Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP.

Hiroko Habuchi,Takahiro Ushida,Kosei Takeuchi,Masashi Izumi,Osami Habuchi,Masahiko Ikeuchi,Junpei Dan,Rosanna Di Paola

doi:10.1371/journal.pone.0252590

Hiroko Habuchi, Takahiro Ushida + Show 6 more

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https://doi.org/10.1371/journal.pone.0252590

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Journal: PloS one	Publication Date: Jun 4, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Aichi Medical University, Kōchi University

Abstract

Conditions that resemble osteoarthritis (OA) were produced by injection of sodium monoiodoacetate (MIA) into the knee joints of mice. Bone marrow derived mast cells (BMMCs) injected into the OA knee joints enhanced spontaneous pain. Since no spontaneous pain was observed when BMMCs were injected into the knee joints of control mice that had not been treated with MIA, BMMCs should be activated within the OA knee joints and release some pain-inducible factors. Protease activated receptor-2 (PAR2) antagonist (FSLLRY-NH2) almost abolished the pain-enhancing effects of BMMCs injected into the OA knee joints, suggesting that tryptase, a mast cell protease that is capable of activating PAR2, should be released from the injected BMMCs and enhance pain through activation of PAR2. When PAR2 agonist (SLIGKV-NH2) instead of BMMCs was injected into the OA knee joints, it was also enhanced pain. Apyrase, an ATP degrading enzyme, injected into the OA knee joints before BMMCs suppressed the pain enhanced by BMMCs. We showed that purinoceptors (P2X4 and P2X7) were expressed in BMMCs and that extracellular ATP stimulated the release of tryptase from BMMCs. These observations suggest that ATP may stimulate degranulation of BMMCs and thereby enhanced pain. BMMCs injected into the OA knee joints stimulated expression of IL-1β, IL-6, TNF-α, CCL2, and MMP9 genes in the infrapatellar fat pads, and PAR2 antagonist suppressed the stimulatory effects of BMMCs. Our study suggests that intermittent pain frequently observed in OA knee joints may be due, at least partly, to mast cells through activation of PAR2 and action of ATP, and that intraarticular injection of BMMCs into the OA knee joints may provide a useful experimental system for investigating molecular mechanisms by which pain is induced in OA knee joints.

Highlights

Osteoarthritis (OA) is the most prevalent chronic joint disease and is a leading cause of impairment of mobility in the elderly population
The cells that were positive to both GFP and mMCP-6 were localized near the synovial membrane in both group A and C, indicating that injected Bone marrow derived mast cells (BMMCs) were retained within the knee joints
A portion of the mMCP6-positive cells showed shapes characteristic of the degranulated BMMCs (Fig 5d, inset). These observations seem to support the idea that BMMCs retained in the joint space of the OA knee joints were activated and released some factors that are capable of inducing pain

Summary

Introduction

Osteoarthritis (OA) is the most prevalent chronic joint disease and is a leading cause of impairment of mobility in the elderly population. It is important to clear the cause and mechanisms of pain in OA for developing better therapies to help reduce symptoms and improve function. Mast cells and their mediators are known to exist in synovium and synovial fluids of OA patients and are suggested to be involved in pathogenesis of OA [2,3,4,5,6,7]. Tryptase could activate protease activated receptor 2 (PAR2) on the plasma membrane of various cells and the activation of PAR2 was reported to be involved in the development of OA and pain generation [10, 11]. ATP has been reported to stimulate degranulation of mast cells [14, 15] and behave as a chemoattractant for mast cells [16]

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