In Vivo Administration of an Inflammatory Stimulant can Trigger Loss of Biomechanical and Biochemical Properties of the Intervertebral Disc

2012 ◽  
Author(s):  
Neena Rajan ◽  
Nate Stetson ◽  
Robert Maidhof ◽  
Mitchell Levine ◽  
Nadeen Chahine
Keyword(s):  
Intervertebral Disc ◽  
Morphological Changes ◽  
Direct Injection ◽  
Biomechanical Properties ◽  
Biochemical Properties ◽  
Post Injury ◽  
Sham Injection ◽  
Tnf Α ◽  
Ivd Degeneration

Human intervertebral disc (IVD) degeneration is accompanied by chronic inflammation, particularly seen in the elevated levels of pro-inflammatory cytokines IL-1β and TNF-α [1–3]. Animal models of disc degeneration (DD) using stab or laceration of the disc generally reproduce morphological changes of IVD degeneration. However, inflammatory changes in these models are thought to be acute and transient post injury [4–6]. The goal of this study is to explore the effect of direct inflammatory stimulation of the IVD on disc biochemical and biomechanical properties in vivo. We utilize lipopolysaccharide (LPS), an inflammatory stimulant that provokes secretion of multiple cytokines by disc cells. We have previously shown that direct injection of LPS into the disc results in significantly higher protein levels of IL-1β, TNF-α, HMGB-1 and MIF vs. sham injection up to 7 days post administration [7]. The goal of this study is to explore the dose-dependent response of this inflammatory stimulation on the biochemical and biomechanical properties of IVD in vivo. We hypothesize that LPS stimulation mimics the pathophysiology of DD by triggering a group of cytokines that are associated with IVD degeneration. LPS is administered using micro needles (<10% disc height) in order to minimize the potential disruption by needle injection.

scholarly journals LRP5-deficiency in OsxCreERT2 mice models intervertebral disc degeneration by aging and compression

2019 ◽  
Author(s):  
Matthew J. Silva ◽  
Nilsson Holguin
Keyword(s):  
Transcription Factor ◽  
Intervertebral Disc ◽  
Wnt Signaling ◽  
Cell Fate ◽  
Biomechanical Properties ◽  
Nucleus Pulposus Cells ◽  
Hypertrophic Chondrocyte ◽  
Age Related ◽  
Ivd Degeneration

ABSTRACTOsterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of WNT signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates differentiation of prehypertrophic chondrocyte-like cells and inactivates WNT signaling, but its interacting role with osterix is unclear. First, compared to young-adult (5mo), mechanical compression of old (18mo) IVD induced greater IVD degeneration. Aging (5 vs 12mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12mo IVD. Next, using an Ai9/td reporter and immunohistochemistry, annulus fibrosus and nucleus pulposus cells of 5mo IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells degenerated the IVD, inactivated WNT signaling, reduced the biomechanical properties by 45-70%, and reduced transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of WNT signaling in osterix-expressing cells may limit regeneration by depleting progenitors and attenuating the expansion of chondrocyte-like cells.

Effect of Inflammation on the Osmotic Response of Nucleus Pulposus Cells

2012 ◽  
Author(s):  
Robert Maidhof ◽  
Neena Rajan ◽  
Nadeen O. Chahine
Keyword(s):  
Nucleus Pulposus ◽  
Biomechanical Properties ◽  
Nucleus Pulposus Cells ◽  
Cellular Mechanisms ◽  
Osmotic Response ◽  
Tnf Α ◽  
Disc Cells ◽  
Cytokine Stimulation ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration is accompanied by elevated levels of pro-inflammatory cytokines, particularly IL-1β and TNF-α [1]. Disc cells from the nucleus pulposus (NPs) respond to cytokine stimulation with increased catabolic breakdown of the tissue, resulting in a positive feedback of disc integrity loss and further inflammation [2]. Previous studies by our group have examined the response of NP cells to Toll-Like Receptor-4 (TLR-4) activation through stimulation with lipopolysaccharide (LPS). TLR-4 is a pattern recognition receptor that is activated in innate immunity and by polysaccharide fragments from degenerated proteoglycans. TLR-4 activation by LPS results in stimulation of multiple cytokines by NP cells [3]. Moreover, we have shown that in vivo LPS injection results in catabolic changes in the IVD, including matrix breakdown, decrease in biomechanical properties and loss of disc height [4]. However, the specific cellular mechanisms for these catabolic changes remain to be elucidated.

scholarly journals Fexofenadine Protects Against Intervertebral Disc Degeneration Through TNF Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Kaiwen Liu ◽  
Jianlu Wei ◽  
Guohua Li ◽  
Ronghan Liu ◽  
Dawang Zhao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Pathological Process ◽  
Mechanism Study ◽  
Tnf Α ◽  
Safranin O ◽  
Factor Α ◽  
Ivd Degeneration

