J:233293

The focus of the current study was to identify quantitative trait loci (QTL) for the osteoarthritis (OA) phenotype. Osteoarthritis is the most common joint disorder in humans. The mouse strain STR/Ort is recognized as a spontaneous model of OA. The STR/Ort mouse is unique in that it develops late onset cartilage degeneration of the tibio-femoral joint, similar to human OA.

Male (C57BL/6N x STR/Ort)F1 mice were backcrossed with female C57BL/6N to generate backcrossed progeny. C57BL/6N was selected since it was the best propagating partner of the STR/Ort mouse and it exhibited the lowest incidence of cartilage degeneration among the strains tested. At 45-50 weeks cartilage degeneration was analyzed in F1 and BC mice.

Both left and right cartilages were analyzed and the maximum score between the cartilages for each mouse was used as the score. Global images of the tibial articular cartilage were used to improve the efficiency and accuracy of phenotyping.

To map loci microsatellite markers that discriminated between STR/Ort and C57BL/6N alleles were used. More than 400 markers for both alleles were genotyped. For the genome-wide QTL analysis, 122 autosomal microsatellite markers were selected; their positions were based on the genetic map on the Whitehead Institute web site. The average spacing of the markers was 9.5 cM. QTL analysis was performed using Map Manager QTX which generates a likelihood ratio statistic (LRS) for each marker. A test of 10,000 permutations was used to determine significance; LRSs>11.8 (p<0.05) was considered significant. The LRS was covered to a LOD score by dividing by 4.6. Additional informative markers were selected to further define a locus interval for regions showing significant deviation in genotype distribution. Male mice were used in the analysis since the penetrance of the OA phenotype of STR/Ort mice is higher in males than females.

QTL analysis of 199 male, backcrossed mice detected significant QTL on Chromosomes 4 and 5. Table 2:

QTL Jcdq1 (joint cartilage degeneration QTL 1) mapped to Chromosome 4, LRS=15.0, LOD=3.26, p=0.0085, at peak marker D4Mit97 (10.9 cM). The STR/Ort allele at Jcdq1 increased the risk of cartilage degeneration. The chromosomal region contains several genes including Mmp16, Gdf6, Map3k7 and Tgfbr1.

QTL Jcdq2 (joint cartilage degeneration QTL 2) mapped to Chromosome 5, LRS=14.0, LOD=3.04, p=0.0147 at peak marker D5Mit223 (77.6 cM). The C57BL/6N allele at Jcdq2 increased the risk of cartilage degeneration. To the author's knowledge this was the first description of a locus in C57BL/6 mice that was significantly related the cartilage degeneration.