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

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.

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Inflammation in intervertebral disc degeneration and regeneration

Journal of The Royal Society Interface ◽

10.1098/rsif.2014.1191 ◽

2015 ◽

Vol 12 (104) ◽

pp. 20141191 ◽

Cited By ~ 104

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.

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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

10.1101/2019.12.23.887018 ◽

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.

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

10.1101/720656 ◽

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.

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

Cell Transplantation ◽

10.1177/09636897211045319 ◽

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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Males and females exhibit distinct relationships between intervertebral disc degeneration and pain in a rat model

Scientific Reports ◽

10.1038/s41598-020-72081-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Grace E. Mosley ◽

Minghui Wang ◽

Philip Nasser ◽

Alon Lai ◽

Daniel A. Charen ◽

...

Keyword(s):

Sex Differences ◽

Network Analysis ◽

Intervertebral Disc ◽

Rat Model ◽

Biomechanical Testing ◽

Sprague Dawley ◽

Discogenic Pain ◽

Males And Females ◽

Ivd Degeneration

Abstract Back pain is linked to intervertebral disc (IVD) degeneration, but clinical studies show the relationship is complex. This study assessed whether males and females have distinct relationships between IVD degeneration and pain using an in vivo rat model. Forty-eight male and female Sprague–Dawley rats had lumbar IVD puncture or sham surgery. Six weeks after surgery, IVDs were evaluated by radiologic IVD height, histological grading, and biomechanical testing. Pain was assessed by von Frey assay and dorsal root ganglia (DRG) expression of Calca and Tac1 genes. Network analysis visualized which measures of IVD degeneration most related to pain by sex. In both females and males, annular puncture induced structural IVD degeneration, but functional biomechanical properties were similar to sham. Females and males had distinct differences in mechanical allodynia and DRG gene expression, even though sex differences in IVD measurements were limited. Network analysis also differed by sex, with more associations between annular puncture injury and pain in the male network. Sex differences exist in the interactions between IVD degeneration and pain. Limited correlation between measures of pain and IVD degeneration highlights the need to evaluate pain or nociception in IVD degeneration models to better understand nervous system involvement in discogenic pain.

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TonEBP regulates the hyperosmotic expression of aquaporin 1 and 5 in the intervertebral disc

Scientific Reports ◽

10.1038/s41598-021-81838-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

J. W. Snuggs ◽

S. Tessier ◽

R. A. B. Bunning ◽

I. M. Shapiro ◽

M. V. Risbud ◽

...

Keyword(s):

Gene Expression ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Central Region ◽

Aquaporin 1 ◽

Enhancer Binding Protein ◽

Ivd Degeneration ◽

Hyperosmotic Environment

AbstractThe central region of the intervertebral disc (IVD) is rich in proteoglycans, leading to a hyperosmotic environment, which fluctuates with daily loading. The cells of the nucleus pulposus (NP cells) have adapted to this environment via the function of tonicity enhancer binding protein (TonEBP), and NP cells have been shown to express several water channels known as aquaporins (AQP). We have previously shown that AQP1 and 5 decrease during IVD degeneration. Here, the regulation of AQP1 and 5 by hyperosmotic conditions and the role of TonEBP in this regulation was investigated. AQP1 and 5 gene expression was upregulated by hyperosmotic conditions mimicking the osmolality of the healthy IVD, which was abrogated by TonEBP knockdown. Furthermore, AQP1 and 5 immunopositivity was significantly reduced in TonEBPΔ/Δ E17.5 mice when compared with wildtype controls, indicating in vivo expression of AQP1 and 5 is controlled at least in part by TonEBP. This hyperosmotic regulation of AQP1 and 5 could help to explain the decreased AQP1 and 5 expression during degeneration, when the osmolality of the NP decreases. Together this data suggests that TonEBP-regulated osmo-adaptation may be disrupted during IVD degeneration when the expression of both AQPs is reduced.

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Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study

BioMed Research International ◽

10.1155/2016/5498271 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Marion Fusellier ◽

Pauline Colombier ◽

Julie Lesoeur ◽

Samy Youl ◽

Stéphane Madec ◽

...

Keyword(s):

Animal Models ◽

Intervertebral Disc ◽

Disc Degeneration ◽

Enzyme Treatment ◽

In Vivo Model ◽

Regenerative Approach ◽

Radiation Induced ◽

Longitudinal Comparison ◽

Ivd Degeneration

Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos’ scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos’ scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration.

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Bony Stress and Its Association With Intervertebral Disc Degeneration in the Lumbar Spine: a Review of Clinical and Basic Science Studies

10.21203/rs.3.rs-51303/v1 ◽

2020 ◽

Author(s):

Daniel Chepurin ◽

Uphar Chamoli ◽

Ashish D. Diwan

Keyword(s):

Lumbar Spine ◽

Intervertebral Disc ◽

Causal Relationship ◽

Basic Science ◽

Science Studies ◽

Biomechanical Testing ◽

Element Analysis ◽

Ivd Degeneration

Abstract BackgroundMultiple components of the lumbar spine interact during the normal and pathological function. Bony stress in the lumbar spine is recognised as a factor in the development of pars defects and stress fractures, but its relationship with intervertebral disc (IVD) degeneration is not well understood. Therefore, a translational review encompassing basic science and clinical evidence was conducted to examine the relationship between bony stress in the lumbar spine and IVD degeneration.MethodsOnline databases Scopus, PubMed and MEDLINE via OVID were searched for relevant studies published between January 1980 – February 2020, using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Two authors independently analysed the data, noting study characteristics and bias.ResultsThirty-two articles were included in the review: eight human studies, nine finite element analysis studies, three in-vivo biomechanical testing studies, and twelve in-vitro biomechanical testing studies. Of the 32 articles, 19 supported, four rejected and nine made no conclusion on the hypothesis that there is a positive associative relationship between IVD degeneration and bony stress. However, not enough evidence was available to confirm or reject a causal relationship.ConclusionMost studies suggest that the prevalence of IVD degeneration increases with the presence of bony stress, but whether a causal relationship exists is unclear. The literature recommends early diagnosis and clinical suspicion of IVD degeneration and bony stress. Longitudinal studies are required to explore causal relationships between IVD degeneration bony stress.

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