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Treatment of Intervertebral Disc Degeneration

Jingguo Xin, Yongjie Wang, Zhi Zheng and 3 more

Orthopaedic Surgery · 2022 · Review · CC BY

doi:10.1111/os.13254

Abstract

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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Intervertebral disc degeneration (IDD) is a pathological change defined as the aging process and damage of intervertebral disc (IVD) caused by a series of complex molecular mechanisms that finally leads to serious clinical symptoms. Low back pain (LBP) is one of the typical clinical symptoms of IDD. It is not only a common reason for patients to go to the hospital, but also one of the leading causes of disability., Almost all people have transient attacks of LBP in their lives, and a small number of people will experience chronic LBP, which places a significant burden on the social economy, including not only the costs of treating patients (direct costs) but also the loss of social productivity (indirect costs)., IDD can be induced by a variety of factors, such as aging, heredity factors, mechanical loading, obesity, and even smoking.,,,,, The degeneration of IVD happens earlier than in other tissues of the body, as early in adolescence., With the increase of age, the number of people affected by IVD increases sharply. About 10% of the 50‐year‐old population suffer from IDD, and in 70‐year‐old people, this number will increases to about 60%.

IVDs are located between the upper and lower vertebrae, firmly connecting the centrums, and the IVDs can decompress, absorb shocks, and increase the range of spinal movement (Figure 1A). Each IVD consists of three elements: nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplate (CEP) (Figure 1B). In normal adults, there are few blood vessels in the IVD and most of the nutrient supply of IVD mainly depends on the infiltration from the CEP, which are the reasons why the IVD easily degenerates. The effect of IDD is mainly to change the movement and biomechanics of IVD, consequently affecting the mechanics of the spine. The intensity of normal IVD is primarily affected by the components of extracellular matrix (ECM). With age, the proteoglycan of ECM is lost and hydration ability decreases gradually, which leads to progressive dehydration of IVD, especially nucleus pulposus (NP)., Although the function of each IVD is about the same, according to the spinal cord segment in which it is located, their structure will change to adapt to the different stresses. The thickness and intensity of different parts of the AF are also different, for example, the posterior part of the lumbar intervertebral disc is thinner, and there is no collagen fiber interweaving in the posterior part, so the intensity of the posterior part is lower than other parts, which explains why disc herniation often occurs at the back of the IVD (Figure 1C). At the cellular level, environmental factors can accelerate the death of the cell through apoptosis or necrosis; these cellular processes, in turn, may further promote the pathogenesis of IDD. For example, the apoptosis and necrosis of NPCs not only reduce the number of functional cells but also release the inflammatory factors, which will further worsen the microenvironment of the IVD, leading to further degeneration of the IVD. Degeneration accumulation will cause clinical symptoms, then the patient needs to go to the hospital. At present, the main clinical treatments for IDD include conservative treatment and surgical treatment, which can relieve symptoms and reduce pain but cannot reverse the IDD, so the scientific community is beginning to study new biotherapy to delay or reverse the IDD. Many experiments in vitro have proved that biotherapy can promote the proliferation of NPCs, inhibit the fibrosis of IVD, preserve the water content and reverse the process of IDD. This article reviews the standard therapy and new biotherapy of IDD and puts forward the direction and prospect in the future.

Conservative Treatment

Conservative treatment is mainly suitable for the treatment of patients with early IDD, its main purpose is to relieve a patient's LBP and improve quality of life, which cannot cure the IVD, so it is regarded as palliative treatment. With the aggravation of IDD, conservative treatment often cannot control the clinical symptoms, and further surgical treatment will be taken.

Drug Therapy

Currently, the commonly used drugs for the treatment of LBP are non‐steroidal anti‐inflammatory drugs (NSAIDs), opioid painkillers, muscle relaxants, benzodiazepines, antidepressants, corticosteroids, antiepileptic drugs, and so on. NSAIDs are widely used to treat LBP patients, including non‐selective NSAIDs and selective COX‐2 NSAIDs. A published Cochrane review suggested that NSAIDs are more effective than placebo for treating LBP (small magnitude) and low risk of side effects (maybe underestimated because of small sample size). Opioids are mainly used in patients with acute attacks, severe pain and are difficult to relieve. Constipation and sedation are the most common adverse symptoms, but the dosage and duration of opioids are controversial because of their addiction and central dependence. Muscle relaxants can relieve muscle spasm around the spine and are effective for patients with LBP. As adjunctive therapy, it could be more effective, however, with a higher risk of central nervous system adverse effects. Benzodiazepines have been used as muscle relaxants to treat LBP and the most common side effects are drowsiness and dizziness. Anoher random controlled trial suggested that benzodiazepines should be considered standard of care for patients with sciatica associated with lumbar disc prolapse. Regarding antidepressants, two systematic reviews reported that they can relieve physical pain,, but a randomized clinical trial suggested there was no difference in improvement in pain intensity between intervention group (low‐dose amitriptyline) and control group (placebo) after 6 months of treatment. Epidural steroid injections are one of the most common pain relief injections. Steroids inhibit the production of inflammatory chemicals in the body's immune system, which may be a source of pain. Chou et al. suggested that using epidural corticosteroid injections to treat spinal stenosis could reduce pain immediately but had no long‐term benefit. Antiepileptic drugs are also considered a useful treatment for LBP. In one study, the researchers chose topiramate for 48 patients with LBP and the results indicated that topiramate is a relatively safe and effective agent in the treatment of LBP. Taken together, these drugs have their unique effects and complications. In clinical practice, the severity of pain, the duration of symptoms, the risk factors of complications, and the cost of treatment should be considered when weighing and selecting treatment drugs. The drug chosen for the patient should be the best choice to balance all factors.

Non‐drug Therapy

Non‐drug therapy mainly includes bed rest, traction, stent fixation, exercise therapy, acupuncture, massage, electromagnetic or electrothermal therapy, psychotherapy, and so on.,, These methods are used in many disciplines and fields and are often combined with drug therapy or surgery. Guo et al. studied the difference between low‐tension traction mode and high‐tension traction mode in traction therapy by establishing a mechanical degeneration model of IVD. The results showed that compared with high‐tension traction mode, low‐tension traction provides a stable microenvironment for the repairment of IVD and protects IVD functional cells better. And they further found that low‐tension traction combined with extracorporeal shock wave therapy could reduce the expression of MMP3, MMP13, and ADAMTS‐4. It is well‐known that MMPs and ADAMTS can promote collagen degradation, which leads to IDD. Therefore, low‐tension traction combined with extracorporeal shock wave therapy can further restore the microenvironment of degenerative IVD, reduce the tension of NP and AF, and alleviate the degeneration of IVD. After IDD, the biomechanical function of IVD decreased, and the spine lacked support and stability. Physical exercise can improve the strength of paraspinal muscles, provide support for the spine, and contribute to the proliferation of IVD cells. Buyukturan et al. conducted a randomized controlled trial that revealed that exercise can relieve pain and enhance muscle endurance. Transcutaneous Electrical Nerve Stimulation can also relieve pain according to two trials,; however, it does not show any advantages compared with the exercise therapy. Although the above treatments cannot reverse the degenerative changes of IVD, they can relieve pain caused by IDD by stimulating cells, promoting metabolite transport, and preventing adhesion and re‐injury. In clinical practice, these treatments have a place in the treatment of patients with early iodine deficiency because they are non‐invasive and low‐cost.

