Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors

Frapin, Leslie; Clouet, Johann; Delplace, Vianney; Fusellier, Marion; Guicheux, Jérôme; Visage, Catherine Le

doi:10.1016/j.addr.2019.08.007

Cited by 73 publications

(79 citation statements)

References 261 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Degenerated disc shows an imbalance of anabolic and catabolic factors that leads to ECM degradation and chronic neck or back pain. 1 To modify decreased anabolism and increased anabolism in IVD degeneration, biological approaches including growth factor injection and cell and gene therapy began to receive considerably more attention over the past 20 years due to limitation of current treatments. 2 Over the past 2 decades, there has been a decisive shift towards large molecules, or biopharmaceuticals, and away from chemically synthesized small molecular weight drugs.…”

Section: Moving Forward: Gene Therapy For Intervertebral Disc Degenermentioning

confidence: 99%

Moving Forward: Gene Therapy for Intervertebral Disc Degeneration

Han

2020

Neurospine

View full text Add to dashboard Cite

Section: Moving Forward: Gene Therapy For Intervertebral Disc Degenermentioning

confidence: 99%

Moving Forward: Gene Therapy for Intervertebral Disc Degeneration

Han

2020

Neurospine

View full text Add to dashboard Cite

“…In the United States, the annual cost of LBP is over $100 billion, which is even more than the total cost of stroke, coronary artery disease, diabetes, rheumatoid disease and respiratory infection (Katz, 2006). Intervertebral disk degeneration is considered to be the main cause of LBP (Frapin et al, 2019), thus, it is of great importance to understand the pathophysiology of IVD.…”

Section: Introductionmentioning

confidence: 99%

Moderate Fluid Shear Stress Regulates Heme Oxygenase-1 Expression to Promote Autophagy and ECM Homeostasis in the Nucleus Pulposus Cells

Chen

Qin

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In vertebrate, the nucleus pulposus (NP), which is an essential component of the intervertebral disk, is constantly impacted by fluid shear stress (FSS); however, molecular mechanism(s) through which FSS modulates the NP homeostasis is poorly understood. Here we show that FSS regulates the extracellular matrix (ECM) homeostasis in NP cells. A moderate dose of FSS (i.e., 12 dyne/cm 2) increases the sulfated glycosaminoglycan (sGAG) content and protein levels of Col2a1 and Aggrecan and decreases those of matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motif 5 (ADMATS5) in rat NP cells, while a higher dose of FSS (i.e., 24 dyne/cm 2) displays opposite effects. Results from RNA sequencing analysis, quantitative real-time RT-PCR analysis and western blotting establish that the heme oxygenase-1 (HO-1) is a key downstream mediator of the FSS actions in NP cells. HO-1 knockdown abolishes FSS-induced alterations in ECM protein production and sGAG content in NP cells, which is reversed by HO-1 induction. Furthermore, FSS activates the autophagic pathway by increasing the LC3-II/LC3-I ratio, Beclin-1 protein level, and formation of autophagosome and autolysosome and thereby regulates ECM protein and sGAG production in a HO-1 dependent manner. Finally, we demonstrate that the intraflagellar transport (IFT) 88, a core trafficking protein of primary cilia, is critically involved in the HO-1-mediated autophagy activation and ECM protein and sGAG production in FSS-treated NP cells. Thus, we for the first time demonstrate that FSS plays an important role in maintaining ECM homeostasis through HO-1-dependent activation of autophagy in NP cells.

show abstract

“…Intervertebral disc (IVD) degeneration is accepted as the most important reason for low back pain. Many in vitro and in vivo studies evidenced that several pathological changes appear in the degenerated discs, including local inflammation, imbalance in the extracellular matrix metabolism, and sensitizing innervation into the disc [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Involvement of the G-Protein-Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc-Like Acidic Microenvironment

Liu

Zhang

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Intervertebral disc (IVD) degeneration is associated with local inflammation and increased expression of neurotrophins. Acidic microenvironment is believed to cause the progression of IVD degeneration. However, there is a paucity of information regarding the relationship between acidic microenvironment and the inflammation and expression of neurotrophins in IVD. G-protein-coupled receptor 4 (GPR4) is a pH-sensing receptor, which can activate the inflammation and increase the expression levels of nerve growth factor in acidic microenvironment. In this study, culture media with pH 7.2 (representing the normal IVD-like acidic condition) and pH 6.5 (degenerated IVD-like acidic condition) were prepared. The gene and protein expression levels of GPR4 in SD rat nucleus pulposus cells were determined under the acidic conditions. And cyclic AMP (cAMP), the second messenger of GPR4, was assayed. Furthermore, the expression levels of receptor activator of nuclear factor κ B (RANK), RANKL ligand (RANKL), osteoprotegerin (OPG), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were also determined. To clarify the involvement of GPR4 in the upregulation of the expression of RANK/RANKL/OPG system and neurotrophins, gene knockdown and forced expression of GPR4 and inhibiting its downstream cAMP accumulation and Ca2+ mobilization were performed. The alternation of the expression levels of matrix metalloproteinase-3 (MMP-3), MMP-13, and aggrecanase-2 (ADAMTS-5) were evaluated by RT-PCR and western blot. The results showed that GPR4 was expressed in rat nucleus pulposus cells, and the expression was upregulated under the degenerated IVD-like acidic microenvironment. cAMP accumulation levels were increased under the degenerated IVD-like acidic culture conditions. The expression levels of RANK, RANKL, OPG, NGF, and BNDF were significantly upregulated under the degenerated IVD-like acidic microenvironment. GPR4 knockdown and reduction of cAMP by the inhibitor SQ22536 abolished the upregulation of the expression of RANK, RANKL, OPG, NGF, and BNDF under the degenerated IVD-like acidic microenvironment. On the opposite, acidosis-induced cAMP accumulation and upregulation of RANK, RANKL, OPG, NGF, and BNDF were further promoted by GPR4 overexpression. The expression levels of MMP-3, MMP-13, and ADAMTS-5 were upregulated under the degenerated IVD-like acidic condition, which can be promoted or attenuated by GPR4 overexpression or knockdown, respectively. We concluded that GPR4-mediated cAMP accumulation was involved in the increased expression of RANK/RANKL/OPG system and neurotrophins by nucleus pulposus cells under the degenerated IVD-like acidic microenvironment.

show abstract

Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors

Cited by 73 publications

References 261 publications

Moving Forward: Gene Therapy for Intervertebral Disc Degeneration

Moving Forward: Gene Therapy for Intervertebral Disc Degeneration

Moderate Fluid Shear Stress Regulates Heme Oxygenase-1 Expression to Promote Autophagy and ECM Homeostasis in the Nucleus Pulposus Cells

Involvement of the G-Protein-Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc-Like Acidic Microenvironment

Contact Info

Product

Resources

About