脂肪间充质干细胞过表达 Fra-1 抑制骨关节炎的作用及其机制研究。

Inhibition of Osteoarthritis by Adipose-Derived Stromal Cells Overexpressing Fra-1 in Mice.

机构信息

University of Erlangen-Nuremberg, Erlangen, Germany.

University of Erlangen-Nuremberg, Erlangen, Germany, and University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

出版信息

Arthritis Rheumatol. 2016 Jan;68(1):138-51. doi: 10.1002/art.39425.

DOI:10.1002/art.39425

PMID:26361381

Abstract

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.

摘要

目的

确定脂肪基质细胞（ADSCs）中激活蛋白 1（AP-1）转录因子 Fra-1 的过度表达是否是胶原酶诱导性骨关节炎（OA）的有效治疗方法。

方法

通过向雄性 C57BL/6 小鼠膝关节内注射胶原酶来诱导 OA。将 8 周龄野生型或 Fra-1 转基因小鼠腹股沟脂肪垫中的 ADSCs 分离出来，并在 OA 诱导后 7 天将其注射到胶原酶诱导的 OA 小鼠的膝关节中。对软骨破坏和软骨细胞死亡进行组织学分析。评估脂肪生成分化能力，分析基质血管部分（SVFs）和 ADSCs 的基因表达，并进行细胞因子谱分析。

结果

与用野生型小鼠 ADSCs 处理的 OA 小鼠膝关节相比，用 Fra-1 转基因小鼠 ADSCs 处理的 OA 小鼠膝关节中的 OA 相关软骨破坏和软骨细胞死亡明显减少。这种作用不是由于在 Fra-1 转基因小鼠脂肪垫中的 SVFs 中观察到的脂肪生成祖细胞数量较高所致，因为与未分选的 ADSCs 相比，注射富含脂肪生成祖细胞的野生型小鼠 ADSCs 并未显示出任何额外的软骨保护作用。然而，Fra-1 转基因小鼠 ADSCs 表现出降低的脂肪生成分化能力。此外，Fra-1 显著抑制促炎白细胞介素 6 和 pentraxin 3 的表达，同时增加细胞外基质蛋白（如 periostin 和 spondin 1）的表达。这些发现表明 Fra-1 的过表达导致 OA 中 ADSCs 的软骨保护作用增加。