Yakar Shoshana, Canalis Ernesto, Sun Hui, Mejia Wilson, Kawashima Yuki, Nasser Philip, Courtland Hayden-William, Williams Valerie, Bouxsein Mary, Rosen Clifford, Jepsen Karl J
Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
J Bone Miner Res. 2009 Aug;24(8):1481-92. doi: 10.1359/jbmr.090226.
Strong correlations between serum IGF-1 levels and fracture risk indicate that IGF-1 plays a critical role in regulating bone strength. However, the mechanism by which serum IGF-1 regulates bone structure and fracture resistance remains obscure and cannot be determined using conventional approaches. Previous analysis of adult liver-specific IGF-1-deficient (LID) mice, which exhibit 75% reductions in serum IGF-1 levels, showed reductions in periosteal circumference, femoral cross-sectional area, cortical thickness, and total volumetric BMD. Understanding the developmental sequences and the resultant anatomical changes that led to this adult phenotype is the key for understanding the complex relationship between serum IGF-1 levels and fracture risk. Here, we identified a unique developmental pattern of morphological and compositional traits that contribute to bone strength. We show that reduced bone strength associated with low levels of IGF-1 in serum (LID mice) result in impaired subperiosteal expansion combined with impaired endosteal apposition and lack of compensatory changes in mineralization throughout growth and aging. We show that serum IGF-1 affects cellular activity differently depending on the cortical surface. Last, we show that chronic reductions in serum IGF-1 indirectly affect bone strength through its effect on the marrow myeloid progenitor cell population. We conclude that serum IGF-1 not only regulates bone size, shape, and composition during ontogeny, but it plays a more fundamental role-that of regulating an individual's ability to adapt its bone structure to mechanical loads during growth and development.
血清胰岛素样生长因子-1（IGF-1）水平与骨折风险之间的强相关性表明，IGF-1在调节骨强度方面起着关键作用。然而，血清IGF-1调节骨结构和抗骨折能力的机制仍不清楚，无法用传统方法确定。先前对成年肝脏特异性IGF-1缺陷（LID）小鼠的分析显示，其血清IGF-1水平降低了75%，同时骨膜周长、股骨横截面积、皮质厚度和总体积骨密度均有所降低。了解导致这种成年表型的发育序列和由此产生的解剖学变化，是理解血清IGF-1水平与骨折风险之间复杂关系的关键。在此，我们确定了一种有助于骨强度的形态和成分特征的独特发育模式。我们发现，血清IGF-1水平低（LID小鼠）导致的骨强度降低，会导致骨膜下扩张受损，同时骨内膜贴附受损，并且在整个生长和衰老过程中矿化缺乏代偿性变化。我们发现，血清IGF-1根据皮质表面的不同而对细胞活性产生不同影响。最后，我们发现血清IGF-1的长期降低通过其对骨髓髓系祖细胞群体的影响间接影响骨强度。我们得出结论，血清IGF-1不仅在个体发育过程中调节骨的大小、形状和组成，而且在生长和发育过程中发挥着更基本的作用，即调节个体使其骨结构适应机械负荷的能力。
