Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration.
Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration.
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DOI：
10.1534/g3.113.007302
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发表时间：
2013-11-06
期刊：
影响因子：
--
通讯作者：
Sandell LJ
中科院分区：
文献类型：
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作者：
Rai MF;Schmidt EJ;McAlinden A;Cheverud JM;Sandell LJ
组织再生是一个复杂的性状，几乎没有可用的遗传模型。小鼠品系LG/J和MRL是特殊的治疗者。使用重组近交系从一个大（LG/J，医治者）和小（SM/J，nonhealer）intercross，我们以前已经显示了积极的遗传相关性耳伤口愈合，膝关节软骨再生，并保护骨关节炎。我们假设一组共同的基因在组织愈合和关节软骨再生中起作用。利用重组近交系的存档组织切片，我们通过直接从组织裂解物中的支链DNA技术分析候选基因的表达。我们确定了候选人的广义遗传力，皮尔逊相关的候选人愈合表型，和沃德最小方差聚类分析菌株。还对候选基因内和附近的等位基因多态性进行了生物信息学评估。几个候选的表达是显着的菌株之间的遗传。虽然有几个基因与耳创伤愈合和软骨愈合在边缘水平相关，但代表DNA修复（Xrcc 2，Pcna）和Wnt信号传导（Axin 2，Wnt 16）途径的四个基因的表达与两种表型显著正相关。聚类分析准确地分类愈合者和nonhealers的七个菌株的基因表达的基础上。LG/J和SM/J之间的特定序列差异被确定为潜在的因果多态性。我们的研究表明组织愈合和骨关节炎易感性之间存在共同的遗传基础。绘制遗传变异导致多种组织中不同愈合反应的差异，可能会揭示寻求新的治疗靶点的通用愈合过程，这些靶点旨在诱导或增强再生，并可能保护骨关节炎。
Tissue regeneration is a complex trait with few genetic models available. Mouse strains LG/J and MRL are exceptional healers. Using recombinant inbred strains from a large (LG/J, healer) and small (SM/J, nonhealer) intercross, we have previously shown a positive genetic correlation between ear wound healing, knee cartilage regeneration, and protection from osteoarthritis. We hypothesize that a common set of genes operates in tissue healing and articular cartilage regeneration. Taking advantage of archived histological sections from recombinant inbred strains, we analyzed expression of candidate genes through branched-chain DNA technology directly from tissue lysates. We determined broad-sense heritability of candidates, Pearson correlation of candidates with healing phenotypes, and Ward minimum variance cluster analysis for strains. A bioinformatic assessment of allelic polymorphisms within and near candidate genes was also performed. The expression of several candidates was significantly heritable among strains. Although several genes correlated with both ear wound healing and cartilage healing at a marginal level, the expression of four genes representing DNA repair (Xrcc2, Pcna) and Wnt signaling (Axin2, Wnt16) pathways was significantly positively correlated with both phenotypes. Cluster analysis accurately classified healers and nonhealers for seven out of eight strains based on gene expression. Specific sequence differences between LG/J and SM/J were identified as potential causal polymorphisms. Our study suggests a common genetic basis between tissue healing and osteoarthritis susceptibility. Mapping genetic variations causing differences in diverse healing responses in multiple tissues may reveal generic healing processes in pursuit of new therapeutic targets designed to induce or enhance regeneration and, potentially, protection from osteoarthritis.