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

Journal of Orthopaedic TranslationVolume 37, November 2022, Pages 23-36Journal of Orthopaedic TranslationAbstractBackground

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.

Keywords

BMP-4

Intervertebral disc regeneration

Nucleus pulposus

Annulus fibrosus

Subchondral bone remodeling

Bone formation

AbbreviationsAB/PR

Alcian blue and picrosirius red

ADAMTS

A disintegrin and metalloproteinase with thrombospondin motifs

BMPs

Bone morphogenetic proteins

CLBP

Chronic low back pain

GDF-8

Growth and differentiation factor-8

IVDD

Intervertebral disc degeneration

Ki-67

Nuclear Ki-67 protein

Micro-CT

Micro-computed tomography

MMPs

Matrix metalloproteinases

MRI

Magnetic resonance imaging

RPL19

Ribosomal protein L19

Saf-O FG

Safranin-O and fast green

SOX-9

SRY-box transcription factor-9

TGF-β

Transforming growth factor-beta

TRAP

Tartrate-resistant acid phosphatase

© 2022 The Authors. Published by Elsevier B.V. on behalf of Chinese Speaking Orthopaedic Society.

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