Intradiscal injection of human recombinant BMP-4 does not reverse intervertebral disc degeneration induced by nuclectomy in sheep

Jie Du, João P Garcia, Frances C Bach, Anna R Tellegen, Sibylle Grad, Zhen Li, René M Castelein, Björn P Meij, Marianna A Tryfonidou*, Laura B Creemers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)23-36
Number of pages14
JournalJournal of Orthopaedic Translation
Early online date23 Sept 2022
Publication statusPublished - Nov 2022


  • Annulus fibrosus
  • BMP-4
  • Bone formation
  • Intervertebral disc regeneration
  • Nucleus pulposus
  • Subchondral bone remodeling


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