Interventional Treatment

The internal mechanics of the IVD can be changed and the neuropathic pain can be treated by heating, radiofrequency or injection of various chemicals into the IVD. These methods include intra‐discal electrothermal therapy (IDET),, radiofrequency myeloplasty, chemical nucleolysis by intradiscal injection such as ozone,, percutaneous discectomy,, and so on. These techniques hope to relieve a patient's symptoms by reconstructing the structure and shape of the IVD. Generally, the heating probe, radiofrequency probe or cutting device is introduced into the pathological area, which usually needs to be operated under the guidance of CT or fluoroscopy. Heating and radiofrequency can reduce inflammation and cause tissue contraction to reduce compression. In general, the common goal of these techniques is to reduce the pressure in the spinal canal, thereby liberating nerve root compression and reducing the clinical symptoms of patients. With the development of endoscope technology in spine surgery, these techniques have changed from non‐visual indirect reduction to visually direct operation. The possible mechanism of IVD injection of ozone in the treatment of IDD is that ozone can reduce the herniated NP and reduce the inflammatory reaction, thus reducing the pain of patients. Studies by Elawamy et al. and Ercalik et al. have shown that IVD injection of ozone can effectively control disc herniation and relieve the pain caused by it. After these conservative treatments, if a patient's symptoms cannot be controlled or are aggravated, further surgical treatments will be needed.

Intervertebral Disc Fusion

Intervertebral disc fusion has always been regarded as the standard for surgical treatment of symptomatic IDD. The choice of the surgical approach includes anterior approach, posterior approach, posterolateral approach, and so on. Minimally invasive surgery and open surgery are both available, and the surgical technique is quite mature, which is suitable for the vast majority of patients with IDD. Some studies have found that in intervertebral disc fusion surgery, compared with open surgery, the clinical effect of minimally invasive surgery is similar to open surgery and has great advantages in reducing muscle edema and surgical bleeding and contributing to postoperative functional recovery., Minimally invasive intervertebral disc fusion surgery uses a smaller skin incision and reduces paraspinal muscle peeling and soft tissue injury. Therefore, intraoperative blood loss and postoperative pain will be less, postoperative functional recovery will be faster, and hospital stay will be shorter. But, the minimally invasive approach takes longer operation time and requires more proficient operators than the open approach.

Intervertebral disc fusion surgery usually involves the following steps. First, the surgeon separates the tissue and removes the damaged IVD, cleans up the IVD space, then places the prepared cage into the intervertebral space, which provides additional support for the spine after the operation. Then pedicle screws are used to fix the upper and lower vertebrae. After completing this critical step, the operator uses X‐rays to observe and correct the angle of screw placement and check the position of the cage. If the operation is not effective or the movement pattern of the adjacent segments is changed, it may lead to further degeneration of additional IVD and motor segments. Once this happens, a second operation may be needed.

In terms of pain relief and functional improvement, the effect of intervertebral disc fusion is effective. Fritzell et al. conducted a clinical randomized controlled study with visual analog scale (VAS) score and Oswestry (OS) questionnaire as criteria for follow‐up. The results revealed that lumbar fusion surgery can effectively reduce pain and disability compared with non‐operative treatment. But the study is considered unreasonable because it compares routine care and fusion surgery rather than more comprehensive conservative treatments such as exercise therapy. After that, Brox et al. also designed a randomized controlled study involving 64 patients, which suggested that fusion surgery relieved pain and improved motor function effectively, but there was no significant statistical difference between conservative treatment and fusion surgery except OS index. The sample size of this study is small and the follow‐up time is only 1 year, so larger samples and longer studies are required to improve the recommendation evidence of intervertebral disc fusion.

Although intervertebral disc fusion can relieve discogenic pain caused by IDD and improve patients' disability, it can cause severe problems in the long run because it eliminates the movement of the adjacent vertebral body. When two vertebrae are fused, it seriously limits the damping effect of the IVD during motion, increasing the load and stress of the surrounding tissue and IVD, which will lead to the degeneration of other IVD in adjacent segments. Therefore, in the past few years there has been a growing interest in total disc replacement because it can maintain the movement of the centrum.

Total Disc Replacement

Total disc replacement (TDA) was used by Fernström firstly in the 1960s. He implanted a stainless steel ball into 191 lumbar IVD and 13 cervical IVD of 125 patients, and the clinical effect was similar to that of intervertebral disc fusion. However, the sinking and squeezing of the ball caused severe complications. With the development of biomaterials and the advent of artificial IVD, disc replacement is successful. At present, a large number of studies have produced evidence about the safety and effectiveness of TDA and proved that it is not inferior to the clinical efficacy of intervertebral disc fusion and provides the mobility of lumbar segments that intervertebral disc fusion surgery cannot provide. Skold et al. compared TDA with intervertebral disc fusion. Although both operations had satisfactory results for pain relief, TDA showed a better trend at 5‐year follow‐up. The randomized controlled trial of Furunes et al. demonstrated that there was no significant difference in the increase in the rate of adjacent segment degeneration after TDA compared with the non‐operative group, indicating that TDA does not increase the risk of adjacent segment degeneration. Berg et al. used distortion‐compensated Roentgen analysis to evaluate the difference between TDA and intervertebral disc fusion. Clinically, the surgical results of the TDA group were better, but there was no conclusion to explain the difference in terms of activity.

Qualified intervertebral disc implants must meet these requirements: (i) maintain or restore the IVD function; (ii) high mobility, low friction, and high wear‐resistance; (iii) high stability when long‐term fixation; (iv) the ability to perform postoperative imaging. Moreover, lumbar disc implants are different from the cervical, not only because the load magnitude of lumbar is greater than cervical but also because of the moving patterns difference.

Compared with intervertebral disc fusion, there seems to be no significant difference in the incidence of surgical complications of TDA. One study indicated that there were more surgical approach‐related complications in the TDA group than in the LIF group, while another study showed that there was no significant difference between the two groups. Disc replacement‐related complications included facet dislocation, pedicle fracture, device dislocation, and vertebral split fracture.,,, Once complications occur, patients may experience postsurgical interventions. There are four types of interventions: revision, device removal, supplemental fixation, and reoperation. The risk of these interventions is time‐specific regardless if a patient is healthy or not.

In the field of surgery, there are always contradictory data in the comparison of intervertebral disc replacement and fusion. Each operation is supported by corresponding evidence and it is also affected by the experience and ability of surgeons. In the actual diagnosis and treatment, in the case of ineffective conservative treatment, we can choose any kind of operation as long as it can reduce the pain of patients. Achieving good patient satisfaction is the most important.

Biotherapy

Recent studies have explored how to use mesenchymal stem cells and gene therapy to prevent, slow down, or even reverse IDD, and may provide a new direction for the treatment of IDD. A brief overview of this section will be given below.

Mesenchymal Stem Cell Therapy

Mesenchymal stem cells (MSCs) are pluripotent adult stem cells with the ability to self‐renew and differentiate into a variety of tissues, including bone marrow mesenchymal stem cells (BM‐MSCs), cartilage mesenchymal stem cells, muscle mesenchymal stem cells, and adipose mesenchymal stem cells.,, In the past few decades, the scientific community has devoted a lot of energy to the study of MCSs in order to apply them to the field of IDD, and some progress has been made.

