IL-17 Inhibits Chondrogenic Differentiation of Human Mesenchymal Stem Cells

Masahiro Kondo,Yoshiya Tanaka,Yosuke Okada,Koshiro Sonomoto,Kunihiro Yamaoka,Koichi Oshita,Shunsuke Fukuyo,Mário A Barbosa

doi:10.1371/journal.pone.0079463

Abstract

ObjectiveMesenchymal stem cells (MSCs) can differentiate into cells of mesenchymal lineages, such as osteoblasts and chondrocytes. Here we investigated the effects of IL-17, a key cytokine in chronic inflammation, on chondrogenic differentiation of human MSCs.MethodsHuman bone marrow MSCs were pellet cultured in chondrogenic induction medium containing TGF-β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.ResultsOver-expression of cartilage matrix and chondrogenic marker genes was noted in chondrogenic cultures, but was inhibited by IL-17 in a dose-dependent manner. Expression and phosphorylation of SOX9, the master transcription factor for chondrogenesis, were induced within 2 days and phosphorylated SOX9 was stably maintained until day 21. IL-17 did not alter total SOX9 expression, but significantly suppressed SOX9 phosphorylation in a dose-dependent manner. At day 7, IL-17 also suppressed the activity of cAMP-dependent protein kinase A (PKA), which is known to phosphorylate SOX9. H89, a selective PKA inhibitor, also suppressed SOX9 phosphorylation, expression of chondrogenic markers and cartilage matrix, and also decreased chondrogenesis.ConclusionsIL-17 inhibited chondrogenesis of human MSCs through the suppression of PKA activity and SOX9 phosphorylation. These results suggest that chondrogenic differentiation of MSCs can be inhibited by a mechanism triggered by IL-17 under chronic inflammation.

Highlights

Chondrocytes were considered as the only cell type that exists in the articular cartilage until recently
The results showed that IL-17 inhibited chondrogenesis through a mechanism involving protein kinase A (PKA) and SRY-type HMG box9 (SOX9) activity
We first estimated the effect of IL-17 on chondrogenesis of human mesenchymal stem cells (MSCs)

Summary

Introduction

Chondrocytes were considered as the only cell type that exists in the articular cartilage until recently. Due to the limited regenerative ability of chondrocytes, cartilage defects in patients with rheumatoid arthritis (RA), osteoarthritis (OA), and trauma are irreversible and cartilage repair is considered difficult. Some reports have characterized mesenchymal stem cells (MSCs) in the articular cartilage as chondrocyte progenitor cells [1,2,3]. MSCs are multipotent cells capable of differentiation into osteoblasts and chondrocytes, and can be obtained from mesodermal tissues, such as bone marrow and adipose tissue [4]. TNF-a has been reported to inhibit chondrogenic differentiation of human MSCs [9] and, correspondingly, the repair of articular cartilage can be observed in some RA patients treated with TNF inhibitors [10]

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