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TGF-βl Suppresses Inflammation in Cell Therapy for Intervertebral Disc Degeneration.

ABSTRACT: Recent studies suggest that cell therapy may be an effective way to repair intervertebral disc degeneration. As a strong immune suppressor, TGF-β1 has been shown to inhibit inflammation respond effectively. The objective of this study was to explore the effects of TGF-β1 during bone marrow mesenchymal stem cells-based therapy for disc degeneration. In vitro assays demonstrated that co-culturing of nucleus pulposus cells with bone marrow mesenchymal stem cells resulted in significantly higher levels of TGF-βl secretion. This increase inhibited IκB phosphorylation and NF-κB activation, detected by western blot analysis. Meanwhile, in a rabbit model, MRI analysis revealed significant recovery of signal intensity in the degenerative discs of rabbits receiving cells transplantation, than receiving cells treated with a TGF-β1 inhibitor or saline. These findings indicated that enhanced TGF-β1 production recovered the degeneration of intervertebral disc. And also immunohistochemical staining detected enhanced collagen II expression in the rabbits treated with cell transplantation. However, the NF-κB positive cells were significantly less than other two control groups. Thus, cell therapy promoted TGF-β1 expression in nucleus pulposus, leading to anti-inflammatory effects via the inhibition of NF-κB, and the amelioration of disc degradation due to increased expression of collagen II and aggrecan in degenerative intervertebral disc.

SUBMITTER: Yang H

PROVIDER: S-EPMC4542522 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Intervertebral disc degeneration

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-04-05 | GSE230809 | GEO

Cell Therapy for Treatment of Intervertebral Disc Degeneration: A Systematic Review.

Project description:Study designSystematic review.ObjectiveTo review, critically appraise, and synthesize evidence on use of cell therapy for intervertebral disc repair.MethodsA systematic search of PubMed/MEDLINE was conducted for literature published through October 31, 2018 and EMBASE and ClinicalTrials.gov databases through April 13, 2018 comparing allogenic or autologous cell therapy for intervertebral disc (IVD) repair in the lumbar or cervical spine. In the absence of comparative studies, case series of ≥10 patients were considered.ResultsFrom 1039 potentially relevant citations, 8 studies across 10 publications on IVD cell therapies in the lumbar spine met the inclusion criteria. All studies were small and primarily case series. For allogenic cell sources, no difference in function or pain between mesenchymal cell treatment and sham were reported in 1 small randomized controlled trial; 1 small case series reported improved function and pain relative to baseline but it was unclear if the change was clinically significant. Similarly for autologous cell sources, limited data across case series suggest pain and function may be improved relative to baseline; whether the changes were clinically significant was not clear. Safety data was sparse and poorly reported. The need for subsequent surgery was reported in 3 case-series studies ranging from 6% to 80%.ConclusionsThe overall strength of evidence for efficacy and safety of cell therapy for lumbar IVD repair was very low primarily due to substantial risk of bias, small sample sizes and lack of a comparator intervention. Methodologically sound studies comparing cell therapies to other treatments are needed.

| S-EPMC6512192 | biostudies-literature

MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology.

Project description:Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of proteincoding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.

| S-EPMC7279351 | biostudies-literature

RNA-Binding Protein HuR Suppresses Inflammation and Promotes Extracellular Matrix Homeostasis via NKRF in Intervertebral Disc Degeneration.

Project description:Intervertebral disc degeneration (IVDD) has been reported to be a major cause of low back pain. Studies have demonstrated that IVDD may be dysregulated at the transcriptional level; however, whether post-transcriptional regulation is involved is still unknown. The current study aimed to illustrate the role of Human antigen R (HuR), an RNA binding protein involved in post-transcriptional regulation, in IVDD. The results showed that the expression of HuR was decreased in degenerative nucleus pulposus (NP) tissues as well as in TNF-?-treated NP cells. Downregulation of HuR may lead to increased inflammation and extracellular matrix (ECM) degradation in TNF-?-treated NP cells; however, these effects were not reversed in HuR overexpressed NP cells. Inhibition of the NF-?B signaling pathway attenuates inflammation and ECM degradation in HuR-deficient NP cells. A mechanism study showed that HuR prompted NKRF mRNA stability via binding to its AU-rich elements, and upregulation of NKRF suppressed inflammation and ECM degradation in HuR-deficient NP cells. Furthermore, we found that NKRF, but not HuR, overexpression ameliorated the process of IVDD in rats in vivo. In conclusion, HuR suppressed inflammation and ECM degradation in NP cells via stabilizing NKRF and inhibiting the NF-?B signaling pathway; NKRF, but not HuR, may serve as a potential therapeutic target for IVDD.

| S-EPMC7732619 | biostudies-literature

MicroRNA‑200c‑3p suppresses intervertebral disc degeneration by targeting RAP2C/ERK signaling.

