Cell cycle progression is disrupted in murine MPS VII growth plate leading to reduced chondrocyte proliferation and transition to hypertrophy.

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 develop adjunct approaches requires an improved 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. Expression of phosphorylated histone H3 was significantly reduced in MPS VII chondrocytes, suggesting less MPS VII chondrocytes progressed to mitotic division. While MPS VII HZ chondrocytes continued to express cyclin D1 and phosphorylated pRb, less MPS VII HZ chondrocytes expressed a marker of cell cycle exit p57kip2, 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 leading to both reduced cell division and transition to the hypertrophic phenotype.

11种黏多糖贮积症（mucopolysaccharidoses, MPS）中有6种会出现软骨内骨生长（endochondral bone growth）异常，进而引发身材矮小、胸腔容积缩减以及手部精细运动能力受损。当前针对MPS的治疗方案对骨生长的改善效果有限，若要开发辅助治疗策略，需进一步阐明MPS患者骨生长异常的潜在分子机制。MPS VII型小鼠模型能够复现人类MPS患者中观察到的长骨与椎骨长度缩短表型。借助该模型，我们发现其生长板（growth plate）出现伸长，但增殖区（proliferative zone）与肥大区（hypertrophic zone）内的软骨细胞（chondrocytes）数量减少。软骨内骨生长在一定程度上受生长板软骨细胞的细胞周期（cell cycle）进出调控。相较于正常小鼠，MPS VII型小鼠的软骨细胞中Ki67（一种细胞周期活跃阶段标志物）的阳性比例更高，提示更多MPS VII型软骨细胞处于细胞周期中。磷酸化组蛋白H3（phosphorylated histone H3）在MPS VII型软骨细胞中的表达水平显著降低，表明MPS VII型软骨细胞向有丝分裂（mitotic division）阶段进展的比例更低。尽管MPS VII型肥大区软骨细胞仍可表达细胞周期蛋白D1（cyclin D1）与磷酸化成视网膜细胞瘤蛋白（phosphorylated pRb），但表达细胞周期退出标志物p57kip2的MPS VII型肥大区软骨细胞数量更少，这意味着能够退出细胞周期的MPS VII型软骨细胞比例更低。此外，MPS VII型小鼠生长板中，增殖区向肥大区转化的多种标志性基因均未出现表达下调，其中尤以Sox9、Pthrpr及Wnt5a最为显著。上述研究结果表明，MPS VII型小鼠生长板的伸长速率慢于正常小鼠，这源于细胞周期进程延迟，进而导致细胞分裂减少以及向肥大表型（hypertrophic phenotype）的转化受阻。