Molecular Mechanisms of Mesenchymal Stem Cells in IDD

In 2003, Sakai et al. found that BM‐MSCs can slow down rabbit IDD, which laid a theoretical foundation for the follow‐up study of BM‐MSCs in IDD. One of the applications of MSCs in the treatment of intervertebral disc degeneration is implanting cells directly into the damaged intervertebral disc. However, the degenerative intervertebral disc is characterized by hypoxia,, low glucose, increased acidity,, high osmotic pressure, mechanical load,, and increased inflammatory factors,, which has a great effect on the survival of MSCs in the intervertebral disc. At the same time, it is also a significant challenge for MSCs in the treatment of intervertebral disc degeneration. Therefore, it is thought that embedding cells with some kind of scaffold and implanting intervertebral disc can promote the inoculation, proliferation, and differentiation of MSCs. In one study rabbit BM‐MSCs were loaded with novel nanofibre sponge microspheres to regenerate NP. The results showed that the complex of this material and BM‐MSCs could promote BM‐MSCs to differentiate into NP phenotype, produce ECM, maintain IVD height, and prevent IVD calcification.

The molecular mechanism of MSCs in the treatment of IDD is very complex. Xu et al. found that overexpression of BMP7 can promote BM‐MSCs to differentiate into NPCs, promote the differentiation and proliferation of NPCs in rabbit IVD, and restore the homeostasis of ECM. At the same time, these effects can be inhibited by Smad1 silencing. Yang et al. found that BM‐MSCs can secrete an anti‐inflammatory protein, TSG‐6, which can inhibit TLR2/NF‐κB pathway to reduce the production of inflammatory factors IL‐6 and TNF‐α, and then delay the inflammatory response in IDD. Growth differentiation factor 6 (GDF6) was found that could promote MSCs differentiation towards NPC type and increase ECM components expression.

Mesenchymal Stem Cell‐related Research in Treating IDD

As mentioned earlier, MSCs is a very potential site for the treatment of IDD. At present, there have been corresponding clinical trials and case reports on the use of MSCs in the treatment of patients with IDD. Kumar et al. conducted a 12‐month phase 1 clinical trial in which autologous adipose‐derived mesenchymal stem cells were obtained from 10 patients and injected into the IVD tissue of patients in conjunction with a hyaluronic acid derivative Tissuefill. Finally, the VAS pain score and ODI score of six patients improved significantly, of which three patients had intervertebral disc rehydration. Pettine et al. recruited 26 patients to receive autologous BM‐MSCs injections. Pain symptoms were alleviated in all subjects, and eight patients improved a Pfirrmann grade. They also suggested that the efficacy of the treatment was related to the concentration of the cells injected. Elabd et al. recruited five patients to receive autologous BM‐MSCs. All patients were followed up for more than 4 years, and all patients showed overall improvement in symptoms, which indicated that BM‐MSCs therapy was safe in the long term.

Although encouraging achievements have been made in the application of MSCs in the treatment of IDD, there are still some problems. First of all, we still need to further study the molecular mechanism of MSCs in the treatment of intervertebral disc degeneration, including their targets and signal pathways, some biomolecules that can promote the efficacy of MSCs and establish a complete molecular mechanism structure. Finally, a large number of high‐quality clinical studies are still needed to test the feasibility and safety of MSCs therapy.

Non‐coding RNAs and its roles in IDD

Non‐coding RNAs (NcRNAs), which include microRNAs (miRNAs), circRNAs, and long non‐coding RNAs (lncRNAs), cannot be transcribed and translated into proteins, but play an important role in molecular regulation. Among them, miRNAs generally directly target a protein or signal pathway to play its regulatory function. circRNAs and lncRNAs generally act as miRNAs sponges and regulate the expression of miRNAs. At present, it has been confirmed that ncRNAs play a vital role in the treatment of tumour and cardiovascular disease, and more and more people study its role in IDD. In recent years, more and more data have shown that there are significant differences in the expression of some ncRNAs between the IVD tissues of patients with IDD and that of normal persons, indicating that ncRNAs are involved in regulating the formation of IDD, some promote the occurrence of IDD, and some inhibit the occurrence of IDD.

Non‐coding RNAs and its targets in IDD

There are a variety of molecular mechanisms and biological effects of ncRNAs in regulating IDD (Table S1).,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, NcRNAs plays a vital role in cell proliferation, cell apoptosis, cell autophagy, ECM degeneration or degradation, inflammation, and so on. Bcl‐2 is a protein related to the regulation of cell apoptosis, and the apoptosis of NPCs is an important link in IDD, so Bcl‐2 is also an important target in IDD. miRNA‐143, miRNA‐155, and miRNA‐222 have been reported to regulate the apoptosis of NPCs by targeting Bcl‐2. lncRNA‐GAS5 acts as a miRNA‐155 sponge to regulate its expression. On the other hand, the degeneration and degradation of ECM is also an important link in IDD. The MMP family is a zinc‐dependent metallopeptidase family that participates in the degradation of ECM components. Therefore, the MMP family is also a research hotspot in the field of IDD. It is reported that miRNA‐202‐3p targeting MMP1; miRNA‐17‐3p, miRNA‐93 targeting MMP2, and MMP3 is the target of miRNA‐31‐5p, which are involved in the regulation of ECM degradation of IVD. Moreover, miRNA‐133a target MMP9 inducing the loss of type Ⅱ collagen which is the important component of ECM. Other MMPs are also reported that relating to the ECM degradation and causing IDD such as MMP13, MMP14 and MMP16.,,, Interestingly, some miRNAs have been reported many times to target different pathways or related proteins involved in the regulation of different aspects of IDD. miRNA‐155 can target TCF7L2, C/EBPβ, ERK1/2, and MMP16 involved in regulating the degradation of ECM and the expression of inflammatory factors in the inflammatory response.

As mentioned earlier, ncRNA is also a potential unit for the treatment of IDD, but how to transform the relationship between ncRNA and IDD into practical treatment is an urgent problem. It is also not known whether the use of ncRNA in the treatment of human IDD can achieve the same effect as at the cellular level and in animal experiments.

Conclusion and Future Perspective

IDD is a common clinical degenerative disease, which can easily lead to low back pain, disc herniation, and other diseases, seriously affecting the quality of life of patients and bringing great economic burden to the society. At present, there are standard treatments for intervertebral disc degeneration in clinic, but these treatments encounter a “bottleneck,” that is, they can not reverse the occurrence of IDD, but can only relieve the pain of patients. Treatments based on MSCs and ncRNA are potential targets for the treatment of IDD and are of great research value. The molecular mechanism of MSCs in the treatment of IDD needs to be further explored, and a large number of clinical trials need to be designed to verify its feasibility and safety. Quite a number of ncRNA experiments have been carried out, but the role of some ncRNA in IDD is still controversial and needs to be verified by further experiments. Verified by reliable clinical trials, these reported data can be directly used in gene therapy for IDD, and drugs targeting ncRNA can also be designed to provide new ideas for the treatment of IDD.

Conflict of Interests

The authors have declared that there are no competing interests.

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    Ramos L, Callegari B, França F, et al. Comparison between transcutaneous electrical nerve stimulation and stabilization exercises in fatigue and Transversus abdominis activation in patients with lumbar disk herniation: a randomized study. J Manipulative Physiol Ther. 2018;41:323–31.

    Not in our library10.1016/j.jmpt.2017.10.010

  33. 33.

    Stamuli E, Kesornsak W, Grevitt MP, Posnett J, Claxton K. A cost‐effectiveness analysis of intradiscal electrothermal therapy compared with circumferential lumbar fusion. Pain Pract. 2018;18:515–22.

    Not in our library10.1111/papr.12641

  34. 34.

    Helm Ii S, Simopoulos TT, Stojanovic M, Abdi S, El Terany MA. Effectiveness of thermal annular procedures in treating discogenic low Back pain. Pain Physician. 2017;20:447–70.

    Not in our library

  35. 35.

