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Year : 2015  |  Volume : 4  |  Issue : 1  |  Page : 5-15

Novel treatment strategies for intervertebral disc degeneration

Department of Nursing, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia

Date of Web Publication13-Feb-2015

Correspondence Address:
Moattar Raza Rizvi
Department of Nursing, College of Applied Medical Sciences, Majmaah University, Majmaah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-0521.151403

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Intervertebral disc degenerative (IVDD) is a common orthopaedic condition characterized by a series of cellular, biochemical, structural and functional changes that imparts a large socioeconomic impact on healthcare system. Progressive loss of normal extracellular matrix constituents, namely proteoglycans and water content, is thought to be a key contributor to IVDD. The ability to sustain or augment normal matrix composition may slow down or reverse disc degeneration. Traditional concepts for treatment of lumbar disc degeneration have aimed at symptomatic relief by limiting motion in the lumbar spine, but novel treatment strategies involving direct injection of active substance, stem cells, growth factors and gene therapy have been attracting more attention in respect to prevent, slow or even reverse disc degeneration. Understanding the pathophysiological basis of disc degeneration will lay the foundation for the emergence of exciting new regenerative or reparative biological treatments for this debilitating condition either by inducing disc regeneration or replacing the degenerated disc.

Keywords: Annulus fibrosus, gene therapy, intervertebral disc degeneration, mesenchymal stem cells, nucleus pulposus, spinal fusion surgery

How to cite this article:
Rizvi MR. Novel treatment strategies for intervertebral disc degeneration. Saudi J Health Sci 2015;4:5-15

How to cite this URL:
Rizvi MR. Novel treatment strategies for intervertebral disc degeneration. Saudi J Health Sci [serial online] 2015 [cited 2022 Jan 24];4:5-15. Available from: https://www.saudijhealthsci.org/text.asp?2015/4/1/5/151403

  Introduction Top

Low back pain (LBP) is a significant cause of morbidity and disability. It is one of the most frequent reasons for clinic visits and surgical treatments, which leads to individual suffering and results in loss of work, time, billions of dollars in treatment expenditure as well as wage compensation every year. [1] About 80% of the adult population would be subjected to neck or back pain at some points in their lives affecting the quality of life and resulting in serious socioeconomic consequences. [2],[3]

LBP is qualified as chronic if the symptoms persist for more than 3 months; in approximately 10-20% of the patients with low back pain, the condition becomes chronic. [4],[5],[6] In 85% of the patients with chronic low back pain, the specific cause of the pain cannot be found. [7] Although LBP is complex in etiology, histological and magnetic resonance imaging (MRI) data have suggested a chronic LBP is associated with lumber intervertebral disc degeneration, which can develop as early as the second decade of life. [8] The disease is of widespread prevalence. The main cause of low back pain is intervertebral disc degeneration (IVDD). [9] Disc degeneration, although in many cases asymptomatic is also associated with sciatica, disc herniation, spinal canal stenosis, spondylolysthesis and degenerative scoliosis. [9],[10] IVDD is a process which is histologically and radiologically characterized by a loss of disc height, subchondral sclerosis of the endplate, formation of osteophyte and radial bulging. [11] The incidence is rising exponentially with current demographic changes and an increased aged population.

Preventive measures and surgical treatments of spinal degenerative diseases in the late stage is at huge cost and result in suboptimal clinical outcomes in many situation [9],[10] musculoskeletal tissues. About 20% of people in their teens have discs with mild signs of degeneration; degeneration increases steeply with age, particularly in males, so that around 10% of 50-year-old discs and 60% of 70-year-old discs are severely degenerated. [12] Thus, early intervention to prevent the progression of IVDD, or regenerate the degenerative disc is of great necessity.