Project description:Intervertebral disc degeneration (IDD) is a major cause of lower back pain. The high morbidity associated with this disease diminishes the quality of life of those who are affected. MicroRNAs (miRs) play crucial roles in various diseases, including IDD. However, the mechanism via which miR‑200c‑3p plays a role in the development of IDD remains unknown. The present study aimed to investigate the effect of miR‑200c‑3p on the progression of IDD and the underlying mechanism. The expression level of miR‑200c‑3p was evaluated in intervertebral disc tissues from patients with IDD. To construct the IDD cell model, the nucleus pulposus (NP) cells were treated with lipopolysaccharide (LPS) 24 h following transfection with miR‑200c‑3p mimic or inhibitor. A luciferase activity assay was performed, while reverse transcription‑quantitative PCR and western blotting were conducted to determine the RNA and protein expression levels, respectively. The expression level of miR‑200c‑3p in the intervertebral disc tissues of patients with IDD was lower than that of normal subjects. LPS treatment reduced the expression level of miR‑200c‑3p in NP cells. Moreover, miR‑200c‑3p mimic inhibited LPS‑induced NP cell apoptosis. It was found that miR‑200c‑3p attenuated inflammatory cytokine levels and extracellular matrix (ECM) degradation in NP cells. Furthermore, miR‑200c‑3p targeted Ras‑related protein 2C (RAP2C) in NP cells. RAP2C promoted apoptosis, inflammatory cytokine levels and ECM degradation by activating ERK signaling. Knockdown of RAP2C and inhibition of ERK signaling by SCH772984 partially reversed the proinflammatory effect of the miR‑200c‑3p inhibitor on LPS‑treated NP cells. Thus, miR‑200c‑3p inhibits NP cell apoptosis, inflammatory cytokine levels and ECM degradation in IDD by targeting RAP2C/ERK signaling.

| S-EPMC8554383 | biostudies-literature

Treatment of Intervertebral Disc Degeneration.

Project description:Intervertebral disc degeneration (IDD) causes a variety of signs and symptoms, such as low back pain (LBP), intervertebral disc herniation, and spinal stenosis, which contribute to high social and economic costs. IDD results from many factors, including genetic factors, aging, mechanical injury, malnutrition, and so on. The pathological changes of IDD are mainly composed of the senescence and apoptosis of nucleus pulposus cells (NPCs), the progressive degeneration of extracellular matrix (ECM), the fibrosis of annulus fibrosus (AF), and the inflammatory response. At present, IDD can be treated by conservative treatment and surgical treatment based on patients' symptoms. However, all of these can only release the pain but cannot reverse IDD and reconstruct the mechanical function of the spine. The latest research is moving towards the field of biotherapy. Mesenchymal stem cells (MSCs) are regard as the potential therapy of IDD because of their ability to self-renew and differentiate into a variety of tissues. Moreover, the non-coding RNAs (ncRNAs) are found to regulate many vital processes in IDD. There have been many successes in the in vitro and animal studies of using biotherapy to treat IDD, but how to transform the experimental data to real therapy which can apply to humans is still a challenge. This article mainly reviews the treatment strategies and research progress of IDD and indicates that there are many problems that need to be solved if the new biotherapy is to be applied to clinical treatment of IDD. This will provide reference and guidance for clinical treatment and research direction of IDD.

| S-EPMC9251272 | biostudies-literature

Intervertebral Disc Biology: Genetic Basis of Disc Degeneration.

Project description:Purpose of reviewThis review aims to highlight recent advances in understanding the genetic basis of intervertebral disc degeneration (IDD).Recent findingsIt has been known for some time that IDD is highly heritable. Recent studies, and in particular the availability of agnostic techniques such as genome-wide association studies, have identified new variants in a variety of genes which contribute to the risk of IDD and to back pain.SummaryA variety of genetic variants are involved in IDD. Some are shared with variants predisposing to back pain, but few have been identified reliably in either phenotype. Further research is required to explain fully the high heritability and how the genetic variants influence cell biology to lead to IDD.

| S-EPMC6223888 | biostudies-literature

Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions.

Project description:Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.

| S-EPMC7846842 | biostudies-literature

Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway.

Project description:Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of low back pain (LBP), which causes an enormous socioeconomic burden. Previous studies demonstrated that the apoptosis of nucleus pulposus (NP) cells and the dyshomeostasis of extracellular matrix (ECM) contributed to the pathogenesis of IDD, and effective therapies were still lacking. Quercetin, a natural flavonoid possessing a specific effect of autophagy stimulation and SIRT1 activation, showed some protective effect on a series of degenerative diseases. Based on previous studies, we hypothesized that quercetin might have therapeutic effects on IDD by inhibiting the apoptosis of NP cells and dyshomeostasis of ECM via the SIRT1-autophagy pathway. In this study, we revealed that quercetin treatment inhibited the apoptosis of NP cells and ECM degeneration induced by oxidative stress. We also found that quercetin promoted the expression of SIRT1 and autophagy in NP cells in a dose-dependent manner. Autophagy inhibitor 3-methyladenine (3-MA) reversed the protective effect of quercetin on apoptosis and ECM degeneration. Moreover, SIRT1 enzymatic activity inhibitor EX-527, suppressed quercetin-induced autophagy and the protective effect on NP cells, indicating that quercetin protected NP cells against apoptosis and prevented ECM degeneration via SIRT1-autophagy pathway. In vivo, quercetin was also demonstrated to alleviate the progression of IDD in rats. Taken together, our results suggest that quercetin prevents IDD by promoting SIRT1-dependent autophagy, indicating one novel and effective therapeutic method for IDD.

| S-EPMC7758489 | biostudies-literature

Preclinical development of a microRNA-based therapy for intervertebral disc degeneration.

Project description:Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). Here we present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. Gain- and loss-of-function studies show that miR-141 drives IDD by inducing nucleus pulposus (NP) apoptosis. Furthermore, miR-141 KO in mice attenuated spontaneous and surgically induced IDD. Mechanistically, miR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-?B pathway. Therapeutically, upregulation or downregulation of miR-141 by nanoparticle delivery in IDD model aggravated or alleviated experimental IDD, respectively. Our findings reveal a novel mechanism by which miR-141, in part, promotes IDD progression by interacting with SIRT1/NF-?B pathway. Blockade of miR-141 in vivo may serve as a potential therapeutic approach in the treatment of IDD.

| S-EPMC6262020 | biostudies-literature

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