The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress–associated dwarfism MCDS.

中文翻译：

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细胞内蛋白水解的增加降低了内质网应激相关性侏儒症的疾病严重性

Schmid型短肢侏儒干meta端软骨发育不良（MCDS）与X型胶原蛋白的突变有关，后者通过诱导突变蛋白的错误折叠并随后破坏肥大的软骨细胞分化而增加了ER应激。在这里，我们显示了卡马西平（CBZ），一种自噬刺激药物，已在临床上批准用于治疗癫痫和双相性疾病，可减轻人细胞培养物中4种不同的MCDS突变型胶原X引起的ER应激。取决于突变的性质，CBZ的应用通过自噬或蛋白酶体降解来刺激错折叠的胶原蛋白X的蛋白水解，从而减少突变胶原蛋白的细胞内积累。在MCDS小鼠中表达Col10a1。pN617K突变，CBZ减少了MCDS相关的生长板肥大区的扩张，减弱了ER应激标志物（如Bip和Atf4）的增强表达，增加了骨生长并减少了骨骼发育不良。CBZ通过减少肥大性软骨细胞分化中与MCDS相关的异常产生了这些有益的作用。因此，使用CBZ治疗刺激细胞内蛋白水解可能是治疗与ER应激相关的侏儒症MCDS的临床可行方法。