Strategies for stopping or reversing disc degeneration in the lumbar spine range from mechanical treatment options that rely on the traditional concept of removing the pain generator, the disc, and eliminating pain by stopping motion to more recently emerging and developing treatment options involving gene therapy, growth factors and cell transplantations. The traditional approach of motion-eliminating fusion surgery, which may be effective for the treatment of pain in some cases, may also increase the rate of degeneration at adjacent spinal motion segments. Furthermore, this strategy does not halt the progression of the degenerative cascade of events that leads to pain and disability. So despite its undeniable significance, lumbar fusion surgery as a treatment of LBP has to be regarded suboptimal, as it targets the symptom of pain rather than its causes. [13]

Although an important public health issue, the pathogenesis of LBP is poorly understood. Only in the last 10-15 years, there exists mechanisms underlying human intervertebral disc (IVD) degeneration been studied in any detail, but the arrival of molecular pathology and similar techniques for examining disease mechanisms in human tissue (e.g. immunohistochemistry, [14] in situ zymography, [15] in situ hybridization [16] and quantitative image analysis [17] and the advent of biotherapeutics [18] stem cell therapy [19] and tissue engineering [20] have brought both methods for and reasons to investigate IVD degeneration. In this short review, we outline the novel treatment strategies for intervertebral disc degeneration. However, the pathogenesis of IVDD has not been elucidated clearly, although it is acknowledged that programmed cell death (PCD) of IVD cells plays an essential role in this process. [21] Numerous studies indicate that a variety of cellular events are disturbed in the progression of IVDD, ranging from matrix synthesis to cytokine expression [Figure 1]. [22]
Figure 1: Changes involved in degeneration of the intervertebral disc at biochemical and molecular level. TNF-α tumor necrosis factor α; TGF: Transforming growth factor; MMPs: Matrix metalloproteinases; ADAMTs; a disintegrin and metalloproteinases; TIMPs: tissue inhibitor of metalloproteinases

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Disc morphology

Intervertebral discs, also known as intervertebral fibrocartilage or spinal discs, are the padding between each vertebra of the spine. They have an elastic structure, made of fibrocartilage tissue. The intervertebral disc has a complex structure with the nucleus pulposus (NP, soft and gelatinous) encapsulated by endplates and the annulus fibrosus (tough and fibrous, and is composed of several overlapping layers. [23] NP extracellular matrix (ECM) consists mainly of loosely assembled collagen type II fibres and proteoglycan (mostly aggrecan and versican) in a ratio of 1:20. Aggrecan is highly hydrophilic, which enable the NP to retain water, thereby cushioning and absorbing the considerable loads placed on the vertebral bodies. Imbalanced metabolism of Nucleus pulposus extracellular matrix is closely correlated to IVDD disease. [24] In a healthy young adult the intervertebral discs consist of about 90% water. As we age, the water content goes down, the padding becomes less thick and the spine becomes slightly shorter as a result. Sometimes the disc might bulge. [25]

Pathogenesis of intervertebral disc degeneration

With advancing age comes pronounced changes in the composition of the disc ECM. [26],[27] Decreasing aggrecan content in the NP leads to reduced hydration, [25] leading in turn to impaired mechanical function. [28],[29] A less hydrated, more fibrous NP is unable to evenly distribute compressive forces between the vertebral bodies. The forces are instead transferred non-uniformly to the surrounding AF, [30] which can result in altered AF mechanical properties [31],[32] and progressive structural deterioration, including the formation of circumferential and radial tears. [33] On occasion, radial tears can progress to a posterior radial bulge or herniation of NP material, [33] resulting in painful symptoms. Decreased disc height is also commonly associated with advanced disc degeneration [34] and results in painful compression of surrounding structures. Multiple interdependent factors, including altered mechanical loading, [35] reduced nutrient supply [36] and hereditary factors, have been implicated in the initiation and progression of the degenerative cascade. Changes to disc extracellular matrix composition with age are attributable to alterations in function and increased death of the cells that make up the disc. [37] The cellular microenvironment of the disc becomes progressively more hostile, and is characterized by upregulated levels of proinflammatory cytokines and associated catabolic enzymes. [38] This is in part due to a reduction in the diffusion of nutrients through the endplates that accompanies thinning and calcification; the reasons for these endplate changes are not well-understood. [36],[39] Mechanical loading might also play a direct role in the progression of disc degeneration. Cell survival and matrix synthesis are both sensitive to compressive stress. [40] Although some mechanical stimulation is necessary to induce nutrient diffusion and to promote matrix synthesis, excessive loading can result in localized tissue injury that is slow to repair and alters strain distribution throughout the extracellular matrix of the entire disc. [35] Finally, hereditary factors also play a role in an individual's susceptibility to disc degeneration. [41] Twin studies suggest that genetics predispose individuals to disc degeneration. [42] Population studies for candidate genes and genome-wide assays are advancing this idea, although the fact that disc degeneration is a multi-factorial process and because large sample sizes are needed for such studies, genetic analyses have been challenging. [43] Additionally, undertaking gene analyses [polymerase chain reaction (PCR), or microarray] for thousands of individuals becomes prohibitively expensive.

