Kronenberg H M, Chung U
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Novartis Found Symp. 2001;232:144-52; discussion 152-7. doi: 10.1002/0470846658.ch10.
Normal development of the growth plate requires coordinated proliferation and differentiation of chondrocytes and osteoblasts. In previous work, we have shown that Indian hedgehog (IHH), produced by prehypertrophic and hypertrophic chondrocytes, stimulates production of parathyroid hormone-related protein (PTHrP) by perichondrial and early chondrocytic cells. PTHrP then maintains chondrocytes in a proliferative, less differentiated state. Because this less differentiated state delays the production of IHH, IHH and PTHrP may participate in a negative feedback loop that synchronizes and determines the pace of differentiation of chondrocytes in the growth plate. To establish the roles of physiological levels of PTHrP and IHH, we have now injected PTH/PTHrP receptor (-/-) embryonic stem (ES) cells into normal blastocysts to generate mice with chimeric growth plates. The PTH/PTHrP receptor cells leave the proliferative cycle and differentiate prematurely in the middle of the normal proliferative columns. The columns of wild-type cells are longer than normal and the adjacent bone collar is also longer than normal. Patterns of gene expression and the use of chimeras using PTH/PTHrP receptor (-/-); IHH (-/-) ES cells suggest that modified patterns of IHH and PTHrP synthesis explain these abnormalities. Thus, IHH is a master regulator of both chondrocyte and osteoblast differentiation.
生长板的正常发育需要软骨细胞和成骨细胞的增殖与分化相互协调。在之前的研究中，我们发现由前肥大和肥大软骨细胞产生的印度刺猬因子（IHH）可刺激软骨膜和早期软骨细胞产生甲状旁腺激素相关蛋白（PTHrP）。然后，PTHrP使软骨细胞维持在增殖性、低分化状态。由于这种低分化状态会延迟IHH的产生，因此IHH和PTHrP可能参与一个负反馈回路，该回路可同步并决定生长板中软骨细胞的分化速度。为了确定生理水平的PTHrP和IHH的作用，我们现在已将PTH/PTHrP受体（-/-）胚胎干细胞注射到正常囊胚中，以生成具有嵌合生长板的小鼠。PTH/PTHrP受体细胞在正常增殖柱的中部提前离开增殖周期并过早分化。野生型细胞柱比正常的长，相邻的骨环也比正常的长。基因表达模式以及使用PTH/PTHrP受体（-/-）；IHH（-/-）胚胎干细胞的嵌合体表明，IHH和PTHrP合成模式的改变解释了这些异常情况。因此，IHH是软骨细胞和成骨细胞分化的主要调节因子。
