Wu Shufang, Yang Wei, De Luca Francesco
Section of Endocrinology and Diabetes (S.W., F.D.L.), St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134; and Center for Translational Medicine (S.W., W.Y.), the First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, People's Republic of China.
Endocrinology. 2015 Jul;156(7):2541-51. doi: 10.1210/en.2014-1983. Epub 2015 Apr 24.
GH stimulates growth plate chondrogenesis and longitudinal bone growth directly at the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2. To determine whether GH has any IGF-independent growth-promoting effects, we generated (TamCart)Igf1r(flox/flox) mice. The systemic injection of tamoxifen in these mice postnatally resulted in the excision of the IGF-1 receptor (Igf1r) gene exclusively in the growth plate. (TamCart)Igf1r(flox/flox) tamoxifen-treated mice [knockout (KO) mice] and their Igf1r(flox/flox) control littermates (C mice) were injected for 4 weeks with GH. At the end of the 4-week period, the tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice. The systemic injection of GH increased the phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 5B in the tibial growth plate of the C and KO mice. In addition, GH increased the mRNA expression of bone morphogenetic protein-2 and the mRNA expression and protein phosphorylation of nuclear factor-κB p65 in both C and KO mice. In cultured chondrocytes transfected with Igf1r small interfering RNA, the addition of GH in the culture medium significantly induced thymidine incorporation and collagen X mRNA expression. In conclusion, our findings demonstrate that GH can promote growth plate chondrogenesis and longitudinal bone growth directly at the growth plate, even when the local effects of IGF-1 and IGF-2 are prevented. Further studies are warranted to elucidate the intracellular molecular mechanisms mediating the IGF-independent, growth-promoting GH effects.
生长激素（GH）直接在生长板刺激生长板软骨形成和纵向骨生长。然而，这些作用是否完全由胰岛素样生长因子-1（IGF-1）和胰岛素样生长因子-2（IGF-2）的局部表达和作用介导，目前尚不清楚。为了确定GH是否具有任何不依赖IGF的促生长作用，我们构建了（TamCart）Igf1r（flox/flox）小鼠。在这些小鼠出生后全身注射他莫昔芬，导致IGF-1受体（Igf1r）基因仅在生长板中被切除。对（TamCart）Igf1r（flox/flox）他莫昔芬处理的小鼠[敲除（KO）小鼠]及其Igf1r（flox/flox）对照同窝小鼠（C小鼠）注射GH 4周。在4周结束时，经GH处理的KO小鼠的胫骨生长和生长板高度大于未处理的C小鼠或未处理的KO小鼠。全身注射GH增加了C小鼠和KO小鼠胫骨生长板中Janus激酶2的磷酸化以及信号转导和转录激活因子5B的磷酸化。此外，GH增加了C小鼠和KO小鼠中骨形态发生蛋白-2的mRNA表达以及核因子-κB p65的mRNA表达和蛋白磷酸化。在用Igf1r小干扰RNA转染的培养软骨细胞中，向培养基中添加GH可显著诱导胸苷掺入和胶原蛋白X mRNA表达。总之，我们的研究结果表明，即使IGF-1和IGF-2的局部作用被阻断，GH仍可直接在生长板促进生长板软骨形成和纵向骨生长。有必要进行进一步研究以阐明介导不依赖IGF、促进生长的GH作用的细胞内分子机制。