  Changes associated with intervertebral disc degeneration Top

Macroscopic and microscopic changes

Obvious macroscopic and microscopic changes happen in IVDD and disrupt its structure. Some macroscopic changes include annulus tear, [11] loss of disc height and hydration, [44] lamella disorganization of annulus [45] and formation of osteophytes. Some other microscopic changes include increased clonal cell proliferation, mucous matrix degeneration, increased cell death, obliteration of blood vessels in endplate and decreased vascularization and innervation. These changes are believed to be the result of the underlying molecular changes in the disc. Theoretically, suppressing these changes by the regulation of the related pathways may prevent, arrest or even reversed the progression of IVD degeneration.

Molecular changes

Degeneration of IVD has been characterized extensively showing that the degeneration involves changes in the composition of the ECM. Such molecular changes have been widely studied, and obvious alternations in both gene and protein expressions as compared with that of young healthy IVD have been demonstrated. [46],[47],[48] In addition, there are studies suggesting that the molecular changes are the result of an upregulation of matrix degradation enzymes and inflammatory mediators in the degenerated IVD. [14],[49] The most common changes which related to matrix synthesis, catabolic mechanism, as well as growth factors and cytokines are discussed briefly in this review.

Matrix synthesis

IVDD is believed to be, in part, the result of imbalance between anabolism and catabolism of ECM. [50]

Anabolic mechanism

Concerning the matrix changes related to the anabolic mechanism, proteoglycans (PG) and collagen are two predominant matrixes that involved in the degeneration process. Decrease of PG content in the NP is one of the first signs of disc degeneration. [51],[52] Among many types of PG in IVD including aggrecan, versican, decorin, biglycan, lumican and perlecan, aggrecan is the most abundant on a weight basis. The overall aggrecan content was found reduced and its gene expression was down regulated in the whole degenerated human disc. [26],[49] This depletion has been generally suggested to be associated with the proteolytic degradation. Apart from the overall decrease of the aggrecan content, the composition of aggrecan in the discs also undergoes alteration during degeneration. [27]

