Du Jie, Garcia João P, Bach Frances C, Tellegen Anna R, Grad Sibylle, Li Zhen, Castelein René M, Meij Björn P, Tryfonidou Marianna A, Creemers Laura B
Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, the Netherlands.
J Orthop Translat. 2022 Sep 23;37:23-36. doi: 10.1016/j.jot.2022.08.006. eCollection 2022 Nov.
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.
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.
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.
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 contradictory results of using BMP-4 on IVD regeneration between and 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.
椎间盘退变被认为是慢性下腰痛（LBP）的主要原因。椎间盘内递送生长因子已被提出作为椎间盘修复和再生的一种有前景的策略。此前，在人髓核（NP）细胞中，骨形态发生蛋白-4（BMP-4）在促进细胞外基质（ECM）产生方面比其他BMP和转化生长因子-β（TGF-β）更有效，这表明其适用于椎间盘再生。
在沉淀培养模型中评估BMP-4对绵羊NP和纤维环（AF）细胞中ECM沉积和细胞增殖的影响。此外，使用髓核摘除诱导的绵羊腰椎间盘退变模型来评估椎间盘内注射BMP-4对椎间盘再生的安全性和效果。通过磁共振成像、微型计算机断层扫描、组织学和生化测量来评估结果。
在体外，BMP-4显著增加蛋白聚糖的产生、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，低浓度BMP-4时较高，随着BMP-4浓度增加而降低。椎间盘内注射BMP-4在体内诱导了椎间盘外新骨形成和施莫尔氏结节样改变。未观察到NP或AF的再生。
我们的研究表明，尽管BMP-4在体外显示出有前景的再生效果，但在大型椎间盘退变动物模型中未观察到类似效果。
在[具体研究]和[具体研究]之间使用BMP-4进行椎间盘再生的矛盾结果表明，不应将直接注射BMP-4用于治疗与椎间盘退变相关的人类慢性下腰痛。此外，我们的结果也可能有助于揭示人类患者病理性终板变化背后的机制，作为一种可能的治疗靶点。
