Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair.

Iris Ribitsch,Sinan Gültekin,Alexander D Aldoshin,Rupert L Mayer,Johann Huber,Maciej M Kańduła,Christopher Gerner,Andrea Bileck,Simone Gabner,Monika Egerbacher,Ulrike Auer,David P Kreil,Florien Jenner

doi:10.3390/ijms22115619

Abstract

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

Highlights

IntroductionTendinopathy is a common, painful, and disabling musculoskeletal condition prevalent among athletes and sedentary subjects, afflicting 25% of the adult population as a result of trauma, overuse, or ageing [1,2]
Adult injured tendons fail to regenerate but form fibrous scar tissue with significantly inferior biomechanical properties that is prone to re-injury and chronic tendinopathy resulting in a significant impact on quality of life and high socioeconomic costs—the annual cost for tendon injury is estimated at USD 30 billion [2,3,13,14]
Compared to the control tendons, we found an up-regulation of tenascin-C, versican, matrix metalloproteinase-2 (MMP2), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinases1 (TIMP1) within and around the lesion site in both age groups

Summary

Introduction

Tendinopathy is a common, painful, and disabling musculoskeletal condition prevalent among athletes and sedentary subjects, afflicting 25% of the adult population as a result of trauma, overuse, or ageing [1,2]. The onset and progression of tendinopathy is a multifactorial process affected by many intrinsic and extrinsic influences such as age, gender, genetics, anatomical variants, body weight, systemic disease, sporting activities, physical loading, occupation, and environmental conditions resulting in accumulated microdamage due to repetitive strain with weakening of the collagen cross-links, the non-collagenous matrix, and the vascular elements [1,7,8]. Adult injured tendons fail to regenerate but form fibrous scar tissue with significantly inferior biomechanical properties that is prone to re-injury and chronic tendinopathy resulting in a significant impact on quality of life and high socioeconomic costs—the annual cost for tendon injury is estimated at USD 30 billion [2,3,13,14]

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