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Inhibition of Osteoarthritis by Adipose‐Derived Stromal Cells Overexpressing Fra‐1 in Mice
Author(s) -
Schwabe Kay,
Garcia Mireia,
Ubieta Kenia,
Hannemann Nicole,
Herbort Bettina,
Luther Julia,
Noël Daniele,
Jorgensen Christian,
Casteilla Louis,
David JeanPierre,
Stock Michael,
Herrmann Martin,
Schett Georg,
Bozec Aline
Publication year - 2016
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.39425
Subject(s) - chondrocyte , stromal cell , progenitor cell , adipogenesis , adipose tissue , collagenase , osteoarthritis , cartilage , fat pad , stem cell , proinflammatory cytokine , type ii collagen , chemistry , microbiology and biotechnology , endocrinology , biology , medicine , immunology , pathology , anatomy , inflammation , biochemistry , alternative medicine , enzyme
Objective To determine whether overexpression of the activator protein 1 (AP‐1) transcription factor Fra‐1 in adipose‐derived stromal cells (ADSCs) is an effective treatment of collagenase‐induced osteoarthritis (OA). Methods OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8‐week‐old wild‐type or Fra‐1–transgenic mice and injected into the knee joints of mice with collagenase‐induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs. Results OA‐related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra‐1–transgenic mice compared to mouse knee joints treated with ADSCs from wild‐type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra‐1–transgenic compared to wild‐type mouse fat pads, since injection of wild‐type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra‐1–transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra‐1 significantly inhibited proinflammatory interleukin‐6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra‐1 overexpression leads to an increased chondroprotective effect of ADSCs in OA. Conclusion ADSCs overexpressing Fra‐1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra‐1 overexpression, may improve their potential to protect articular cartilage against OA‐mediated damage.