Oichi Takeshi, Kodama Joe, Wilson Kimberly, Tian Hongying, Imamura Kawasawa Yuka, Usami Yu, Oshima Yasushi, Saito Taku, Tanaka Sakae, Iwamoto Masahiro, Otsuru Satoru, Enomoto-Iwamoto Motomi
Department of Orthopedics, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.
Sensory & Motor System Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 1138655, Japan.
Bone Res. 2023 Apr 21;11(1):20. doi: 10.1038/s41413-023-00258-9.
Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate, where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone. The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate. Malnutrition is a leading cause of growth retardation in children; however, after recovery from nutrient deprivation, bone growth is accelerated beyond the normal rate, a phenomenon termed catch-up growth. Although nutritional status is a known regulator of long bone growth, it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient availability. Here, using fate-mapping analysis in Axin2Cre mice, we showed that dietary restriction increased the number of Axin2 chondroprogenitors in the resting zone and simultaneously inhibited their differentiation. Once nutrient deficiency was resolved, the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns, contributing to accelerated growth. Furthermore, we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors, decreasing their numbers. Our study of Axin2Cre revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.
纵向骨生长依赖于软骨生长板中的软骨内成骨，软骨细胞在该生长板中聚集并合成被骨替代的基质支架。静止区的软骨祖细胞维持生长板中软骨细胞的持续更新。营养不良是儿童生长发育迟缓的主要原因；然而，从营养缺乏中恢复后，骨生长会加速超过正常速度，这一现象称为追赶生长。尽管营养状况是长骨生长的已知调节因子，但软骨祖细胞是否以及如何对营养可利用性的偏差做出反应在很大程度上尚不清楚。在这里，我们利用Axin2Cre小鼠的命运图谱分析表明，饮食限制增加了静止区Axin2软骨祖细胞的数量，同时抑制了它们的分化。一旦营养缺乏得到解决，积累的软骨祖细胞立即重新开始分化并形成软骨细胞柱，促进生长加速。此外，我们表明营养剥夺降低了静止区磷酸化Akt的水平，而外源性IGF-1恢复了磷酸化Akt的水平并刺激了汇集的软骨祖细胞的分化，减少了它们的数量。我们对Axin2Cre的研究表明，营养可利用性调节生长板中软骨祖细胞积累与分化之间的平衡，并进一步证明IGF-1通过促进软骨祖细胞的定向分化部分介导了这种调节。
