Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis

C Cherifi,A Latourte,S Vettorazzi,J Tuckermann,S Provot,H.-K Ea,A Ledoux,J Casas,O Cuvillier,P Richette,A Ostertag,E Hay,M Cohen-Solal

doi:10.1016/j.joca.2021.06.001

Abstract

Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.

Highlights

Cartilage remodeling is a physiological process that is disrupted in osteoarthritis (OA), leading to a loss of cartilage matrix[1]
Despite the reduction in OA observed in SphK1LysMCre mice, we investigated whether Sphingosine 1-phosphate (S1P) released in synovial fluid may contribute to cartilage damage since S1P is expressed in synovial tissues of patients with OA and arthritis[37]
We show that OC-derived S1P controls the secretion of matrix metalloproteinase (MMP) by chondrocytes via S1P2 signaling, thereby promoting cartilage extracellular matrix breakdown

Summary

Introduction

Cartilage remodeling is a physiological process that is disrupted in osteoarthritis (OA), leading to a loss of cartilage matrix[1]. C. Cherifi et al / Osteoarthritis and Cartilage 29 (2021) 1335e1345 osteoclasts (OCs)[14], and anti-resorptive therapies targeting OCs prevent OA in murine models[15,16]. Subchondral bone OCs precursors may directly contribute to chondrocyte catabolism, the factors involved in this crosstalk, the role of the OC secretome in cartilage breakdown, remain elusive. Besides the intracellular role of S1P, most of its biological effects are explained by its binding to a family of five G protein-coupled receptors, S1P1-5, that mediate specific effects according to the predominant subtypes expressed in cells[21]. S1P regulates bone remodeling: S1P lyase-deficient mice, which have high circulating S1P levels, show a high bone mass phenotype[22]. Increased S1P secretion in OCs triggered osteoblast differentiation in a paracrine manner[28]

Methods

Results

Conclusion