Fetal Immunomodulatory Environment Following Cartilage Injury-The Key to CARTILAGE Regeneration?

Iris Ribitsch,Florien Jenner,Simone Gabner,Lukas Janker,Andrea Bileck,Monika Egerbacher,Rupert L Mayer,Christopher Gerner

doi:10.3390/ijms222312969

Abstract

Fetal cartilage fully regenerates following injury, while in adult mammals cartilage injury leads to osteoarthritis (OA). Thus, in this study, we compared the in vivo injury response of fetal and adult ovine articular cartilage histologically and proteomically to identify key factors of fetal regeneration. In addition, we compared the secretome of fetal ovine mesenchymal stem cells (MSCs) in vitro with injured fetal cartilage to identify potential MSC-derived therapeutic factors. Cartilage injury caused massive cellular changes in the synovial membrane, with macrophages dominating the fetal, and neutrophils the adult, synovial cellular infiltrate. Correspondingly, proteomics revealed differential regulation of pro- and anti-inflammatory mediators and growth-factors between adult and fetal joints. Neutrophil-related proteins and acute phase proteins were the two major upregulated protein groups in adult compared to fetal cartilage following injury. In contrast, several immunomodulating proteins and growth factors were expressed significantly higher in the fetus than the adult. Comparison of the in vitro MSCs proteome with the in vivo fetal regenerative signature revealed shared upregulation of 17 proteins, suggesting their therapeutic potential. Biomimicry of the fetal paracrine signature to reprogram macrophages and modulate inflammation could be an important future research direction for developing novel therapeutics.

Highlights

IntroductionAdult cartilage has only negligible inherent reparative capacity but responds to injury by producing mechanically and functionally inferior fibrocartilage [3]
Fetal cartilage fully regenerates following injury [1,2]
In a comparison of fetal and adult tendon healing, we found a pronounced inflammatory response in adult injured tendons accompanied by activation of neutrophils and significant upregulation of pro-inflammatory factors and neutrophil-attracting chemokines

Summary

Introduction

Adult cartilage has only negligible inherent reparative capacity but responds to injury by producing mechanically and functionally inferior fibrocartilage [3]. Cartilage injury in adult mammals, leads to chronic degenerative joint disease: osteoarthritis (OA) [3]. OA is characterized by a failure to repair damaged cartilage, it is a disease of the entire joint, affecting all articular tissues because of their physical and functional association [10]. The pathogenesis of OA is multifaceted, involving mechanical, cellular and molecular processes, inflammation, metabolic dysfunction and epigenetic modifications, and is orchestrated by intricate crosstalk including chondrocytes, synovial macrophages and fibroblasts, osteocytes and infiltrating leukocytes [11,12,13,14,15,16,17,18,19,20,21]. Cartilage ECM debris and intracellular alarmins released into the synovial microenvironment activate synovial macrophages, synovial fibroblasts, and chondrocytes to produce inflammatory and catabolic mediators, which in turn disrupt cellular homeostasis and the balance between matrix synthesis and degradation and create a vicious cycle of inflammation and cartilage breakdown [11,12,13,14,15]

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