title: Molecular insight into the association between cartilage regeneration and ear wound healing in genetic mouse models: targeting new genes in regeneration.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110.
authors.forename: Muhammad Farooq
authors.initials: MF
authors.lastname: Rai
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Schmidt
authors.forename: Audrey
authors.initials: A
authors.lastname: McAlinden
authors.forename: James M
authors.initials: JM
authors.lastname: Cheverud
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Sandell
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000502:physiology*; D019295:Computational Biology; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004423:Ear / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008957:Models, Genetic; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D059467:Transcriptome; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D018809:Proliferating Cell Nuclear Antigen; D051153:Wnt Proteins; C585687:Wnt16 protein, mouse; C491866:Xrcc2 protein, mouse
keywords: QuantiGene Plex assay; articular cartilage; osteoarthritis; recombinant inbred lines; tissue regeneration