Objective: Fexofenadine (FFD) is an antihistamine drug with an anti-inflammatory effect. The intervertebral disc (IVD) degeneration process is involved in inflammation in which tumor necrosis factor-α (TNF-α) plays an important role. This study aims to investigate the role of FFD in the pathological process of IVD degeneration.Methods: Safranin O staining was used for the measurement of cartilageous tissue in the disc. Hematoxylin-Eosin (H&amp;E) staining was used to determine the disc construction. A rat needle puncture model was taken advantage of to examine the role of FFD in disc degeneration in vivo. Western Blotting assay, immunochemistry, and immunoflurence staining were used for the determination of inflammatory molecules. ELISA assay was performed to detect the release of inflammatory cytokines. A real-time PCR assay was analyzed to determine the transcriptional expressions of molecules.Results: Elevated TNF-α resulted in inflammatory disc degeneration, while FFD protected against TNF-α-induced IVD degeneration. Mechanism study found FFD exhibited a disc protective effect through at least two pathways. (a) FFD inhibited TNF-α-mediated extracellular matrix (ECM) degradation and (b) FFD rescued TNF-α induced inflammation in disc degeneration. Furthermore, the present study found that FFD suppressed TNF-α mediated disc degeneration via the cPLA2/NF-κB signaling pathway.Conclusions: FFD provided another alternative for treating disc degeneration through a novel mechanism. Additionally, FFD may also be a potential target for the treatment of other inflammatory-related diseases, including IVD degeneration.

Recovery of Intervertebral Disc Degeneration Post Enzymatic Treatment is Mediated by Matrix Metalloproteinases

2011 ◽  
Author(s):  
Nadeen Chahine ◽  
Nate Stetson ◽  
Neena Rajan ◽  
Daniel Grande ◽  
Mitchell Levine
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Enzymatic Degradation ◽  
Intervertebral Disc Degeneration ◽  
Biomechanical Properties ◽  
Enzymatic Treatment ◽  
Disc Injury ◽  
Herniated Discs ◽  
Dose Dependent

Enzymatic degradation of the intervertebral disc (IVD) with chondroitinase ABC (ChABC) reduces proteoglycan content of the IVD, thus simulating the GAG loss seen clinically in patients suffering from disc degeneration. This approach has been employed in models of disc injury in rats, rabbits and goats when administered over a large range of dosages [1–3]. Moreover, ChABC has also been used to induce repair of herniated discs in rabbits via chemonucleolysis [4, 5]. Despite the effectiveness of ChABC treatment to reduce the GAG content of the IVD, several recent studies including our own, have shown that this GAG loss is reversible at extended time points post enzymatic treatment [2,6,7]. The goal of the current study is to examine the dose dependent response of IVDs to degradation by ChABC in vivo. We hypothesize that administration of ChABC will result in dose dependent GAG loss and reduced mechanical properties. We administered ChABC at 0.1 U/ml, 1.0 U/ml and 10 U/ml and examined the changes in biomechanical properties, biochemical content, and gene expression in order to examine the biophysical and molecular mechanism by which GAG loss occurs in this model.

scholarly journals Injectable Hydrogel Combined with Nucleus Pulposus-Derived Mesenchymal Stem Cells for the Treatment of Degenerative Intervertebral Disc in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Feng Wang ◽  
Li-ping Nan ◽  
Shi-feng Zhou ◽  
Yang Liu ◽  
Ze-yu Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Rat Model ◽  
Injectable Hydrogel ◽  
Cell Scaffold ◽  
Ivd Degeneration

Stem cell-based tissue engineering in treating intervertebral disc (IVD) degeneration is promising. An appropriate cell scaffold can maintain the viability and function of transplanted cells. Injectable hydrogel has the potential to be an appropriate cell scaffold as it can mimic the condition of the natural extracellular matrix (ECM) of nucleus pulposus (NP) and provide binding sites for cells. This study was aimed at investigating the effect of injectable hydrogel-loaded NP-derived mesenchymal stem cells (NPMSC) for the treatment of IVD degeneration (IDD) in rats. In this study, we selected injectable 3D-RGD peptide-modified polysaccharide hydrogel as a cell transplantation scaffold. In vitro, the biocompatibility, microstructure, and induced differentiation effect on NPMSC of the hydrogel were studied. In vivo, the regenerative effect of hydrogel-loaded NPMSC on degenerated NP in a rat model was evaluated. The results showed that NPMSC was biocompatible and able to induce differentiation in hydrogel in vivo. The disc height index (almost 87%) and MRI index (3313.83±227.79) of the hydrogel-loaded NPMSC group were significantly higher than those of other groups at 8 weeks after injection. Histological staining and immunofluorescence showed that the hydrogel-loaded NPMSC also partly restored the structure and ECM content of degenerated NP after 8 weeks. Moreover, the hydrogel could support long-term NPMSC survival and decrease cell apoptosis rate of the rat IVD. In conclusion, injectable hydrogel-loaded NPMSC transplantation can delay the level of IDD and promote the regeneration of the degenerative IVD in the rat model.

