CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes

Michel Malaise,Edith Charlier,Dominique de Seny,Alain Chariot,Sophie Neuville,William Kurth,Philippe Gillet,Olivier Malaise,Céline Deroyer

doi:10.1038/s41419-019-1377-8

Abstract

CEMIP (for “Cell migration-inducing protein” also called KIAA1199 and Hybid for “Hyaluronan-binding protein”) expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, αSMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated β-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted αSMA expression, a fibrosis marker, and TGFβ signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. αSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with αSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into “chondro-myo-fibroblasts” expressing α-SMA and type III collagen, two fibrosis markers. Moreover, these “chondro-myo-fibroblasts” were found in OA cartilage but not in healthy cartilage.

Highlights

CEMIP for “Cell migration-inducing protein”, was originally detected in the inner ear and reported as the cause of nonsyndromic hearing loss[1,2]
IHC quantification was performed on tibia and femur of DMM mice after 4 and 8 weeks of surgery and CEMIP expression was significantly increased at both time in the cartilage of DMM mice compared to healthy cartilage of sham mice (Fig. 1b, c)
Many studies have shown that it plays a critical role in cancer cell survival, proliferation and migration, three critical processes involved in cancer development and dissemination[5,6]

Summary

Introduction

CEMIP for “Cell migration-inducing protein” ( called KIAA1199 and Hybid), was originally detected in the inner ear and reported as the cause of nonsyndromic hearing loss[1,2]. The increase of CEMIP expression was observed in various cancers[3,4], and described as a key regulator of cell survival, growth and invasion[5,6]. CEMIP expression was enhanced in human and rheumatoid arthritis (RA) and is detected in the synovium of RA patients and referred to as an angiogenic marker[8,9]. A role of CEMIP in endochondral ossification has been highlighted[10]. The role of CEMIP in OA chondrocytes remains unknown. OA is a degenerative disease affecting the entire joint. It is mainly characterized by cartilage degradation, synovial

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Results

Conclusion