    Kapural L, Vrooman B, Sarwar S, et al. A randomized, placebo‐controlled trial of transdiscal radiofrequency, biacuplasty for treatment of discogenic lower back pain. Pain Med. 2013;14:362–73.

    Not in our library10.1111/pme.12023

  36. 36.

    Ezeldin M, Leonardi M, Princiotta C, et al. Percutaneous ozone nucleolysis for lumbar disc herniation. Neuroradiology. 2018;60:1231–41.

    Not in our library10.1007/s00234-018-2083-4

  37. 37.

    Das G, Ray S, Ishwarari S, Roy M, Ghosh P. Ozone nucleolysis for management of pain and disability in prolapsed lumber intervertebral disc. A prospective cohort study. Interv Neuroradiol. 2009;15:330–4.

    Not in our library10.1177/159101990901500311

  38. 38.

    Pan M, Li Q, Li S, et al. Percutaneous endoscopic lumbar discectomy: indications and complications. Pain Physician. 2020;23:49–56.

    Not in our library

  39. 39.

    Hirsch JA, Singh V, Falco FJ, Benyamin RM, Manchikanti L. Automated percutaneous lumbar discectomy for the contained herniated lumbar disc: a systematic assessment of evidence. Pain Physician. 2009;12:601–20.

    Not in our library

  40. 40.

    Elawamy A, Kamel EZ, Hassanien M, Wahba OM, Amin SE. Implication of two different doses of Intradiscal ozone‐oxygen injection upon the pain alleviation in patients with low Back pain: a randomized, single‐blind study. Pain Physic. 2018;21:E25–31.

    Not in our library

  41. 41.

    Ercalik T, Kilic M. Efficacy of Intradiscal ozone therapy with or without Periforaminal steroid injection on lumbar disc herniation: a double‐blinded controlled study. Pain Physician. 2020;23:477–84.

    Not in our library

  42. 42.

    Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine (Phila Pa 1976). 2012;37:67–76.

    Not in our library10.1097/brs.0b013e31820cccfb

  43. 43.

    Taher F, Essig D, Lebl DR, et al. Lumbar degenerative disc disease: current and future concepts of diagnosis and management. Adv Orthop. 2012;2012:970752.

    Not in our library10.1155/2012/970752

  44. 44.

    Park Y, Ha JW. Comparison of one‐level posterior lumbar interbody fusion performed with a minimally invasive approach or a traditional open approach. Spine (Phila Pa 1976). 2007;32:537–43.

    Not in our library10.1097/01.brs.0000256473.49791.f4

  45. 45.

    Stevens KJ, Spenciner DB, Griffiths KL, et al. Comparison of minimally invasive and conventional open posterolateral lumbar fusion using magnetic resonance imaging and retraction pressure studies. J Spinal Disord Tech. 2006;19:77–86.

    Not in our library10.1097/01.bsd.0000193820.42522.d9

  46. 46.

    Lin EY, Kuo YK, Kang YN. Effects of three common lumbar interbody fusion procedures for degenerative disc disease: a network meta‐analysis of prospective studies. Int J Surg. 2018;60:224–30.

    Not in our library10.1016/j.ijsu.2018.11.009

  47. 47.

    Fritzell P, Hägg O, Wessberg P, Nordwall A. 2001 Volvo award winner in clinical studies: lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish lumbar spine study group. Spine (Phila Pa 1976). 2001;26:2521–32; discussion 2532–2534.

    Not in our library10.1097/00007632-200112010-00002

  48. 48.

    Brox JI, Sørensen R, Friis A, et al. Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration. Spine (Phila Pa 1976). 2003;28:1913–21.

    Not in our library10.1097/01.brs.0000083234.62751.7a

  49. 49.

    Kumar MN, Jacquot F, Hall H. Long‐term follow‐up of functional outcomes and radiographic changes at adjacent levels following lumbar spine fusion for degenerative disc disease. Eur Spine J. 2001;10:309–13.

    Not in our library10.1007/s005860000207

  50. 50.

    Fernström U. Arthroplasty with intercorporal endoprothesis in herniated disc and in painful disc. Acta Chir Scand Suppl. 1966;357:154–9.

    Not in our library

  51. 51.

    Sköld C, Tropp H, Berg S. Five‐year follow‐up of total disc replacement compared to fusion: a randomized controlled trial. Eur Spine J. 2013;22:2288–95.

    Not in our library10.1007/s00586-013-2926-y

  52. 52.

    Furunes H, Hellum C, Espeland A, et al. Adjacent disc degeneration after lumbar Total disc replacement or nonoperative treatment: a randomized study with 8‐year follow‐up. Spine (Phila Pa 1976). 2018;43:1695–703.

    Not in our library10.1097/brs.0000000000002712

  53. 53.

    Berg S, Tropp HT, Leivseth G. Disc height and motion patterns in the lumbar spine in patients operated with total disc replacement or fusion for discogenic back pain. Results from a randomized controlled trial. Spine J. 2011;11:991–8.

    Not in our library10.1016/j.spinee.2011.08.434

  54. 54.

    Taksali S, Grauer JN, Vaccaro AR. Material considerations for intervertebral disc replacement implants. Spine J. 2004;4:231S–8S.

    Not in our library10.1016/j.spinee.2004.07.012

  55. 55.

    Lee WT, Liu G, Thambiah J, Wong HK. Clinical outcomes of single‐level lumbar artificial disc replacement compared with transforaminal lumbar interbody fusion in an Asian population. Singapore Med J. 2015;56:208–11.

    Not in our library10.11622/smedj.2015032

  56. 56.

    Holt RT, Majd ME, Isaza JE, et al. Complications of lumbar artificial disc replacement compared to fusion: results from the prospective, randomized, multicenter US Food and Drug Administration investigational device exemption study of the Charité artificial disc. SAS J. 2007;1:20–7.

    Not in our library10.1016/sasj-2006-0004-rr

  57. 57.

    Aunoble S, Donkersloot P, Le Huec JC. Dislocations with intervertebral disc prosthesis: two case reports. Eur Spine J. 2004;13:464–7.

    Not in our library10.1007/s00586-004-0687-3

  58. 58.

    Shim CS, Lee S, Maeng DH, Lee SH. Vertical split fracture of the vertebral body following total disc replacement using ProDisc: report of two cases. J Spinal Disord Tech. 2005;18:465–9.

    Not in our library10.1097/01.bsd.0000159035.35365.df

  59. 59.

    van Ooij A, Oner FC, Verbout AJ. Complications of artificial disc replacement: a report of 27 patients with the SB Charité disc. J Spinal Disord Tech. 2003;16:369–83.

    Not in our library10.1097/00024720-200308000-00009

  60. 60.

    Sott AH, Harrison DJ. Increasing age does not affect good outcome after lumbar disc replacement. Int Orthop. 2000;24:50–3.

    Not in our library10.1007/s002640050013

  61. 61.

    Ament JD, Yang Z, Nunley P, Stone MB, Kim KD. Cost‐effectiveness of cervical total disc replacement vs fusion for the treatment of 2‐level symptomatic degenerative disc disease. JAMA Surg. 2014;149:1231–9.

    Not in our library10.1001/jamasurg.2014.716

  62. 62.

    Li H, Ghazanfari R, Zacharaki D, Lim HC, Scheding S. Isolation and characterization of primary bone marrow mesenchymal stromal cells. Ann N Y Acad Sci. 2016;1370:109–18.

    Not in our library10.1111/nyas.13102

  63. 63.

    Pavyde E, Maciulaitis R, Mauricas M, et al. Skeletal muscle‐derived stem/progenitor cells: a potential strategy for the treatment of acute kidney injury. Stem Cells Int. 2016;2016:9618480.

