Endochondral bone growth is abnormal in 6 of the 11 types of mucopolysaccharidoses (MPS) disorders; resulting in short stature, reduced size of the thoracic cavity and compromised manual dexterity. Current therapies for MPS have had a limited effect on bone growth and to improve these therapies or develop adjunct approaches requires an understanding of the underlying basis of abnormal bone growth in MPS. The MPS VII mouse model replicates the reduction in long bone and vertebral length observed in human MPS. Using this model we have shown that the growth plate is elongated but contains fewer chondrocytes in the proliferative and hypertrophic zones. Endochondral bone growth is in part regulated by entry and exit from the cell cycle by growth plate chondrocytes. More MPS VII chondrocytes were positive for Ki67, a marker for active phases of the cell cycle, suggesting that more MPS VII chondrocytes were in the cell cycle. The number of cells positive for phosphorylated histone H3 was significantly reduced in MPS VII chondrocytes, suggesting fewer MPS VII chondrocytes progressed to mitotic division. While MPS VII HZ chondrocytes continued to express cyclin D1 and more cells were positive for E2F1 and phos pRb than normal, fewer MPS VII HZ chondrocytes were positive for p57kip2 a marker of terminal differentiation, suggesting fewer MPS VII chondrocytes were able to exit the cell cycle. In addition, multiple markers typical of PZ to HZ transition were not downregulated in MPS VII, in particular Sox9, Pthrpr and Wnt5a. These findings are consistent with MPS VII growth plates elongating at a slower rate than normal due to a delay in progression through the cell cycle, in particular the transition between G1 and S phases, leading to both reduced cell division and transition to the hypertrophic phenotype.

中文翻译：

---

小鼠 MPS VII 生长板中的细胞周期进程被破坏，导致软骨细胞增殖减少并过渡到肥大

在 11 种粘多糖症 (MPS) 疾病中，有 6 种的软骨内骨生长异常；导致身材矮小、胸腔缩小和手部灵活性受损。目前的 MPS 疗法对骨生长的影响有限，为了改进这些疗法或开发辅助方法，需要了解 MPS 异常骨生长的潜在基础。MPS VII 小鼠模型复制了在人类 MPS 中观察到的长骨和椎骨长度的减少。使用这个模型，我们已经表明生长板被拉长，但在增殖和肥大区包含较少的软骨细胞。软骨内骨生长部分受生长板软骨细胞进入和退出细胞周期的调节。更多的 MPS VII 软骨细胞对 Ki67 呈阳性，细胞周期活跃期的标志物，表明更多的 MPS VII 软骨细胞处于细胞周期中。MPS VII 软骨细胞中磷酸化组蛋白 H3 呈阳性的细胞数量显着减少，表明进展到有丝分裂的 MPS VII 软骨细胞较少。虽然 MPS VII HZ 软骨细胞继续表达细胞周期蛋白 D1，并且 E2F1 和 phos pRb 呈阳性的细胞比正常细胞多，但较少的 MPS VII HZ 软骨细胞对 p57kip2（一种终末分化的标志物）呈阳性，这表明能够退出细胞周期的 MPS VII 软骨细胞较少. 此外，在 MPS VII 中，典型的 PZ 到 HZ 转变的多个标记没有下调，特别是 Sox9、Pthrpr 和 Wnt5a。