Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain.

Freija Ter Heegde,Chantal Chenu,Fraser Welsh,Sonia Santana‐Varela,Iain P Chessell,John N Wood,Ana P Luiz

doi:10.1002/art.40835

Abstract

ObjectiveMechanisms responsible for osteoarthritic (OA) pain remain poorly understood, and current analgesic therapies are often insufficient. This study was undertaken to characterize and pharmacologically test the pain phenotype of a noninvasive mechanical joint loading model of OA, thus providing an alternative murine model for OA pain.MethodsThe right knees of 12‐week‐old male C57BL/6 mice were loaded at 9N or 11N (40 cycles, 3 times per week for 2 weeks). Behavioral measurements of limb disuse and mechanical and thermal hypersensitivity were acquired before mechanical joint loading and monitored for 6 weeks postloading. The severity of articular cartilage lesions was determined postmortem with the Osteoarthritis Research Society International scoring system. To assess efficacy of various treatments for pain, 9N‐loaded mice were treated for 4 weeks with diclofenac (10 mg/kg), gabapentin (100 mg/kg), or anti–nerve growth factor (anti‐NGF) (3 mg/kg).ResultsMechanical hypersensitivity and weight bearing worsened significantly in 9N‐loaded mice (n = 8) and 11N‐loaded mice (n = 8) 2 weeks postloading, compared to baseline values and nonloaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N‐loaded mice (mean ± SEM 2.8 ± 0.2; P < 0.001) and 11N‐loaded mice (5.3 ± 0.3; P < 0.001), compared to nonloaded controls (1.0 ± 0.0). Gabapentin and diclofenac restored pain behaviors to baseline values after 2 weeks of daily treatment, and gabapentin was more effective than diclofenac. A single injection of anti‐NGF alleviated nociception 2 days after treatment and remained effective for 2 weeks, with a second dose inducing stronger and more prolonged analgesia.ConclusionOur findings show that mechanical joint loading induces OA lesions in mice and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of mechanical joint loading as an alternative model for the study of OA pain.

Highlights

Osteoarthritis (OA) is a common degenerative joint disease associated with chronic, debilitating pain in the affected joints which significantly reduces mobility and quality of life in patients [1]
OA pathology and progression have been examined in detail, but mechanisms contributing to OA pain and the relationship between pain and OA pathology remain poorly understood
In the monosodium iodoacetate (MIA) model, a single intraarticular injection of MIA is administered in the knee joint and inhibits the glycolytic pathway, causing chondrocytic cell death and an acute inflammation leading to cartilage erosion and joint disruption [6,7]

Summary

Introduction

Osteoarthritis (OA) is a common degenerative joint disease associated with chronic, debilitating pain in the affected joints which significantly reduces mobility and quality of life in patients [1]. There is a need for a well-characterized, noninvasive murine model of OA pain that exhibits both a robust, reproducible pain phenotype and histologic evidence of OA pathology. The 2 most commonly used OA models in the preclinical field of OA pain are the monosodium iodoacetate (MIA) model used to induce inflammatory OA [3] and surgical destabilization of the joint typically used to model posttraumatic OA [4,5]. In the MIA model, a single intraarticular injection of MIA is administered in the knee joint and inhibits the glycolytic pathway, causing chondrocytic cell death and an acute inflammation leading to cartilage erosion and joint disruption [6,7].

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Conclusion