The genetics of osteoarthritis in STR/ort mice.
OBJECTIVE
The complex genetics of osteoarthritis (OA) are still poorly defined. To circumvent the problems of genetic and environmental diversity hampering the analysis in humans, we investigated quantitative trait loci (QTL) associated with murine OA in the STR/ort strain which spontaneously develops osteoarthritic changes of the knee joints, overweight and elevated serum cartilage oligomeric matrix protein (COMP) levels.


METHODS
Two hundred and seventy six male F2 intercross (STR/ortxC57BL/6) animals were genotyped using 96 microsatellite markers and phenotyped by analyzing weight, serum COMP levels and osteoarthritic changes of the knee joints. Quantitative trait analyses were performed using the R/qtl software.


RESULTS
Elevated weight, serum COMP levels and osteoarthritic changes of the knee joints in the F2 generation compared to C57BL/6 parental animals confirm Mendelian inheritance. Quantitative trait analyses revealed three weight-, one serum COMP- and one OA-locus.


CONCLUSIONS
The weight-QTL coincide with previously described genes and QTL involved in fatty acid metabolism and offer a plausible explanation for the observed phenotype in STR/ort mice. The exact match of the COMP-QTL and the COMP gene itself suggests a regulatory polymorphism to account for elevated serum levels in STR/ort mice and questions the robustness of serum COMP as a prognostic marker in human knee OA. The newly identified QTL associated with degenerative changes of the knee joints support the concept of OA resulting from a defective chondrocyte metabolism and/or altered apoptosis rate. However, we also discuss the unlikelihood of one QTL being responsible for OA in STR/ort mice and the inherent limitations of microsatellite analyses for complex genetic diseases.
Jaeger
K
K
Institute of Immunology, University of Rostock, Rostock, Germany.
Selent
C
C
Jaehme
W
W
Mahr
S
S
Goebel
U
U
Ibrahim
S
S
Vollmar
B
B
Mueller-Hilke
B
B
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000235:genetics; D064236:Cartilage Oligomeric Matrix Protein; D003433:Crosses, Genetic; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000097:blood; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000097:blood; D008126:Lod Score; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats; D010003:Osteoarthritis / Q000235:genetics*; D050177:Overweight / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci
D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; C577553:TSP5 protein, human