A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth
A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth
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DOI：
10.1242/dmm.013342
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发表时间：
2013-11-01
影响因子：
4.3
通讯作者：
Briggs, Michael D.
中科院分区：
文献类型：
--
作者：
Gualeni, Benedetta;Rajpar, M. Helen;Briggs, Michael D.
导致不同形式软骨发育不良的疾病机制包括细胞外基质（ECM）改变和细胞内应激导致软骨细胞增殖和存活的异常变化。描述这两种疾病机制的相对贡献是理解遗传性骨骼疾病病理生理学的主要挑战，也是开发有效治疗方法的先决条件。为了确定细胞内应激和软骨细胞表型变化对软骨发育不良的影响，我们将G2320R突变型甲状腺球蛋白的表达靶向于静息和增殖软骨细胞的内质网（ER）。先前对这种突变蛋白的研究表明，它诱导细胞内聚集并导致甲状腺细胞应激和死亡。这种外源性突变蛋白在静止和增殖的软骨细胞中的表达和保留导致慢性细胞应激反应、生长板发育不良和骨生长减少，而不会引起软骨ECM的结构和组织的任何改变。更重要的是，骨生长的下降似乎是转基因小鼠生长板增殖区软骨细胞增殖减少的直接结果，而没有经典的未折叠蛋白反应（UPR）或细胞凋亡的转录激活。总的来说，这些数据表明，静息区和增殖区软骨细胞内质网中突变蛋白的保留足以导致骨生长中断。突变蛋白保留触发的特定疾病途径不一定涉及原型UPR，但所有途径都影响软骨生长板中的软骨细胞增殖。
Disease mechanisms leading to different forms of chondrodysplasia include extracellular matrix (ECM) alterations and intracellular stress resulting in abnormal changes to chondrocyte proliferation and survival. Delineating the relative contribution of these two disease mechanisms is a major challenge in understanding disease pathophysiology in genetic skeletal diseases and a prerequisite for developing effective therapies. To determine the influence of intracellular stress and changes in chondrocyte phenotype to the development of chondrodysplasia, we targeted the expression of the G2320R mutant form of thyroglobulin to the endoplasmic reticulum (ER) of resting and proliferating chondrocytes. Previous studies on this mutant protein have shown that it induces intracellular aggregates and causes cell stress and death in the thyroid gland. The expression and retention of this exogenous mutant protein in resting and proliferating chondrocytes resulted in a chronic cell stress response, growth plate dysplasia and reduced bone growth, without inducing any alterations to the architecture and organization of the cartilage ECM. More significantly, the decreased bone growth seemed to be the direct result of reduced chondrocyte proliferation in the proliferative zone of growth plates in transgenic mice, without transcriptional activation of a classical unfolded protein response (UPR) or apoptosis. Overall, these data show that mutant protein retention in the ER of resting and proliferative zone chondrocytes is sufficient to cause disrupted bone growth. The specific disease pathways triggered by mutant protein retention do not necessarily involve a prototypic UPR, but all pathways impact upon chondrocyte proliferation in the cartilage growth plate.