    Not in our library10.1155/2016/9618480

  64. 64.

    Rodriguez AM, Elabd C, Amri EZ, Ailhaud G, Dani C. The human adipose tissue is a source of multipotent stem cells. Biochimie. 2005;87:125–8.

    Not in our library10.1016/j.biochi.2004.11.007

  65. 65.

    Sakai D, Mochida J, Yamamoto Y, et al. Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials. 2003;24:3531–41.

    Not in our library10.1016/s0142-9612(03)00222-9

  66. 66.

    Bartels EM, Fairbank JC, Winlove CP, Urban JP. Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine (Phila Pa 1976). 1998;23:1–7. discussion 8.

    Not in our library10.1097/00007632-199801010-00001

  67. 67.

    Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine (Phila Pa 1976). 2004;29:2700–9.

    Not in our library10.1097/01.brs.0000146499.97948.52

  68. 68.

    Risbud MV, Shapiro IM. Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit Rev Eukaryot Gene Expr. 2011;21:29–41.

    Not in our library10.1615/critreveukargeneexpr.v21.i1.30

  69. 69.

    Neidlinger‐Wilke C, Galbusera F, Pratsinis H, et al. Mechanical loading of the intervertebral disc: from the macroscopic to the cellular level. Eur Spine J. 2014;23(Suppl 3):S333–43.

    Not in our library10.1007/s00586-013-2855-9

  70. 70.

    Vergroesen PP, Kingma I, Emanuel KS, et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr Cartil. 2015;23:1057–70.

    Not in our library10.1016/j.joca.2015.03.028

  71. 71.
    Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile · 2007
    No notice
  72. 72.

    Chen ZH, Jin SH, Wang MY, et al. Enhanced NLRP3, caspase‐1, and IL‐ 1β levels in degenerate human intervertebral disc and their association with the grades of disc degeneration. Anat Rec (Hoboken). 2015;298:720–6.

    Not in our library10.1002/ar.23059

  73. 73.

    Wuertz K, Godburn K, Neidlinger‐Wilke C, Urban J, Iatridis JC. Behavior of mesenchymal stem cells in the chemical microenvironment of the intervertebral disc. Spine (Phila Pa 1976). 2008;33:1843–9.

    Not in our library10.1097/brs.0b013e31817b8f53

  74. 74.

    Feng G, Zhang Z, Dang M, Rambhia KJ, Ma PX. Nanofibrous spongy microspheres to deliver rabbit mesenchymal stem cells and anti‐miR‐199a to regenerate nucleus pulposus and prevent calcification. Biomaterials. 2020;256:120213.

    Not in our library10.1016/j.biomaterials.2020.120213

  75. 75.

    Xu J, Xiao‐Qiang E, Wang N‐X, et al. BMP7 enhances the effect of BMSCs on extracellular matrix remodeling in a rabbit model of intervertebral disc degeneration. FEBS J. 2016;283:1689–700.

    Not in our library10.1111/febs.13695

  76. 76.

    Yang H, Tian W, Wang S, et al. TSG‐6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF‐κB signaling pathway. Lab Invest. 2018;98:755–72.

    Not in our library10.1038/s41374-018-0036-5

  77. 77.

    Kawarai Y, Jang SH, Lee S, et al. Exercise attenuates low back pain and alters epigenetic regulation in intervertebral discs in a mouse model. Spine J. 2021;21:1938–49.

    Not in our library10.1016/j.spinee.2021.06.002

  78. 78.
    Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study · 2017
    No notice
  79. 79.

    Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015;33:146–56.

    Not in our library10.1002/stem.1845

  80. 80.

    Elabd C, Centeno CJ, Schultz JR, Lutz G, Ichim T, Silva FJ. Intra‐discal injection of autologous, hypoxic cultured bone marrow‐derived mesenchymal stem cells in five patients with chronic lower back pain: a long‐term safety and feasibility study. J Transl Med. 2016;14:253.

    Not in our library10.1186/s12967-016-1015-5

  81. 81.
    Noncoding RNAs in cancer therapy resistance and targeted drug development · 2019
    No notice
  82. 82.

    Poller W, Dimmeler S, Heymans S, et al. Non‐coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. Eur Heart J. 2018;39:2704–16.

    Not in our library10.1093/eurheartj/ehx165

  83. 83.

    Zhao K, Zhang Y, Kang L, et al. Epigenetic silencing of miRNA‐143 regulates apoptosis by targeting BCL2 in human intervertebral disc degeneration. Gene. 2017;628:259–66.

    Not in our library10.1016/j.gene.2017.07.043

  84. 84.

    Wang Y, Song Q, Huang X, et al. Long noncoding RNA GAS5 promotes apoptosis in primary nucleus pulposus cells derived from the human intervertebral disc via Bcl‐2 downregulation and caspase‐3 upregulation. Mol Med Rep. 2019;19:2164–72.

    Not in our library10.3892/mmr.2019.9883

  85. 85.

    Wang W, Wang J, Zhang J, Taq W, Zhang Z. miR‐222 induces apoptosis in human intervertebral disc nucleus pulposus cells by targeting Bcl‐2. Mol Med Rep. 2019;20:4875–82.

    Not in our library10.3892/mmr.2019.10732

  86. 86.

    Shi C, Wu L, Lin W, et al. MiR‐202‐3p regulates interleukin‐1β‐induced expression of matrix metalloproteinase 1 in human nucleus pulposus. Gene. 2019;687:156–65.

    Not in our library10.1016/j.gene.2018.11.056

  87. 87.

    Song J, Wang HL, Song KH, et al. CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA. Exp Mol Med. 2018;50:1–12.

    Not in our library10.1038/s12276-018-0125-y

  88. 88.

    Gao D, Hao L, Zhao Z. Long non‐coding RNA PART1 promotes intervertebral disc degeneration through regulating the miR‐93/MMP2 pathway in nucleus pulposus cells. Int J Mol Med. 2020;46:289–99.

    Not in our library10.3892/ijmm.2020.4580

  89. 89.

    Yang Y, Zhong Z, Zhao Y, Ren K, Li N. LincRNA‐SLC20A1 (SLC20A1) promotes extracellular matrix degradation in nucleus pulposus cells in human intervertebral disc degeneration by targeting the miR‐31‐5p/MMP3 axis. Int J Clin Exp Pathol. 2019;12:3632–43.

    Not in our library

  90. 90.

    Xu YQ, Zhang ZH, Zheng YF, Feng SQ. Dysregulated miR‐133a mediates loss of type II collagen by directly targeting matrix metalloproteinase 9 (MMP9) in human intervertebral disc degeneration. Spine (Phila Pa 1976). 2016;41:E717–24.

    Not in our library10.1097/brs.0000000000001375

  91. 91.

    Hua WB, Wu XH, Zhang YK, et al. Dysregulated miR‐127‐5p contributes to type II collagen degradation by targeting matrix metalloproteinase‐13 in human intervertebral disc degeneration. Biochimie. 2017;139:74–80.

    Not in our library10.1016/j.biochi.2017.05.018

  92. 92.

    Li HR, Cui Q, Dong ZY, Zhang JH, Li HQ, Zhao L. Downregulation of miR‐27b is involved in loss of type II collagen by directly targeting matrix metalloproteinase 13 (MMP13) in human intervertebral disc degeneration. Spine (Phila Pa 1976). 2016;41:E116–23.

    Not in our library10.1097/brs.0000000000001139

  93. 93.

    Ji ML, Zhang XJ, Shi PL, et al. Downregulation of microRNA‐193a‐3p is involved in invertebral disc degeneration by targeting MMP14. J Mol Med (Berl). 2016;94:457–68.

