2007 Apr 4.
Indian hedgehog (Ihh) is essential for chondrocyte and osteoblast proliferation/differentiation during prenatal endochondral bone formation. The early lethality of various Ihh-ablated mutant mice, however, prevented further analysis of its role in postnatal bone growth and development. In this study, we describe the generation and characterization of a mouse model in which the Ihh gene was successfully ablated from postnatal chondrocytes in a temporal/spatial-specific manner; postnatal deletion of Ihh resulted in loss of columnar structure, premature vascular invasion, and formation of ectopic hypertrophic chondrocytes in the growth plate. Furthermore, destruction of the articular surface in long bones and premature fusion of growth plates of various endochondral bones was evident, resulting in dwarfism in mutant mice. More importantly, these mutant mice exhibited continuous loss of trabecular bone over time, which was accompanied by reduced Wnt signaling in the osteoblastic cells. These results demonstrate, for the first time, that postnatal chondrocyte-derived Ihh is essential for maintaining the growth plate and articular surface and is required for sustaining trabecular bone and skeletal growth.
印度刺猬因子（Ihh）在产前软骨内成骨过程中对软骨细胞和成骨细胞的增殖/分化至关重要。然而，各种Ihh基因敲除突变小鼠的早期致死性阻碍了对其在出生后骨骼生长和发育中作用的进一步分析。在本研究中，我们描述了一种小鼠模型的构建和特征，在该模型中，Ihh基因以时间/空间特异性方式成功地从出生后的软骨细胞中敲除；Ihh基因在出生后的缺失导致生长板柱状结构丧失、血管过早侵入以及异位肥大软骨细胞形成。此外，长骨关节面破坏以及各种软骨内骨生长板过早融合明显，导致突变小鼠出现侏儒症。更重要的是，这些突变小鼠随着时间的推移小梁骨持续丢失，同时成骨细胞中Wnt信号传导减少。这些结果首次证明，出生后软骨细胞来源的Ihh对于维持生长板和关节面至关重要，并且是维持小梁骨和骨骼生长所必需的。
