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 ؋ DBA/1)F 1 , and (MRL ؋ 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 ؋ DBA/1)F 1 , and (MRL ؋ 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.

Interleukin-17 is a critical target for the treatment of ankylosing enthesitis and psoriasis-like dermatitis in mice

“…The affected ankles obtained from these mice commonly displayed histopathological characteristics of the tarsal ankylosis: ossification of and chondrocyte proliferation in the tarsal joints, enthesis and periosteum around the calcaneocuboid joint, resulting in loss of joint structure of the tarsal region (data not shown). These findings largely follow the observations previously reported in aged male DBA/1 mice [24]. In the advanced stages, remarkable periosteal thickening with chondrocyte proliferation was observed in the metatarsal bones, suggesting the onset of dactylitis.…”

“…Aged male DBA/1 mice caged together develop T cellindependent ankylosing enthesitis that is histopathologically similar to human AS or PsA [24][25][26][27]. In the present study, and in accordance with data from human cases of SpA, circulating IL-17 levels elevate as age of male DBA/1 mice caged together, and they readily and spontaneously develop psoriasis-like dermatitis with ankylosing enthesitis.…”

“…Male DBA/1 mice caged together spontaneously develop ankylosis with pathological and clinical similarities to human AS [24][25][26]. An experimental approach using this model has provided evidence that a TNFa signaling blockade using a soluble TNF receptor (Etanercept) has little impact on the incidence, severity and progression of spontaneous arthritis in male DBA/1 mice [26], indicating that other critical pathogenic pathways are involved.…”

Characterization of histopathology and gene-expression profiles of synovitis in early rheumatoid arthritis using targeted biopsy specimens

“…This was highly expressed in group I in this study. Itgb2 was a candidate gene for enthesopathy [31] and coincidentally for sialoadenitis [32], and was also highly expressed in group I.…”

A non-major histocompatibility locus determines tissue specificity in the pathogenic process underlying synovial proliferation in a mouse arthropathy model

“…Although the remodelling process for ankylosis has not been completely characterised, recent studies using rodent ankylosis models have evaluated the pathological proliferation of a particular region, where a joint capsule or ligament attaches to a bone. [1][2][3][4] The histological characteristics are proliferation, cartilage formation and, subsequently, replacement of cartilage by bone, a process typical of endochondral bone formation. The process is called ankylosing enthesitis.…”