A novel mice model of acute flares in osteoarthritis elicited by intra-articular injection of cultured mast cells

Junpei Dan,Shogo Takaya,Koji Aso,Takahiro Ushida,Masahiko Ikeuchi,Yusuke Kasai,Hiroko Habuchi,Ryuzo Hayashi,Osami Habuchi,Masashi Izumi

doi:10.1186/s40634-021-00391-6

Junpei Dan, Shogo Takaya + Show 8 more

Open Access

https://doi.org/10.1186/s40634-021-00391-6

Copy DOI

Abstract

PurposeMast cells are multifunctional in osteoarthritis (OA), and infiltration of activated mast cells likely contributes to disease severity and progression. However, the detailed mechanisms of action are unclear. The purpose of this study was to elucidate the role of mast cell infiltration in OA at histological level using a new mice model and to investigate pharmacological inhibitory effects of existing mast cell stabilizers in this model.MethodsMice were injected intra-articularly with monosodium iodoacetate (MIA 0.5 mg) or PBS on day 0, and PBS, with or without mast cells (MC: 1 × 106 cells) on day 14. They were divided into four groups: OA flare (MIA + MC), OA (MIA + PBS), MC non-OA (PBS + MC), and PBS non-OA (PBS + PBS). In OA flare, the MC stabilizer drug (tranilast: 400 mg/kg/day) or PBS was administered intraperitoneally from days 15 to 21.ResultsHistologically, modified Mankin score of the OA flare was significantly higher than that of OA (7.0 [1.8] vs. 3.3 [1.3], P < 0.05), and a larger number of mast cells was observed in OA flare than in OA (34.5 [6.3]/mm2 vs. 27.2 [2.3]/mm2, P < 0.05) on day 22. OA flare also showed acute exacerbation of pain and increased gene expression of pro-inflammatory cytokines and aggrecanase compared with OA. Administration of tranilast to OA flare-up provoked significant improvements in term of histological changes, pain, and gene expression at day 22.ConclusionOur novel model possibly mimics OA flare conditions, which may open a new strategy of disease-modifying treatment for OA, focused on controlling the multiple functions of mast cells.

Highlights

Osteoarthritis (OA) is the most common form of arthritis in the elderly and has long been considered a non-inflammatory condition characterized by progressive degeneration of articular cartilage [9]
Immunofluorescence staining (A) 1 day, (B) 3 days, and (C) 7 days after mast cells (MC) injection showed that MC labelled with Green fluorescent protein (GFP) and mast cell protease-6 (MCP-6) was observed in (A) and (B), which demonstrated that exogenous MC existed at that time
The MC non-OA group showed no pain and paw hyperalgesia, which was comparable to the Phosphate buffered saline (PBS) non-OA group (Fig. 4)

Summary

Introduction

Osteoarthritis (OA) is the most common form of arthritis in the elderly and has long been considered a non-inflammatory condition characterized by progressive degeneration of articular cartilage [9]. A growing body of evidence has shown that local inflammation, that is, synovitis, plays an essential role in the pathophysiology of OA as it is a key predictor of joint failure and a determinant of pain [22]. Infiltration of immune cells into synovial tissue is an important phenomenon in the development and progression of OA. The underlying cellular and molecular mechanisms such as rheumatoid arthritis have not been fully elucidated, the most frequent types of immune cells found in OA joints are macrophages, T cells, and mast cells (MC) [16, 17]. There is limited research in the role of MCs in the pathophysiology of OA as compared to that of macrophages and T cells. Previous reports from the 1990s, showed that the number of MCs increased in the synovium and synovial fluid, which

Objectives

Methods

Results

Discussion

Conclusion