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/jci15463
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发表时间：
2002-09
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影响因子：
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通讯作者：
S. Yakar;C. Rosen;W. Beamer;C. Ackert-Bicknell;Yiping Wu;Jun-li Liu;G. Ooi;Jennifer Setser;J. Frystyk;Y. Boisclair;D. Leroith
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文献类型：
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作者：
S. Yakar;C. Rosen;W. Beamer;C. Ackert-Bicknell;Yiping Wu;Jun-li Liu;G. Ooi;Jennifer Setser;J. Frystyk;Y. Boisclair;D. Leroith
IGF-1是一种促进生长的多肽，对正常生长和发育至关重要。在血清中，大多数IGFs存在于150-kDa的复合物中，包括IGF分子、IGF结合蛋白3（IGFBP-3）和酸不稳定亚基（ALS）。这种复合物延长了血清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%。通过杂交LID+ALSKO小鼠产生双基因破坏的小鼠。这些小鼠表现出血清IGF-1水平的进一步降低和线性生长的显著降低。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。在这些小鼠中，骨矿物质密度也降低10%，骨膜周长和皮质厚度降低35%以上。IGF-1治疗4周恢复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的阈值浓度是正常骨生长所必需的，并表明IGF-1、IGFBP-3和ALS在骨质疏松症的病理生理学中起着重要作用。
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.