    Not in our library10.1007/s00109-015-1371-2

  94. 94.

    Zhang WL, Chen YF, Meng HZ, et al. Role of miR‐155 in the regulation of MMP‐16 expression in intervertebral disc degeneration. J Orthop Res. 2017;35:1323–34.

    Not in our library10.1002/jor.23313

  95. 95.

    Sun J, Hong J, Sun S, et al. Transcription factor 7‐like 2 controls matrix degradation through nuclear factor κB signaling and is repressed by microRNA‐155 in nucleus pulposus cells. Biomed Pharmacother. 2018;108:646–55.

    Not in our library10.1016/j.biopha.2018.09.076

  96. 96.

    Zhou J, Liang A, Hong J, et al. MicroRNA‐155 suppresses the catabolic effect induced by TNF‐α and IL‐1β by targeting C/EBPβ in rat nucleus pulposus cells. Connect Tissue Res. 2019;60:165–77.

    Not in our library10.1080/03008207.2018.1483356

  97. 97.

    Ye D, Dai L, Yao Y, et al. miR‐155 inhibits nucleus Pulposus Cells' degeneration through targeting ERK 1/2. Dis Markers. 2016;2016:6984270.

    Not in our library10.1155/2016/6984270

  98. 98.

    Wang H, He P, Pan H, et al. Circular RNA circ‐4099 is induced by TNF‐α and regulates ECM synthesis by blocking miR‐616‐5p inhibition of Sox9 in intervertebral disc degeneration. Exp Mol Med. 2018;50:1–14.

    Not in our library10.1038/s12276-018-0056-7

  99. 99.
    CircRNA-CIDN mitigated compression loading-induced damage in human nucleus pulposus cells via miR-34a-5p/SIRT1 axis · 2020
    Not checked
  100. 100.
    CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis · 2019
    No notice
  101. 101.

    Guo W, Zhang B, Mu K, et al. Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk. Cell Death Dis. 2018;9:319.

    Not in our library10.1038/s41419-017-0232-z

  102. 102.

    Wang X, Wang B, Zou M, et al. CircSEMA4B targets miR‐431 modulating IL‐1β‐induced degradative changes in nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway. Biochim Biophys Acta Mol Basis Dis. 2018;1864:3754–68.

    Not in our library10.1016/j.bbadis.2018.08.033

  103. 103.

    Cheng X, Zhang L, Zhang K, et al. Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR‐200c and X linked inhibitor‐of‐apoptosis protein. Ann Rheum Dis. 2018;77:770–9.

    Not in our library10.1136/annrheumdis-2017-212056

  104. 104.

    Mi D, Cai C, Zhou B, et al. Long non‐coding RNA FAF1 promotes intervertebral disc degeneration by targeting the Erk signaling pathway. Mol Med Rep. 2018;17:3158–63.

    Not in our library10.3892/mmr.2017.8237

  105. 105.

    Wei R, Chen Y, Zhao Z, Gu Q, Wu J. LncRNA FAM83H‐AS1 induces nucleus pulposus cell growth via targeting the Notch signaling pathway. J Cell Physiol. 2019;234:22163–71.

    Not in our library10.1002/jcp.28780

  106. 106.

    Wang X, Zou M, Li J, et al. LncRNA H19 targets miR‐22 to modulate H(2) O(2) ‐induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling. J Cell Biochem. 2018;119:4990–5002.

    Not in our library10.1002/jcb.26738

  107. 107.

    Xi Y, Jiang T, Wang W, et al. Long non‐coding HCG18 promotes intervertebral disc degeneration by sponging miR‐146a‐5p and regulating TRAF6 expression. Sci Rep. 2017;7:13234.

    Not in our library10.1038/s41598-017-13364-6

  108. 108.

    Zhan S, Wang K, Song Y, et al. Long non‐coding RNA HOTAIR modulates intervertebral disc degenerative changes via Wnt/β‐catenin pathway. Arthritis Res Ther. 2019;21:201.

    Not in our library10.1186/s13075-019-1986-8

  109. 109.

    Shao T, Hu Y, Tang W, Shen H, Yu Z, Gu J. The long noncoding RNA HOTAIR serves as a microRNA‐34a‐5p sponge to reduce nucleus pulposus cell apoptosis via a NOTCH1‐mediated mechanism. Gene. 2019;715:144029.

    Not in our library10.1016/j.gene.2019.144029

  110. 110.

    Wang XB, Wang H, Long HQ, Li DY, Zheng X. LINC00641 regulates autophagy and intervertebral disc degeneration by acting as a competitive endogenous RNA of miR‐153‐3p under nutrition deprivation stress. J Cell Physiol. 2019;234:7115–27.

    Not in our library10.1002/jcp.27466

  111. 111.

    Zhao K, Zhang Y, Yuan H, Zhao M, Zhao D. Long noncoding RNA LINC00958 accelerates the proliferation and matrix degradation of the nucleus pulposus by regulating miR‐203/SMAD3. Aging (Albany NY). 2019;11:10814–25.

    Not in our library10.18632/aging.102436

  112. 112.

    Yu L, Hao Y, Xu C, Zhu G, Cai Y. LINC00969 promotes the degeneration of intervertebral disk by sponging miR‐335‐3p and regulating NLRP3 inflammasome activation. IUBMB Life. 2019;71:611–8.

    Not in our library10.1002/iub.1989

  113. 113.

    Wang K, Song Y, Liu W, et al. The noncoding RNA linc‐ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression. Clin Sci (Lond). 2017;131:965–79.

    Not in our library10.1042/cs20160918

  114. 114.

    Jiang Z, Zeng Q, Li D, et al. Long non‐coding RNA MALAT1 promotes high glucose‐induced rat cartilage endplate cell apoptosis via the p38/MAPK signalling pathway. Mol Med Rep. 2020;21:2220–6.

    Not in our library10.3892/mmr.2020.11009

  115. 115.

    Zhang H, Li J, Duan D, She W, Wang L, Zhang F. The role of lncRNA MALAT1 in intervertebral degenerative disc disease. Int J Clin Exp Pathol. 2017;10:10611–7.

    Not in our library

  116. 116.

    Ruan Z, Ma H, Li J, Liu H, Jia H, Li F. The long non‐coding RNA NEAT1 contributes to extracellular matrix degradation in degenerative human nucleus pulposus cells. Exp Biol Med (Maywood). 2018;243:595–600.

    Not in our library10.1177/1535370218760774

  117. 117.

    Wang X, Lv G, Li J, Wang B, Zhang Q, Lu C. LncRNA‐RP11‐296A18.3/miR‐138/HIF1A pathway regulates the proliferation ECM synthesis of human nucleus pulposus cells (HNPCs). J Cell Biochem. 2017;118:4862–71.

    Not in our library10.1002/jcb.26166

  118. 118.

    Tan H, Zhao L, Song R, Liu Y, Wang L. The long noncoding RNA SNHG1 promotes nucleus pulposus cell proliferation through regulating miR‐326 and CCND1. Am J Physiol Cell Physiol. 2018;315:C21–7.

    Not in our library10.1152/ajpcell.00220.2017

  119. 119.

    Wang X, Li D, Wu H, et al. LncRNA TRPC7‐AS1 regulates nucleus pulposus cellular senescence and ECM synthesis via competing with HPN for miR‐4769‐5p binding. Mech Ageing Dev. 2020;190:111293.

    Not in our library10.1016/j.mad.2020.111293

  120. 120.

