Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Abstract

Objective: To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy.

Methods: MRL, DBA/1, (MRL x DBA/1)F(1), and (MRL x DBA/1)F(2) intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0-3 and 0-5 scale, respectively). A genome-wide scan of 271 male F(2) intercross mice with polymorphic microsatellite markers was performed.

Results: Only male DBA/1, (MRL x DBA/1)F(1), and (MRL x DBA/1)F(2) mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F(2) mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F(2) mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy.

Conclusion: Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/MpJ-lpr/lpr mice.