Circulating levels of IGF-1 directly regulate bone growth and density
Circulating levels of IGF-1 directly regulate bone growth and density
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DOI：
10.1172/jci200215463
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发表时间：
2002-09-01
影响因子：
15.9
通讯作者：
LeRoith, D
中科院分区：
文献类型：
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作者：
Yakar, S;Rosen, CJ;LeRoith, D
IGF-1 是一种生长促进多肽，对于正常生长和发育至关重要。在血清中，大多数 IGF 存在于 150 kDa 复合物中，包括 IGF 分子、IGF 结合蛋白 3 (IGFBP-3) 和酸不稳定亚基 (ALS)。该复合物可延长血清 IGF 的半衰期并促进其内分泌作用。肝脏 IGF-1 缺陷 (LID) 小鼠和 ALS 敲除 (ALSKO) 小鼠表现出相对正常的生长和发育，尽管血清 IGF-1 水平分别降低了 75% 和 65%。通过LID+ALSKO小鼠杂交产生双基因破坏小鼠。这些小鼠的血清 IGF-1 水平进一步降低，线性生长显着降低。 LID+ALSKO小鼠胫骨近端生长板的总高度以及软骨细胞增殖区和肥大区的高度较小。这些小鼠的骨矿物质密度也下降了 10%，骨膜周长和皮质厚度下降了 35% 以上。 IGF-1治疗4周恢复了胫骨近端生长板的总高度。因此，双基因破坏 LID+ALSKO 小鼠模型表明，循环 IGF-1 的阈值浓度对于正常骨骼生长是必需的，并表明 IGF-1、IGFBP-3 和 ALS 在骨质疏松症的病理生理学中发挥着重要作用。
IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.