    Chen J, Jia YS, Liu GZ, et al. Role of LncRNA TUG1 in intervertebral disc degeneration and nucleus pulposus cells via regulating Wnt/β‐catenin signaling pathway. Biochem Biophys Res Commun. 2017;491:668–74.

    Not in our library10.1016/j.bbrc.2017.07.146

  121. 121.

    Hai B, Ma Y, Pan X, et al. Melatonin benefits to the growth of human annulus fibrosus cells through inhibiting miR‐106a‐5p/ATG7 signaling pathway. Clin Interv Aging. 2019;14:621–30.

    Not in our library10.2147/cia.s193765

  122. 122.

    Niu CC, Lin SS, Yuan LJ, et al. Upregulation of miR‐107 expression following hyperbaric oxygen treatment suppresses HMGB1/RAGE signaling in degenerated human nucleus pulposus cells. Arthritis Res Ther. 2019;21:42.

    Not in our library10.1186/s13075-019-1830-1

  123. 123.

    Ma JF, Zang LN, Xi YM, Yang WJ, Zou D. MiR‐125a Rs12976445 polymorphism is associated with the apoptosis status of nucleus pulposus cells and the risk of intervertebral disc degeneration. Cell Physiol Biochem. 2016;38:295–305.

    Not in our library10.1159/000438630

  124. 124.

    Yang W, Sun P. Downregulation of microRNA‐129‐5p increases the risk of intervertebral disc degeneration by promoting the apoptosis of nucleus pulposus cells via targeting BMP2. J Cell Biochem. 2019;120:19684–90.

    Not in our library10.1002/jcb.29274

  125. 125.

    Liu W, Xia P, Feng J, et al. MicroRNA‐132 upregulation promotes matrix degradation in intervertebral disc degeneration. Exp Cell Res. 2017;359:39–49.

    Not in our library10.1016/j.yexcr.2017.08.011

  126. 126.

    Wang B, Wang D, Yan T, Yuan H. MiR‐138‐5p promotes TNF‐α‐induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling. Exp Cell Res. 2016;345:199–205.

    Not in our library10.1016/j.yexcr.2016.05.011

  127. 127.

    Zhang Q, Weng Y, Jiang Y, Zhao S, Zhou D, Xu N. Overexpression of miR‐140‐5p inhibits lipopolysaccharide‐induced human intervertebral disc inflammation and degeneration by downregulating toll‐like receptor 4. Oncol Rep. 2018;40:793–802.

    Not in our library10.3892/or.2018.6488

  128. 128.
    Preclinical development of a microRNA-based therapy for intervertebral disc degeneration · 2018
    No notice
  129. 129.

    Yang Q, Guo XP, Cheng YL, Wang Y. MicroRNA‐143‐5p targeting eEF2 gene mediates intervertebral disc degeneration through the AMPK signaling pathway. Arthritis Res Ther. 2019;21:97.

    Not in our library10.1186/s13075-019-1863-5

  130. 130.

    Zhou J, Sun J, Markova DZ, et al. MicroRNA‐145 overexpression attenuates apoptosis and increases matrix synthesis in nucleus pulposus cells. Life Sci. 2019;221:274–83.

    Not in our library10.1016/j.lfs.2019.02.041

  131. 131.

    Lv F, Huang Y, Lv W, et al. MicroRNA‐146a ameliorates inflammation via TRAF6/NF‐κB pathway in intervertebral disc cells. Med Sci Monit. 2017;23:659–64.

    Not in our library10.12659/msm.898660

  132. 132.

    Qin C, Lv Y, Zhao H, Yang B, Zhang P. MicroRNA‐149 suppresses inflammation in nucleus pulposus cells of intervertebral discs by regulating MyD88. Med Sci Monit. 2019;25:4892–900.

    Not in our library10.12659/msm.915858

  133. 133.

    Zhang Y, Zhang YS, Li XJ, et al. Overexpression of miR‐150 inhibits the NF‐κB signal pathway in intervertebral disc degeneration through targeting P2X7. Cells Tissues Organs. 2019;207:165–76.

    Not in our library10.1159/000503281

  134. 134.

    Cai P, Yang T, Jiang X, Zheng M, Xu G, Xia J. Role of miR‐15a in intervertebral disc degeneration through targeting MAP3K9. Biomed Pharmacother. 2017;87:568–74.

    Not in our library10.1016/j.biopha.2016.12.128

  135. 135.

    Kang L, Yang C, Yin H, et al. MicroRNA‐15b silencing inhibits IL‐1β‐induced extracellular matrix degradation by targeting SMAD3 in human nucleus pulposus cells. Biotechnol Lett. 2017;39:623–32.

    Not in our library10.1007/s10529-016-2280-3

  136. 136.

    Li W, Wang P, Zhang Z, Wang W, Liu Y, Qi Q. MiR‐184 regulates proliferation in nucleus pulposus cells by targeting GAS1. World Neurosurg. 2017;97:710–715.e1.

    Not in our library10.1016/j.wneu.2016.01.024

  137. 137.

    Kong L, Sun M, Jiang Z, Li L, Lu B. MicroRNA‐194 inhibits lipopolysaccharide‐induced inflammatory response in nucleus pulposus cells of the intervertebral disc by targeting TNF receptor‐associated factor 6 (TRAF6). Med Sci Monit. 2018;24:3056–67.

    Not in our library10.12659/msm.907280

  138. 138.

    Chen Z, Han Y, Deng C, et al. Inflammation‐dependent downregulation of miR‐194‐5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B. J Cell Physiol. 2019;234:19977–89.

    Not in our library10.1002/jcp.28595

  139. 139.

    Liu MH, Sun C, Yao Y, et al. Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR‐20a targeting ANKH expression. Sci Rep. 2016;6:25401.

    Not in our library10.1038/srep25401

  140. 140.

    Wang WJ, Yang W, Ouyang ZH, et al. MiR‐21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. Biomed Pharmacother. 2018;99:725–34.

    Not in our library10.1016/j.biopha.2018.01.154

  141. 141.
    Mesenchymal stem cells deliver exogenous miR‐21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration · 2017
    No notice
  142. 142.
    Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4 · 2016
    Not checked
  143. 143.

    Wang C, Zhang ZZ, Yang W, et al. MiR‐210 facilitates ECM degradation by suppressing autophagy via silencing of ATG7 in human degenerated NP cells. Biomed Pharmacother. 2017;93:470–9.

    Not in our library10.1016/j.biopha.2017.06.048

  144. 144.

    Penolazzi L, Lambertini E, Scussel Bergamin L, et al. Reciprocal regulation of TRPS1 and miR‐221 in intervertebral disc cells. Cells. 2019;8(10):1170.

    Not in our library10.3390/cells8101170

  145. 145.

    Penolazzi L, Lambertini E, Bergamin LS, et al. MicroRNA‐221 silencing attenuates the degenerated phenotype of intervertebral disc cells. Aging (Albany NY). 2018;10:2001–15.

    Not in our library10.18632/aging.101525

  146. 146.

    Sheng B, Yuan Y, Liu X, et al. Protective effect of estrogen against intervertebral disc degeneration is attenuated by miR‐221 through targeting estrogen receptor α. Acta Biochim Biophys Sin (Shanghai). 2018;50:345–54.

    Not in our library10.1093/abbs/gmy017

  147. 147.

    Yeh CH, Jin L, Shen F, Balian G, Li XJ. miR‐221 attenuates the osteogenic differentiation of human annulus fibrosus cells. Spine J. 2016;16:896–904.

    Not in our library10.1016/j.spinee.2016.03.026

  148. 148.

