Objective

We undertook this study to assess the therapeutic benefits of intervertebral disc matrix repair and regeneration by evaluating the potential synergistic effect of insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein 7 (BMP-7) on bovine spine discs and by elucidating the relevant molecular/cellular mechanisms.



Methods

Bovine nucleus pulposus (NP) cells were treated with BMP-7 and IGF-1. The subsequent anabolic effects driven by NP cells were assessed for proteoglycan (PG) synthesis by 35S-sulfate incorporation and for PG accumulation by dimethylmethylene blue assays. Matrix formation was visualized by particle exclusion assay. Key matrix components and transcription factors were analyzed by real-time reverse transcription–polymerase chain reaction to determine the signaling pathways by which IGF-1 suppresses noggin, a potent inhibitor of BMP-7. Western blotting and nuclear translocation experiments were performed to assess the activation of Smad proteins.



Results

Stimulation of bovine NP cells by both IGF-1 and BMP-7 greatly potentiated anabolism through complementary and synergistic mechanisms on matrix formation compared with treatment with either growth factor alone. The exogenously added decoy ligand, noggin, attenuated the anabolic effects of BMP-7, and noggin was substantially increased by BMP-7, suggesting a negative feedback regulatory mechanism. In contrast, IGF-1 significantly suppressed noggin expression via the phosphatidylinositol 3-kinase/Akt pathway and thus potentiated BMP-7 signaling in bovine NP cells. Upon combination treatment, IGF-1 activated Smad2, while BMP-7 activated Smad1/5/8 and Smad3, thus inducing all Smad signaling pathways and mimicking the effects of the combination of transforming growth factor β and BMP-7



Conclusion

Combination growth factor therapy using BMP-7 and IGF-1 may have considerable promise in the treatment of spine disc degeneration.

Insulin-like growth factor 1 synergizes with bone morphogenetic protein 7-mediated anabolism in bovine intervertebral disc cells.

Low back pain is the leading cause of disability worldwide and in many patients the source of pain can be attributed to pathological changes within the intervertebral disc (IVD). As present treatment options fail to address the underlying biological problem, novel therapies are currently subject to intense research. The physiologic IVD microenvironment features a highly complex interaction of biochemical and mechanical factors influencing cell metabolism and extracellular matrix turnover and is therefore difficult to simulate for research purposes on IVD pathology. The first whole organ culture models were not able to sufficiently replicate human in vivo conditions as mechanical loading, the predominant way of IVD nutrient supply and waste exchange, remained disregarded. To mimic the unique IVD niche more realistically, whole organ culture bioreactors have been developed, allowing for dynamic loading of IVDs and nutrient exchange. Recent advancements on bioreactor systems have facilitated whole organ culture of various IVDs for extended periods. IVD organ culture bioreactors have the potential to bridge the gap between in vitro and in vivo systems and thus may give valuable insights on IVD pathology and/or potential novel treatment approaches if the respective model is adjusted according to a well-defined research question. In this review, we outline the potential of currently utilized IVD bioreactor systems and present suggestions for further developments to more reliably investigate IVD biology and novel treatment approaches.

Intervertebral disc organ culture for the investigation of disc pathology and regeneration - benefits, limitations, and future directions of bioreactors.

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase which cleaves IGF binding protein (BP)-4 in the extracellular matrix, making IGF available to nearby cells. We have shown that PAPP-A is present in the human intervertebral disc, and is significantly upregulated in more degenerated discs where increased proinflammatory cytokine levels are present. We hypothesized that increased proinflammatory cytokines present in the degenerating disc might be related to PAPP-A expression. Experiments exposed human annulus cells to IL-1-β or TNF-α to test this hypothesis. Treated cells showed significantly increased PAPP-A in conditioned media versus controls (p < 0.001). PAPP-A production following exposure to IL-1β was significantly greater in cells derived from more degenerated versus healthier discs (p = 0.05). PAPP-A gene expression (microarray analysis) was significantly upregulated in IL-1β- or TNF-α-exposed cells (p = 0.01-0.004). Quantitative RT-PCR confirmed significant upregulation of IGFBP-4 in IL-1β- or TNF-α-exposed cells. Data have potential relevance to future cell-based biologic therapies for disc degeneration.

Human annulus cells regulate PAPP-A and IGFBP-4 expression, and thereby insulin-like growth factor bioavailability, in response to proinflammatory cytokine exposure in vitro

Background
Different biologic approaches to treat disc regeneration, including growth factors (GFs) application, are currently under investigation. Human annulus fibrosus (hAF) repair or regeneration is one of the key elements for maintenance and restoration of nucleus pulposus function. However, so far there is no effective treatment for this purpose. The aim of the present study was to investigate the response of hAF cells to different combinations of GFs, and develop a protocol for efficient culture expansion.

/pdf/development-of-a-two-step-protocol-for-culture-expansion-of-1iyqdwkzyu.pdf

Development of a two-step protocol for culture expansion of human annulus fibrosus cells with TGF-β1 and FGF-2

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jor.20803

Nucleus pulposus explant culture model.

Degenerative disc disease is a leading source of pain as well as increased health care costs in the United States, and research efforts into understanding the pathophysiology of this disease are necessary for the development of new management strategies. Addition of growth factors to stimulate chondrocyte development are on the horizon as new treatment modalities for degenerative disc disease, but increasing growth factor concentrations in the body may have adverse affects on vital organs. The objective of this study was to investigate the use of sustained delivery of insulin-like growth factor-1 (IGF-1) for treatment of degenerative discs using the adult male rat as a model. The results showed increased chondrocyte proliferation and decreased apoptosis at the traumatized disc after 28 days. Analysis of the vital organs revealed slight increases in kidney wet weights, and closer histomorphometric evaluation of the tissue revealed changes in the proximal tubules. Further investigation to evaluate the potential physiological or pathophysioloigcal effects of the growth factors at the organ levels is warranted before use as therapeutic agent to treat degenerative disc disease.

Effects of sustained delivery of IGF-1 in a rat degenerative disc model.

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Effects of sustained delivery of IGF-1 in a rat degenerative disc model.