Background

Intervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-β in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration.

Methods

The effects of BMP-4 on ECM deposition and cell proliferation were assessed in sheep NP and annulus fibrosus (AF) cells in a pellet culture model. Further, a nuclectomy induced sheep lumbar IVD degeneration model was used to evaluate the safety and effects of intradiscal BMP-4 injection on IVD regeneration. Outcomes were assessed by magnetic resonance imaging, micro-computed tomography, histological and biochemical measurements.

Results

In vitro, BMP-4 significantly increased the production of proteoglycan and deposition of collagen type II and proliferation of NP and AF cells. Collagen type I deposition was not affected in NP cells, while in AF cells it was high at low BMP-4 concentrations, and decreased with increasing concentration of BMP-4. Intradiscal injection of BMP-4 induced extradiscal new bone formation and Schmorl's node-like changes in vivo. No regeneration in the NP nor AF was observed.

Conclusion

Our study demonstrated that although BMP-4 showed promising regenerative effects in vitro, similar effects were not observed in a large IVD degeneration animal model.

The Translational Potential of This Article

The contradictory results of using BMP-4 on IVD regeneration between in vitro and in vivo demonstrate that direct BMP-4 injection for disc degeneration-associated human chronic low back pain should not be undertaken. In addition, our results may also shed light on the mechanisms behind pathological endplate changes in human patients as a possible target for therapy.

中文翻译：

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人重组BMP-4椎间盘内注射不能逆转羊核切除术引起的椎间盘退变

背景

椎间盘 (IVD) 变性被认为是慢性腰痛 (LBP) 的主要原因。已经提出将生长因子的椎间盘内递送作为IVD修复和再生的有前景的策略。此前，BMP-4 在促进人髓核 (NP) 细胞中的细胞外基质 (ECM) 产生方面比其他 BMP 和 TGF-β 更有效，这表明其可用于椎间盘再生。

方法

在颗粒培养模型中评估了绵羊 NP 和纤维环 (AF) 细胞中 BMP-4 对 ECM 沉积和细胞增殖的影响。此外，使用髓核切除术诱导的羊腰椎IVD变性模型来评估椎间盘内BMP-4注射对IVD再生的安全性和影响。结果通过磁共振成像、微型计算机断层扫描、组织学和生化测量进行评估。

结果

在体外，BMP-4 显着增加了蛋白多糖的产生和 II 型胶原蛋白的沉积以及 NP 和 AF 细胞的增殖。I 型胶原蛋白沉积在 NP 细胞中不受影响，而在 AF 细胞中，在低 BMP-4 浓度时它很高，并且随着 BMP-4 浓度的增加而降低。椎间盘内注射 BMP-4 在体内诱导椎间盘外新骨形成和 Schmorl 节点样变化。未观察到 NP 和 AF 的再生。

结论

我们的研究表明，尽管 BMP-4 在体外显示出有希望的再生效果，但在大型 IVD 变性动物模型中未观察到类似的效果。

本文的转化潜力

使用 BMP-4 进行体外和体内体外诊断再生的相互矛盾的结果表明，不应直接注射 BMP-4 治疗与椎间盘退变相关的人类慢性腰痛。此外，我们的研究结果还可能揭示人类患者病理性终板变化背后的机制，作为治疗的可能目标。