Persistence of intracellular and extracellular changes after incompletely suppressing expression of the R789C (p.R989C) and R992C (p.R1192C) collagen II mutants.
Persistence of intracellular and extracellular changes after incompletely suppressing expression of the R789C (p.R989C) and R992C (p.R1192C) collagen II mutants.
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DOI：
10.1002/humu.21506
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发表时间：
2011-07
期刊：
影响因子：
3.9
通讯作者：
Fertala, Andrzej
中科院分区：
文献类型：
--
作者：
Jensen, Deborah A.;Steplewski, Andrzej;Gawron, Katarzyna;Fertala, Andrzej
COL2A1 突变会产生一系列疾病，其标志特征是骨骼发育的改变。由于无法选择性抑制突变等位基因，并且无法输送足够数量的表达野生型胶原蛋白的细胞，因此在分子水平上抵消胶原蛋白突变影响的尝试相对无效。此外，这些方法受到阻碍，因为尚不清楚允许细胞外基质重塑和细胞从应激中恢复的最低治疗条件。在这里，我们采用四环素诱导系统来表达 R789C 或 R992C 胶原蛋白 II 突变体，使我们能够将突变蛋白的产量相对于初始产量减少 25%、50%、75% 或 100%。通过对细胞内和细胞外参数的分析，我们表明，只有当突变胶原蛋白的 100% 表达被关闭时，受影响的细胞/基质系统才能从突变引起的畸变中恢复，但如果系统中持续存在少量突变分子的表达则无法恢复。我们的数据表明，受不耐热胶原蛋白突变体影响的组织的有效重塑可能取决于它们的完全消除而不是部分减少。
Mutations in COL2A1 produce a spectrum of disorders whose hallmark feature is alterations in skeletal development. Attempts to counteract the effects of collagen mutations at the molecular level have been relatively ineffective due to the inability to selectively suppress a mutant allele, and failure to deliver a sufficient number of cells expressing wild-type collagen. Moreover, these approaches are hampered because the minimal therapeutic conditions that would allow extracellular matrix remodeling and recovery of cells from stress are not known. Here, we employed a tetracycline-inducible system for expressing the R789C or R992C collagen II mutants, allowing us to decrease the production of mutant proteins by 25, 50, 75, or 100% with respect to their initial production. Through analysis of intracellular and extracellular parameters we have shown that affected cell/matrix systems are able to recover from mutation-induced aberrations only when 100% expression of mutant collagens is shut off, but not if the expression of small amounts of mutant molecules persists in the system. Our data suggest that efficient remodeling of tissues affected by the presence of thermolabile collagen mutants may depend on their complete elimination rather than on partial reduction.
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影响因子：
6.2
作者：
Donahue, LR;Chang, B;Davisson, MT
通讯作者：
Davisson, MT
影响因子：
4
作者：
Hoornaert, KP;Dewinter, C;Mortier, GR
通讯作者：
Mortier, GR
影响因子：
14.9
作者：
Dawson, PA;Marini, JC
通讯作者：
Marini, JC
影响因子：
82.9
作者：
Horwitz, EM;Prockop, DJ;Brenner, MK
通讯作者：
Brenner, MK
DOI：
10.1073/pnas.132252399
发表时间：
2002-06-25
影响因子：
11.1
作者：
Horwitz, EM;Gordon, PL;Hofmann, T
通讯作者：
Hofmann, T