Aggrecan possesses both chondroitin sulfate (CS) and keratan sulfate (KS) in mature human IVD, [53] and the proportion of KS to CS is generally higher in degenerated than normal disc. [27] This was postulated to be a result of decreased oxygen supply and vasculature during degeneration, as oxidation is a prerequisite for the formation of the glucuronic acid during synthesis of CS, whereas formation of galactose during synthesis of KS does not require oxidation. [54] This molecular change was considered to be a mechanism strived to maintain the high negative charge density to retain the osmotic properties of the discs. In addition, the proportion of non-aggregating PGs relative to the total proteoglycan content also increases during disc degeneration, particularly in the NP. [53] These non-aggregating PGs are suggested to be derived from intact aggrecans by proteolytic degradation. The non-aggregating PGs differ in composition, including the CS-rich and KS-rich depending on the sites of cleavage. Other PGs including versican, biglycan and decorin also undergo extensive degradation during aging and degeneration; however, the exact role of the molecular changes and the degradation consequence is still not clear. [27] Fibronectin, a cell and matrix protein, was found to be elevated in degenerated disc. It was hypothesized that the presence of fibronectin modifies the cell-matrix interaction and results in enhanced proteolytic activity, which subsequently promotes the degeneration of a disc. [55] Apart from fibronectin, a novel small leucin-rich proteoglycan (SLRP) named asporin has been recently shown to be highly localized in human degenerated disc, and degenerated disc also showed higher gene expression of asporin than non-degenerated one. [56] Many studies are now underway to elucidate the role of these biomolecules in disc degeneration. Collagen also changes its distribution and composition when IVD is degenerated. In early degeneration, the abundance of Types III, V and VI collagen increases in the NP and that of Type I collagen increases in the AF. [57] Other studies also found that the gene expression of Type I collagen was upregulated in the whole degenerated discs even in the NP, [46],[47],[48] while Type II collagen was downregulated in NP [26],[48],[49] with more advanced degeneration, furthermore, Types III and VI collagen has also been reported to appear in the NP, and the expression of Type V collagen was slightly upregulated in NP. [58],[59]

Catabolic metabolism

Apart from molecular changes in terms of matrix synthesis, the alteration in catabolic metabolism also involves during disc degeneration. Matrix metalloproteinases (MMPs) and a desintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) are the most commonly proposed enzymes which are involved in the ECM degradation and have been reported to enhance catabolic metabolism within the discs. This degeneration may be caused by losing a balance between the production and activation of these catabolic enzymes relative to their inhibition by tissue inhibitors. [60] Metalloproteinase is known to cleave major matrix molecules, mainly that of aggrecan, collagen, versican and link proteins. Many members from this catabolic enzyme family including MMP-1, 3, 7, 9, 13 have been shown to be involved in IVD degeneration. The number of immunopositive cells for MMP-1, 3, 7, 13 increased with the severity of the degeneration in human NP, and gene expression of MMP-1, 7, 9, 13 was found to be increased in rabbit degenerative model and human disc. [14],[61] A family member of metalloproteinase, referred to as aggrecanase, is involved mainly in the degradation of aggrecan and versican. [14] Considering ADAMTS, the protein expression for ADAMTS-2 and 14 were found upregulated in degenerated disc in goat, [47] and same was true for ADAMTS-4, 5, 9 and 15, as confirmed in a recent study using human degenerated discs. [62]

Growth factors

Numerous growth factors including bone morphogenetic proteins (BMPs), insulin-like growth factor-1 (IGF-1), transforming growth factor-b (TGF-b), etc., have been reported to have therapeutic effect of slowing or reversing IVDD. The upregulation of bFGF, BMP and TGF-β expression has been observed in degenerated discs, and have been supposed to be involved in the degradation processes. [63],[64],[65],[66],[67],[68] Recent genetic evidence has indicated the role of TGF-β and BMP signalling in the pathogenesis of IVDD as well as osteoarthritis. [69],[70] Members of the TGF-β family are the best-characterized growth factors. [71] In cartilage, TGF-β has been shown to participate in processes including chondrogensis, production of metalloproteinase and inflammatory responses. [72],[73] The gene expression of TGF-β was found promoted in osteoarthritic cells, which is similar to that observed in degenerative disc cells. [74] Both TGF-β and TGF-β receptor type II are generally found in disc cells from specimens of herniated [75],[76] and non-herniated [63],[67] degenerated human discs. However, the findings are still contradictory as TGF-β was only found in a minority of the herniated disc tissues. [77] More recently, two growth factors named nerve growth factor (NGF) [78] and connective tissue growth factor (CTGF) [79] have been discovered to be highly associated with degenerative discs which are accompanied with pain. The expression of these growth factors has been shown to be higher in painful human degenerated discs than asympomatic ones.