Effect of Shear Force on Intervertebral Disc (IVD) Degeneration: An In Vivo Rat Study

2012 ◽  
Vol 40 (9) ◽  
pp. 1996-2004 ◽  
Author(s):  
Jaehyun Kim ◽  
Seok-Jo Yang ◽  
Hyunchul Kim ◽  
Yoonsang Kim ◽  
Joon B. Park ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Shear Force ◽  
Rat Study ◽  
Ivd Degeneration

scholarly journals Inflammation in intervertebral disc degeneration and regeneration

2015 ◽  
Vol 12 (104) ◽  
pp. 20141191 ◽  
Author(s):  
Maria Molinos ◽  
Catarina R. Almeida ◽  
Joana Caldeira ◽  
Carla Cunha ◽  
Raquel M. Gonçalves ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Intervertebral Disc Degeneration ◽  
Cellular Interactions ◽  
Disc Disease ◽  
Discogenic Pain ◽  
Extracellular Matrix Remodelling ◽  
Ivd Degeneration ◽  
Regenerative Therapies

Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players.

scholarly journals Leptin signaling and the intervertebral disc: Sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model

2019 ◽  
Author(s):  
Devorah M. Natelson ◽  
Alon Lai ◽  
Divya Krishnamoorthy ◽  
Rob C. Hoy ◽  
James C. Iatridis ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Intervertebral Disc ◽  
Leptin Receptor ◽  
Leptin Signaling ◽  
Band Area ◽  
Obesity And Diabetes ◽  
Cell Proliferation And Differentiation ◽  
Ivd Degeneration

AbstractType 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.

scholarly journals Follistatin-Like 1 Attenuation Suppresses Intervertebral Disc Degeneration in Mice through Interacting with TNF-α and Smad Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shaoyi Wang ◽  
Jianlu Wei ◽  
Jie Shi ◽  
Qiting He ◽  
Xiaocong Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Inflammatory Diseases ◽  
Morphological Changes ◽  
Intervertebral Discs ◽  
Inflammatory Factors ◽  
Wild Type ◽  
Tnf Α

Background. Inflammation plays an important role in intervertebral disc degeneration (IDD). The protein follistatin-like 1 (FSTL1) plays a proinflammatory role in a variety of inflammatory diseases. Objectives. The purpose of this study was to investigate whether IDD could be delayed by inhibiting FSTL-1 expression. Methods. We established a puncture-induced IDD model in wild-type and FSTL-1+/- mice and collected intervertebral discs (IVDs) from the mice. Safranin O staining was used to detect cartilage loss of IVD tissue, and HE staining was used to detect morphological changes of IVD tissue. We measured the expression of FSTL-1 and related inflammatory indicators in IVD tissues by immunohistochemical staining, real-time PCR, and Western blotting. Results. In the age-induced model of IDD, the level of FSTL-1 increased with the exacerbation of degeneration. In the puncture-induced IDD model, FSTL-1-knockdown mice showed a reduced degree of degeneration compared with that of wild-type mice. Further experiments showed that FSTL-1 knockdown also significantly reduced the level of related inflammatory factors in IVD. In vitro experiments showed that FSTL-1 knockdown significantly reduced TNF-α-induced inflammation. Specifically, the expression levels of the inflammatory factors COX-2, iNOS, MMP-13, and ADAMTS-5 were reduced. Knockdown of FSTL-1 attenuated inflammation by inhibiting the expression of P-Smad1/5/8, P-Erk1/2, and P-P65. Conclusion. Knockdown of FSTL-1 attenuated inflammation by inhibiting the TNF-α response and Smad pathway activity and ultimately delayed IDD.

scholarly journals Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis

2021 ◽  
Vol 30 ◽  
pp. 096368972110453
Author(s):  
Wen-Cheng Lo ◽  
Chi-Sheng Chiou ◽  
Feng-Chou Tsai ◽  
Chun-Hao Chan ◽  
Samantha Mao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
In Vivo Studies ◽  
Nicotine Treatment ◽  
Physiological Processes ◽  
Signaling Axis ◽  
Cellular Apoptosis ◽  
Ivd Degeneration ◽  
Dose Dependent

Apart from aging process, adult intervertebral disc (IVD) undergoes various degenerative processes. However, the nicotine has not been well identified as a contributing etiology. According to a few studies, nicotine ingestion through smoking, air or clothing may significantly accumulate in active as well as passive smokers. Since nicotine has been demonstrated to adversely impact various physiological processes, such as sympathetic nervous system, leading to impaired vasculature and cellular apoptosis, we aimed to investigate whether nicotine could induce IVD degeneration. In particular, we evaluated dose-dependent impact of nicotine in vitro to simulate its chronic accumulation, which was later treated by platelet-derived biomaterials (PDB). Further, during in vivo studies, mice were subcutaneously administered with nicotine to examine IVD-associated pathologic changes. The results revealed that nicotine could significantly reduce chondrocytes and chondrogenic indicators (Sox, Col II and aggrecan). Mice with nicotine treatment also exhibited malformed IVD structure with decreased Col II as well as proteoglycans, which was significantly increased after PDB administration for 4 weeks. Mechanistically, PDB significantly restored the levels of IGF-1 signaling proteins, particularly pIGF-1 R, pAKT, and IRS-1, modulating ECM synthesis by chondrocytes. Conclusively, the PDB impart reparative and tissue regenerative processes by inhibiting nicotine-initiated IVD degeneration, through regulating IGF-1/AKT/IRS-1 signaling axis.

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