锶雷尼酸酯通过抑制 Wnt/β-连环蛋白通路促进软骨生成。
Strontium ranelate promotes chondrogenesis through inhibition of the Wnt/β-catenin pathway.
机构信息
Department of Prosthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, China.
Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200001, China.
出版信息
Stem Cell Res Ther. 2021 May 20;12(1):296. doi: 10.1186/s13287-021-02372-z.
BACKGROUND
Cartilage regeneration is a key step in functional reconstruction for temporomandibular joint osteoarthritis (TMJ-OA) but is a difficult issue to address. Strontium ranelate (SrR) is an antiosteoporosis drug that has been proven to affect OA in recent years, but its effect on chondrogenesis and the underlying mechanism are still unclear.
METHODS
Bone mesenchymal stem cells (BMSCs) from Sprague-Dawley (SD) rats were induced in chondrogenic differentiation medium with or without SrR, XAV-939, and LiCl. CCK-8 assays were used to examine cell proliferation, and alcian blue staining, toluidine blue staining, immunofluorescence, and PCR analysis were performed. Western blot (WB) analyses were used to assess chondrogenic differentiation of the cells. For an in vivo study, 30 male SD rats with cartilage defects on both femoral condyles were used. The defect sites were not filled, filled with silica nanosphere plus gelatine-methacryloyl (GelMA), or filled with SrR-loaded silica nanosphere plus GelMA. After 3 months of healing, paraffin sections were made, and toluidine blue staining, safranin O/fast green staining, and immunofluorescent or immunohistochemical staining were performed for histological evaluation. The data were analyzed by SPSS 26.0 software.
RESULTS
Low concentrations of SrR did not inhibit cell proliferation, and the cells treated with SrR (0.25 mmol/L) showed stronger chondrogenesis than the control. XAV-939, an inhibitor of β-catenin, significantly promoted chondrogenesis, and SrR did not suppress this effect, while LiCl, an agonist of β-catenin, strongly suppressed chondrogenesis, and SrR reversed this inhibitory effect. In vivo study showed a significantly better cartilage regeneration and a lower activation level of β-catenin by SrR-loaded GelMA than the other treatments.
CONCLUSION
SrR could promote BMSCs chondrogenic differentiation by inhibiting the Wnt/β-catenin signaling pathway and accelerate cartilage regeneration in rat femoral condyle defects.
背景
软骨再生是颞下颌关节骨关节炎（TMJ-OA）功能重建的关键步骤，但这是一个难以解决的问题。锶雷尼酸酯（SrR）是一种近年来被证明能影响骨关节炎的抗骨质疏松药物，但它对软骨生成的影响及其潜在机制尚不清楚。
方法
用或不用 SrR、XAV-939 和 LiCl 在软骨分化培养基中诱导 Sprague-Dawley（SD）大鼠的骨髓间充质干细胞（BMSCs）。用 CCK-8 检测细胞增殖，进行茜素蓝染色、甲苯胺蓝染色、免疫荧光和 PCR 分析。用 Western blot（WB）分析评估细胞的软骨分化。在一项体内研究中，使用 30 只双侧股骨髁软骨缺损的雄性 SD 大鼠。缺损部位不填充、填充硅纳米球加明胶甲基丙烯酰（GelMA）或填充 SrR 负载硅纳米球加 GelMA。愈合 3 个月后，制作石蜡切片，进行甲苯胺蓝染色、番红 O/快绿染色、免疫荧光或免疫组织化学染色进行组织学评估。数据用 SPSS 26.0 软件进行分析。
结果
低浓度 SrR 不会抑制细胞增殖，用 SrR（0.25mmol/L）处理的细胞比对照组表现出更强的软骨生成能力。β-连环蛋白抑制剂 XAV-939 显著促进软骨生成，SrR 没有抑制这种作用，而β-连环蛋白激动剂 LiCl 强烈抑制软骨生成，SrR 逆转了这种抑制作用。体内研究表明，SrR 负载 GelMA 治疗的软骨再生明显更好，β-连环蛋白的激活水平更低。
结论
SrR 可通过抑制 Wnt/β-连环蛋白信号通路促进 BMSCs 软骨分化，并加速大鼠股骨髁缺损的软骨再生。
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