Wang J, Zhou J, Cheng C M, Kopchick J J, Bondy C A
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892, USA.
J Endocrinol. 2004 Feb;180(2):247-55. doi: 10.1677/joe.0.1800247.
The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-I-dependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.
生长激素（GH）对长骨生长具有独立于胰岛素样生长因子-I（IGF-I）的作用这一可能性长期以来一直存在争议。如果这是真的，那么长骨生长应该会受到GH缺失（因为GH和GH刺激的IGF-I作用都不存在）的影响比单独IGF-I缺失（因为GH仍然存在且实际上升高）更严重。为了验证这一假设，我们比较了Igf1基因靶向缺失小鼠与生长激素受体（Ghr）基因靶向缺失小鼠的长骨生长情况。在出生后第20天至40天之间，Igf1基因敲除小鼠的胫骨线性生长速率降低了约35%，而Ghr基因敲除小鼠降低了约65%，这是正常纵向生长过程中GH作用的高峰期。Igf1基因敲除小鼠的生长板生发层明显增大；软骨细胞增殖和数量正常，但软骨细胞肥大明显减少。相比之下，Ghr基因敲除小鼠的生发层发育不全，软骨细胞增殖和数量明显减少，软骨细胞肥大也减少。我们之前已经证明IGF-II在生长板生发层和增殖区高度表达，所以我们考虑了GH刺激IGF-II产生可能促进Igf1基因敲除小鼠生长板生发层扩张并维持正常增殖的可能性。支持这一观点的是，Igf1基因敲除小鼠生长板中IGF-II mRNA增加，而Ghr基因敲除小鼠生长板中IGF-II mRNA减少。因此，在Igf1基因敲除小鼠完全缺乏IGF-I但GH升高的情况下，软骨细胞肥大的减少似乎是纵向骨生长的主要缺陷。然而，在Ghr基因敲除小鼠完全没有GH作用的情况下，软骨细胞的生成和肥大均受到损害，导致长骨生长出现复合性缺陷。这些观察结果支持了GH在促进纵向骨生长中的双重作用：在生长板软骨细胞生成中具有不依赖IGF-I的作用，以及在促进软骨细胞肥大中具有依赖IGF-I的作用。然而，GH是否对软骨细胞生成有直接作用的问题仍然没有解决，因为现在看来IGF-II可能介导了其中一些对生长板的作用。
