The pro-inflammatory cytokine 14-3-3ε is a ligand of CD13 in cartilage.

Meriam Nefla,Claire Jacques,Sabrina Priam,Guillaume Denat,Francis Berenbaum,Gwenaëlle Andre-Leroux,Laure Sudre

doi:10.1242/jcs.169573

Abstract

ABSTRACTOsteoarthritis is a whole-joint disease characterized by the progressive destruction of articular cartilage involving abnormal communication between subchondral bone and cartilage. Our team previously identified 14-3-3ε protein as a subchondral bone soluble mediator altering cartilage homeostasis. The aim of this study was to investigate the involvement of CD13 (also known as aminopeptidase N, APN) in the chondrocyte response to 14-3-3ε. After identifying CD13 in chondrocytes, we knocked down CD13 with small interfering RNA (siRNA) and blocking antibodies in articular chondrocytes. 14-3-3ε-induced MMP-3 and MMP-13 was significantly reduced with CD13 knockdown, which suggests that it has a crucial role in 14-3-3ε signal transduction. Aminopeptidase N activity was identified in chondrocytes, but the activity was unchanged after stimulation with 14-3-3ε. Direct interaction between CD13 and 14-3-3ε was then demonstrated by surface plasmon resonance. Using labeled 14-3-3ε, we also found that 14-3-3ε binds to the surface of chondrocytes in a manner that is dependent on CD13. Taken together, these results suggest that 14-3-3ε might directly bind to CD13, which transmits its signal in chondrocytes to induce a catabolic phenotype similar to that observed in osteoarthritis. The 14-3-3ε–CD13 interaction could be a new therapeutic target in osteoarthritis.

Highlights

Osteoarthritis is a chronic joint disease characterized by a progressive degradation of articular cartilage, synovial inflammation and remodeling of subchondral bone in response to a variety of stimuli, such as proinflammatory cytokines and mechanical loading (Bijlsma et al, 2011; Martel-Pelletier and Pelletier, 2010)
CD13 mRNA and protein expression was verified in human osteoarthritis articular chondrocytes by quantitative realtime PCR (qRT-PCR) and western blot analysis (Fig. 1C), respectively, and by immunocytochemistry (Fig. 1D)
The results obtained by qRT-PCR were not interpretable. These results show that treatment with an antibody that blocks only the receptor role of CD13 greatly inhibits the 14-3-3ε-mediated mRNA and protein expression of both matrix metalloproteinases (MMPs)-3 and MMP-13 in murine and human chondrocytes, which suggests that CD13 has a receptor role in transmitting the 14-3-3ε signal in chondrocytes and inducing a procatabolic phenotype

Summary

Introduction

Osteoarthritis is a chronic joint disease characterized by a progressive degradation of articular cartilage, synovial inflammation and remodeling of subchondral bone in response to a variety of stimuli, such as proinflammatory cytokines and mechanical loading (Bijlsma et al, 2011; Martel-Pelletier and Pelletier, 2010). Several studies have suggested that subchondral bone and articular cartilage form a functional unit, which might play a role in joint maintenance and degeneration. Hepatocyte growth factor is found in the deep layers of cartilage; it is produced by osteoarthritis osteoblasts and found in cartilage, even though it is not expressed by chondrocytes. These results suggest the passage of this molecule from bone to cartilage (Guevremont et al, 2003)

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