Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate.
Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate.
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DOI：
10.1038/s41413-023-00258-9
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发表时间：
2023-04-21
期刊：
影响因子：
12.7
通讯作者：
Enomoto-Iwamoto, Motomi
中科院分区：
文献类型：
--
作者：
Oichi, Takeshi;Kodama, Joe;Wilson, Kimberly;Tian, Hongying;Kawasawa, Yuka Imamura;Usami, Yu;Oshima, Yasushi;Saito, Taku;Tanaka, Sakae;Iwamoto, Masahiro;Otsuru, Satoru;Enomoto-Iwamoto, Motomi
纵向骨生长依赖于软骨生长板中的软骨内骨化，其中软骨细胞积累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迟缓的主要原因;然而，从营养缺乏中恢复后，骨骼生长加速超过正常速度，这种现象称为追赶性生长。虽然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用性的偏差做出反应在很大程度上是未知的。在这里，使用Axin 2CreERT 2小鼠的命运映射分析，我们发现饮食限制增加了静息区Axin 2+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，有助于加速生长。此外，我们发现，营养剥夺降低了静息区磷酸化Akt的水平，外源性IGF-1恢复了磷酸化Akt的水平，刺激了合并的软骨祖细胞的分化，减少了它们的数量。我们对Axin 2CreERT 2的研究表明，营养物质的可利用性调节生长板中软骨祖细胞的积累和分化之间的平衡，并进一步证明IGF-1通过促进软骨祖细胞的定向分化来部分介导这种调节。
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 Axin2CreERT2 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 Axin2CreERT2 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.
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