Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2.

Craig M Keenan,Lorenzo Ramos-Mucci,David Abraham,Andrew Leask,George Bou-Gharios,Blandine Poulet,Peter I Milner,Ioannis Kanakis

doi:10.1242/dmm.044719

Abstract

ABSTRACTCCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. Ccn2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). Ccn2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-computed tomography and processed for histology. Sections were stained with Toluidine Blue and scored using the Osteoarthritis Research Society International (OARSI) grading system. In the non-invasive model, cartilage lesions were present in the lateral femur, but no significant differences were observed between wild-type (WT) and Ccn2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments, but no significant differences were observed between WT and Ccn2 KO mice at 2, 4 and 8 weeks post-surgery. We conclude that Ccn2 deletion in chondrocytes does not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a crucial factor in protecting cartilage from the degeneration associated with PTOA.This article has an associated First Person interview with the first author of the paper.

Highlights

Osteoarthritis (OA) is a major chronic degenerative disease of the joint, with limited therapies available to inhibit or slow disease progression
Ccn2 was successfully deleted in chondrocytes in adult mice To verify that deletion of Ccn2 in chondrocytes had occurred in response to tamoxifen injection, a tail tip containing ACAN
We have found that despite its importance during skeletal development and its increased expression by OA chondrocytes, CCN2 in articular cartilage (AC) chondrocytes in adult joints did not play a significant role in preventing post-traumatic OA (PTOA) development

Summary

Introduction

Osteoarthritis (OA) is a major chronic degenerative disease of the joint, with limited therapies available to inhibit or slow disease progression. OA, with mouse models of post-traumatic OA (PTOA) being widely used to study OA development. These include surgical models for development of different degrees of OA severity (Kamekura et al, 2005) and non-invasive repetitive joint trauma models, including the one established by Poulet et al (2011). Both surgical and non-invasive models show similar hallmarks to those seen in human OA, including progressive articular cartilage (AC) degradation, subchondral bone sclerosis, osteophyte formation and synovial fibrosis and activation. We used both a surgical model and a non-invasive model to determine the role of the matricellular protein CCN2 in severe and moderate PTOA

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