Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGF\u03b2-dependent manner and limits osteoarthritis in mice

Hilène Lin,Hang-Korng Ea,Martine Cohen-Solal,Abdel-Majid Khatib,Augustin Latourte,Thomas Funck-Brentano,Wafa Bouaziz,Eric Hay,Pascal Richette

doi:10.1038/s41598-018-28713-2

Abstract

Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor α1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), α1-PDX (14 µg/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 ± 0.75 vs 9.16 ± 0.6, p < 0.01), and the number of MMP-13(+) chondrocytes was lower (4.96 ± 0.60% vs 20.96 ± 8.49%, p < 0.05). Moreover, furin prevented the increase in ALK1/ALK5 ratio in cartilage induced by OA. Conversely, α1-PDX had no effect on OA cartilage structure. These results support a protective role for furin in OA by maintaining ALK5 receptor levels and reducing MMP-13 expression. Therefore, furin might be a potential target mediating the development of OA.

Highlights

Osteoarthritis (OA) is the most prevalent form of arthritis and a leading cause of pain and physical disability, especially in the elderly[1]
Furin did not significantly change the mRNA expression of Adamts[4] and Adamts[5], but these levels were enhanced with α1-PDX, which suggests the protective role of furin in the presence of interleukin 1 (IL-1) (Fig. 1B)
In cells transfected with siALK5, furin had no effect on IL-1-induced matrix metalloproteinase (MMP)-13 expression (Fig. 2E). These findings demonstrate that activin receptor-like kinase 5 (ALK5)/Smad[3] pathway mediates the protective effects of furin on MMP-13 production induced by IL-1 in chondrocytes

Summary

Introduction

Osteoarthritis (OA) is the most prevalent form of arthritis and a leading cause of pain and physical disability, especially in the elderly[1]. One major hallmark of the disease is the breakdown of articular cartilage matrix, especially type II collagen and proteoglycans, by several proteases[2]. Aggrecanases, such as a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS)−4 and −5, mediate cartilage remodelling[3] and their inhibition prevents OA-associated aggrecan degradation[4]. Increased expression of MMP-13 is observed in human OA cartilage[7,8], and its knockout protects against cartilage destruction in murine OA9 Both Adamts[5] and Mmp[13] are target genes for transforming growth factor beta (TGFβ) in articular chondrocytes[10]. We investigated the impact of furin on TGFβ-induced MMP-13 activation in chondrocytes, and assessed its effect in an experimental model of murine OA

Methods

Results

Conclusion