Inflammation and bone remodeling in the delayed-type hypersensitivity (DTH) arthritis model

TY - ABST

T1 - Inflammation and bone remodeling in the delayed-type hypersensitivity (DTH) arthritis model

AU - Atkinson, Sara Marie

AU - Thorn, Mette

AU - Autzen Usher, Pernille

AU - Fox, Brian

AU - Serikawa, Kyle

AU - Biswas, Shameek

AU - Haase, Claus

AU - Skov, Søren

AU - Nansen, Anneline

PY - 2013

Y1 - 2013

N2 - Background: Rheumatoid arthritis (RA) is a destructive autoimmune disease characterised by joint inflammation and bone erosion. To better understand RA various experimental arthritis models have been developed in inbred mouse strains. DTH arthritis is a newly established arthritis model in C57BL/6 mice affecting one hind paw. It is induced by modifying a protein Ag-induced DTH response by administering anti-type II collagen antibodies between immunisation and challenge. This leads to arthritis with synchronised onset, 100% incidence and low variation [1]. The mono-paw phenotype makes the model suitable for analysis of inflammation and bone destruction, as the unaffected hind paw can be used as an intra-animal control. Objectives: The purpose of this study was to improve our understanding of DTH arthritis-associated inflammation and bone destruction. Methods: A histopathological scoring system for paws was established and histopathological analysis carried out on arthritic animals. Paw homogenates were analysed for a range of cytokines/chemokines using bioplex. An mRNA expression analysis was performed using deep sequencing techniques. Fluorescence molecular tomography (FMT) was used to in vivo image cathepsin K activity and bisphosphonate incorporation as a measure of bone remodeling. Arthritic mice were treated with anti-TNFα mAb and their paws scored histopathologically and serum analysed for inflammatory biomarkers. Results: In the affected paw we observed osteoclast activation, bone erosion/remodelling, and cartilage destruction. FMT revealed increased cathepsin K activity and bisphosphonate incorporation in the affected paw. Serum levels of systemic inflammatory biomarkers were increased in arthritic mice, and levels of several protein and mRNA markers associated with inflammation and bone erosion were increased in the paw. Treatment with anti-TNFα led to a decrease in the histopathological score and levels of protein biomarkers in serum. Conclusions: The present study verified the arthritic phenotype of DTH arthritis and identified several potentially useful biomarkers of inflammation and bone erosion, and together the results indicate that DTH arthritis shares features with RA. We believe these results provide highly valuable model insights from which efforts into development of novel biologics targeting RA can benefit. References: 1. Atkinson SM, Usher PA, Kvist PH, Markholst H, Haase C, Nansen A: Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice. Arthritis Res Ther 2012, 14:R134.

AB - Background: Rheumatoid arthritis (RA) is a destructive autoimmune disease characterised by joint inflammation and bone erosion. To better understand RA various experimental arthritis models have been developed in inbred mouse strains. DTH arthritis is a newly established arthritis model in C57BL/6 mice affecting one hind paw. It is induced by modifying a protein Ag-induced DTH response by administering anti-type II collagen antibodies between immunisation and challenge. This leads to arthritis with synchronised onset, 100% incidence and low variation [1]. The mono-paw phenotype makes the model suitable for analysis of inflammation and bone destruction, as the unaffected hind paw can be used as an intra-animal control. Objectives: The purpose of this study was to improve our understanding of DTH arthritis-associated inflammation and bone destruction. Methods: A histopathological scoring system for paws was established and histopathological analysis carried out on arthritic animals. Paw homogenates were analysed for a range of cytokines/chemokines using bioplex. An mRNA expression analysis was performed using deep sequencing techniques. Fluorescence molecular tomography (FMT) was used to in vivo image cathepsin K activity and bisphosphonate incorporation as a measure of bone remodeling. Arthritic mice were treated with anti-TNFα mAb and their paws scored histopathologically and serum analysed for inflammatory biomarkers. Results: In the affected paw we observed osteoclast activation, bone erosion/remodelling, and cartilage destruction. FMT revealed increased cathepsin K activity and bisphosphonate incorporation in the affected paw. Serum levels of systemic inflammatory biomarkers were increased in arthritic mice, and levels of several protein and mRNA markers associated with inflammation and bone erosion were increased in the paw. Treatment with anti-TNFα led to a decrease in the histopathological score and levels of protein biomarkers in serum. Conclusions: The present study verified the arthritic phenotype of DTH arthritis and identified several potentially useful biomarkers of inflammation and bone erosion, and together the results indicate that DTH arthritis shares features with RA. We believe these results provide highly valuable model insights from which efforts into development of novel biologics targeting RA can benefit. References: 1. Atkinson SM, Usher PA, Kvist PH, Markholst H, Haase C, Nansen A: Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice. Arthritis Res Ther 2012, 14:R134.

U2 - 10.1111/sji.12036

DO - 10.1111/sji.12036

M3 - Conference abstract in journal

SN - 0301-6323

VL - 77

SP - 304

JO - Scandinavian Journal of Immunology, Supplement

JF - Scandinavian Journal of Immunology, Supplement

IS - 4

ER -