Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Orthopedic Biomechanical Laboratory, Department of Orthopedic surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
J Shoulder Elbow Surg. 2022 Aug;31(8):1617-1627. doi: 10.1016/j.jse.2022.01.137. Epub 2022 Feb 20.
Rotator cuff healing is improved by reconstructing the fibrocartilaginous structure of the tendon-to-bone enthesis. Fibroblast growth factor (FGF)-18 (sprifermin) is a well-known growth factor that improves articular cartilage repair via its anabolic effect. This study aimed to investigate the effect of recombinant human FGF-18 (rhFGF-18) on the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro and tendon-to-bone healing in a rat model of rotator cuff repair.
Histological and reverse transcription-quantitative real-time polymerase chain reaction analyses of chondral pellets cultured with different concentrations of rhFGF-18 were performed. Bilateral detachment and repair of the supraspinatus tendon were performed on rats. The rats were administered 0.2 mL of sodium alginate (SA) hydrogel with (rhFGF-18/SA group, n = 12) or without (SA group, n = 12) 20 μg of rhFGF-18 into the repaired side. The simple repair group (n = 12) served as a control. At 4 and 8 weeks after surgery, histological analysis and biomechanical tests were performed.
After chondrogenesis induction, compared with the control group, 10 ng/mL of rhFGF-18 increased pellet volume significantly (P = .002), with improved histological staining. It was noted that 10 ng/mL of rhFGF-18 upregulated the mRNA expression (relative ratio to control) of aggrecan (2.59 ± 0.29, P < .001), SRY-box transcription factor 9 (1.88 ± 0.05, P < .001), and type II collagen (1.46 ± 0.18, P = .009). At 4 and 8 weeks after surgery, more fibrocartilage and cartilaginous extracellular matrix was observed in rhFGF-18/SA-treated rats. The semiquantitative data from picrosirius red staining test were 31.1 ± 4.5 vs. 61.2 ± 4.1 at 4 weeks (P < .001) and 61.5 ± 2.8 vs. 80.5 ± 10.5 at 8 weeks (P = .002) (control vs. rhFGF-18/SA). Ultimate failure load (25.42 ± 3.61 N vs. 18.87 ± 2.71 N at 4 weeks and 28.63 ± 5.22 N vs. 22.15 ± 3.11 N at 8 weeks; P = .006 and P = .03, respectively) and stiffness (18.49 ± 1.38 N/mm vs. 14.48 ± 2.01 N/mm at 8 weeks, P = .01) were higher in the rhFGF-18/SA group than in the control group.
rhFGF-18 promoted chondrogenesis in the hBMSCs in vitro. rhFGF-18/SA improved tendon-to-bone healing in the rats by promoting regeneration of the fibrocartilage enthesis. rhFGF-18 (sprifermin) may be beneficial in improving tendon-to-bone healing after rotator cuff repair.
通过重建肌腱-骨结合处的纤维软骨结构，可改善肩袖愈合。成纤维细胞生长因子（FGF）-18（司利美森）是一种众所周知的生长因子，通过其合成代谢作用可改善关节软骨修复。本研究旨在研究重组人 FGF-18（rhFGF-18）对体外人骨髓间充质干细胞（hBMSCs）软骨分化的影响以及在肩袖修复大鼠模型中对肌腱-骨愈合的影响。
对不同浓度 rhFGF-18 培养的软骨小球进行组织学和逆转录定量实时聚合酶链反应分析。对大鼠进行双侧冈上肌腱分离和修复。将 0.2 mL 海藻酸钠（SA）水凝胶（rhFGF-18/SA 组，n = 12）或不含有 rhFGF-18（SA 组，n = 12）的 20μg rhFGF-18 注入修复侧。简单修复组（n = 12）作为对照。术后 4 周和 8 周时进行组织学分析和生物力学测试。
软骨生成诱导后，与对照组相比，10ng/mL rhFGF-18 显著增加小球体积（P =.002），并改善了组织学染色。结果表明，10ng/mL rhFGF-18 上调了聚集蛋白（相对对照比）的 mRNA 表达（2.59±0.29，P <.001），SRY 盒转录因子 9（1.88±0.05，P <.001）和 II 型胶原（1.46±0.18，P =.009）。术后 4 周和 8 周，rhFGF-18/SA 治疗的大鼠中观察到更多的纤维软骨和软骨细胞外基质。番红 O 染色试验的半定量数据为 4 周时 31.1±4.5 对 61.2±4.1（P <.001）和 8 周时 61.5±2.8 对 80.5±10.5（P =.002）（对照组与 rhFGF-18/SA）。最终失效负荷（4 周时 25.42±3.61 N 对 18.87±2.71 N，8 周时 28.63±5.22 N 对 22.15±3.11 N；P =.006 和 P =.03）和刚度（8 周时 18.49±1.38 N/mm 对 14.48±2.01 N/mm，P =.01）在 rhFGF-18/SA 组中均高于对照组。
rhFGF-18 促进了体外 hBMSCs 的软骨生成。rhFGF-18/SA 通过促进纤维软骨结合处的再生改善了大鼠的肌腱-骨愈合。rhFGF-18（司利美森）可能有益于改善肩袖修复后的肌腱-骨愈合。
