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Contribution of the Interleukin‐6/STAT‐3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells
Author(s) -
Kondo Masahiro,
Yamaoka Kunihiro,
Sakata Kei,
Sonomoto Koshiro,
Lin Lin,
Nakano Kazuhisa,
Tanaka Yoshiya
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39036
Subject(s) - chondrogenesis , aggrecan , mesenchymal stem cell , microbiology and biotechnology , cartilage , chemistry , cellular differentiation , immunology , biology , anatomy , medicine , pathology , osteoarthritis , biochemistry , articular cartilage , alternative medicine , gene
Objective Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC‐like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self‐repair mechanism. Interleukin‐6 (IL‐6) is a cytokine with a wide range of physiologic functions, which are produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL‐6 signaling in MSC differentiation into chondrocytes. Methods Human bone marrow–derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression. Results IL‐6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL‐6 receptor (IL‐6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT‐3. Addition of IL‐6 and soluble IL‐6R (sIL‐6R) to the chondrogenic culture resulted in concentration‐dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL‐6 and sIL‐6R. STAT‐3 knockdown suppressed chondrogenic differentiation. IL‐6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis. Conclusion During differentiation of human MSCs into chondrocytes, the activation of IL‐6/STAT‐3 signaling positively regulated chondrogenic differentiation. The presence of IL‐6 around MSC‐like cells in the cartilage tissue was identified, suggesting that IL‐6 contributes to homeostasis and cartilage self‐repair by promoting chondrogenic differentiation.