    Zhang Y, Yang J, Zhou X, et al. Knockdown of miR‐222 inhibits inflammation and the apoptosis of LPS‐stimulated human intervertebral disc nucleus pulposus cells. Int J Mol Med. 2019;44:1357–65.

    Not in our library10.3892/ijmm.2019.4314

  149. 149.

    Liu J, Yu J, Jiang W, He M, Zhao J. Targeting of CDKN1B by miR‐222‐3p may contribute to the development of intervertebral disc degeneration. FEBS Open Biol. 2019;9:728–35.

    Not in our library10.1002/2211-5463.12609

  150. 150.

    Wang H, Hao P, Zhang H, Xu C, Zhao J. MicroRNA‐223 inhibits lipopolysaccharide‐induced inflammatory response by directly targeting Irak1 in the nucleus pulposus cells of intervertebral disc. IUBMB Life. 2018;70:479–90.

    Not in our library10.1002/iub.1747

  151. 151.

    Guo Y, Tian L, Liu X, He Y, Chang S, Shen Y. ERRFI1 inhibits proliferation and inflammation of nucleus Pulposus and is negatively regulated by miR‐2355‐5p in intervertebral disc degeneration. Spine (Phila Pa 1976). 2019;44:E873–81.

    Not in our library10.1097/brs.0000000000003011

  152. 152.

    Yang S, Li L, Zhu L, et al. Bu‐Shen‐Huo‐Xue‐Fang modulates nucleus pulposus cell proliferation and extracellular matrix remodeling in intervertebral disk degeneration through miR‐483 regulation of Wnt pathway. J Cell Biochem. 2019;120:19318–29.

    Not in our library10.1002/jcb.26760

  153. 153.

    Chen Z, Liu M, Zhang W, Deng M, Zhou Y, Li Y. miR‐24‐3p induces human intervertebral disc degeneration by targeting insulin‐like growth factor binding protein 5 and the ERK signaling pathway. Life Sci. 2020;243:117288.

    Not in our library10.1016/j.lfs.2020.117288

  154. 154.

    Zhao Z, Zheng J, Ye Y, Zhao K, Wang R, Wang R. MicroRNA‐25‐3p regulates human nucleus pulposus cell proliferation and apoptosis in intervertebral disc degeneration by targeting Bim. Mol Med Rep. 2020;22:3621–8.

    Not in our library10.3892/mmr.2020.11483

  155. 155.

    Fan Y, Zhao L, Xie W, et al. Serum miRNAs are potential biomarkers for the detection of disc degeneration, among which miR‐26a‐5p suppresses Smad1 to regulate disc homeostasis. J Cell Mol Med. 2019;23:6679–89.

    Not in our library10.1111/jcmm.14544

  156. 156.

    Lv J, Li S, Wan T, Yang Y, Cheng Y, Xue R. Inhibition of microRNA‐30d attenuates the apoptosis and extracellular matrix degradation of degenerative human nucleus pulposus cells by up‐regulating SOX9. Chem Biol Interact. 2018;296:89–97.

    Not in our library10.1016/j.cbi.2018.09.010

  157. 157.
    Dysregulated MiR-3150a-3p Promotes Lumbar Intervertebral Disc Degeneration by Targeting Aggrecan · 2018
    Not checked
  158. 158.

    Liu W, Zhang Y, Feng X, et al. Inhibition of microRNA‐34a prevents IL‐1β‐induced extracellular matrix degradation in nucleus pulposus by increasing GDF5 expression. Exp Biol Med (Maywood). 2016;241:1924–32.

    Not in our library10.1177/1535370216657444

  159. 159.

    Zheng Q, Li XX, Xiao L, et al. MicroRNA‐365 functions as a mechanosensitive microRNA to inhibit end plate chondrocyte degeneration by targeting histone deacetylase 4. Bone. 2019;128:115052.

    Not in our library10.1016/j.bone.2019.115052

  160. 160.

    Xiao L, Xu S, Xu Y, et al. TGF‐β/SMAD signaling inhibits intermittent cyclic mechanical tension‐induced degeneration of endplate chondrocytes by regulating the miR‐455‐5p/RUNX2 axis. J Cell Biochem. 2018;119:10415–25.

    Not in our library10.1002/jcb.27391

  161. 161.

    Chai X, Si H, Song J, Chong Y, Wang J, Zhao G. miR‐486‐5p inhibits inflammatory response, matrix degradation and apoptosis of nucleus pulposus cells through directly targeting FOXO1 in intervertebral disc degeneration. Cell Physiol Biochem. 2019;52:109–18.

    Not in our library10.33594/000000008

  162. 162.

    Sun JC, Zheng B, Sun RX, et al. MiR‐499a‐5p suppresses apoptosis of human nucleus pulposus cells and degradation of their extracellular matrix by targeting SOX4. Biomed Pharmacother. 2019;113:108652.

    Not in our library10.1016/j.biopha.2019.108652

  163. 163.

    Sun Z, Jian Y, Fu H, Li B. MiR‐532 downregulation of the Wnt/β‐catenin signaling via targeting Bcl‐9 and induced human intervertebral disc nucleus pulposus cells apoptosis. J Pharmacol Sci. 2018;138:263–70.

    Not in our library10.1016/j.jphs.2018.10.007

  164. 164.

    Wang R, Wen B, Sun D. miR‐573 regulates cell proliferation and apoptosis by targeting Bax in nucleus pulposus cells. Cell Mol Biol Lett. 2019;24:2.

    Not in our library10.1186/s11658-018-0132-y

  165. 165.

    Dong W, Liu J, Lv Y, et al. miR‐640 aggravates intervertebral disc degeneration via NF‐κB and WNT signalling pathway. Cell Prolif. 2019;52:e12664.

    Not in our library10.1111/cpr.12664

  166. 166.

    Zhang HJ, Ma XH, Xie SL, Qin SL, Liu CZ, Zhang ZG. Knockdown of miR‐660 protects nucleus pulposus cells from TNF‐a‐induced apoptosis by targeting serum amyloid A1. J Orthop Surg Res. 2020;15:7.

    Not in our library10.1186/s13018-019-1538-6

  167. 167.

    Tan H, Zhao L, Song R, Liu Y, Wang L. microRNA‐665 promotes the proliferation and matrix degradation of nucleus pulposus through targeting GDF5 in intervertebral disc degeneration. J Cell Biochem. 2018;119:7218–25.

    Not in our library10.1002/jcb.26888

  168. 168.

    Liu W, Zhang Y, Xia P, et al. MicroRNA‐7 regulates IL‐1β‐induced extracellular matrix degeneration by targeting GDF5 in human nucleus pulposus cells. Biomed Pharmacother. 2016;83:1414–21.

    Not in our library10.1016/j.biopha.2016.08.062

  169. 169.

    Yang X, Liu H, Zhang Q, et al. MiR‐96 promotes apoptosis of nucleus pulpous cells by targeting FRS2. Hum Cell. 2020;33:1017–25.

    Not in our library10.1007/s13577-020-00389-9

  170. 170.

    Tao B, Yi J, Huang C, et al. microRNA‐96 regulates the proliferation of nucleus pulposus cells by targeting ARID2/AKT signaling. Mol Med Rep. 2017;16:7553–60.

    Not in our library10.3892/mmr.2017.7560

  171. 171.

    Ji ML, Lu J, Shi PL, et al. Dysregulated miR‐98 contributes to extracellular matrix degradation by targeting IL‐6/STAT3 signaling pathway in human intervertebral disc degeneration. J Bone Miner Res. 2016;31:900–9.

    Not in our library10.1002/jbmr.2753

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