Pro-inflammatory cytokines

IL-1α52, 53, IL-1β53, 54, IL-653, 55, 56, IL-852,55 and TNF-α40, 52, 53 are the most commonly studied cytokines in relation to the degeneration of IVD. Disc cells have potential to produce these inflammatory cytokines mainly for mediating and propagating the inflammatory reaction. [71] All of these cytokines were found upregulated in degenerated IVD, which are believed to be responsible for the enhancement of catabolic degradation of ECM. Downstream to interleukin IL-1β, a mediator named nitric oxide (NO), which has been implicated in osteoarthritis [80],[81] was reported to be produced in higher quantities in degenerated discs that were associated with herniation, when compared with the normal discs. [82] The production of NO was increased in response to IL-1β56, and its ability at inhibiting PG synthesis in lumbar discs was also discovered. [83] Apart from NO, prostaglandin is another mediator of inflammatory reaction which is a possible intermediary in the suppression of PG synthesis. The prostaglandin E2 was also detected in significantly higher amounts in degenerated discs which were associated with herniation. [82] However, the precise role of these biochemical mediators of inflammation is still not well-understood and is currently being investigated.

Treatment strategies for degenerative disc disease

Currently, the therapeutic strategies for treating IVDD are mainly empirical and concentrates at alleviating symptoms rather than targeting the mechanism of underlying disease. The continually increasing burden of disease and the patient experience suggest that this approach has limited success. It could be argued that therapeutic advances might be facilitated were more known about the causes of back pain and the underlying tissue processes [Figure 2].

Arguably, the two main foci of this work are in restoring the normal environment of the IVD and in regenerating functional IVD tissue. In the former, the major targets are the altered load consequent upon disturbed matrix composition and the abnormal cytokine environment of the degenerate IVD. These have given rise to research on delivery of cytokine modulators to the degenerate IVD, [84],[85] novel biomaterials to replace the function of the NP [86] and the use of stem cells to replace deficient IVD cells [87],[88],[89]
Figure 2: Current strategies to treat intervertebral disc disease consist of conservative measures or surgical decompression. The new treatment strategies can be applied at different stages of intervertebral disc degeneration, with salvage procedures being applied in late-stage degeneration/disease, functional repair being applied in intermediate-stage degeneration, and intervertebral disc regeneration being applied in early-stage degeneration. NP: Nucleus Pulposus; AF: Annulus Fibrosus

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Reliable new treatments for discogenic back pain based on this new knowledge are a long way off, but the tide of translational research is running in that direction. There are also new research areas developing particularly around mechanotransduction and prevention of degeneration based on recognizing genetically programmed 'at risk' groups. Clinical subtyping of patients to identify those who might benefit from the new therapies is one of the area that has been neglected to some extent. Advance in this area will be essential if the new therapeutics are to be of any value, and will go wider than the history and clinical examination but will also encompass clinical technologies such as novel imaging and the wealth of different 'omics'. This is an exciting time to be working on back pain and there is little doubt that the clinical management of the patient with discogenic back pain and/or IVDD will be distinctly different in 10-years' time.

Conservative or medical treatment

Conservative treatment consists of providing analgesic support, often with non-steroidal anti-inflammatory drugs (NSAIDs) and opioids in the acute phase. Anti-inflammatory medication, consisting of corticosteroids or NSAIDs, is applied to counter the inflammatory response and to treat the spinal pain. NSAIDs are preferred to corticosteroids, because NSAIDs have similar analgesic and anti-inflammatory effects but significantly fewer side effects. [90] Controlled and dosed exercise and physical therapy is also beneficial. Adjunct treatments, such as nutraceuticals and weight loss, are often used as well. Conservative treatment also consists of restricting activities that could exacerbate the neural compression, to prevent more NP material from herniating and to facilitate consolidation of the (partially) herniated disc. Extruded NP material is resorbed over a period of 4 to 6 weeks and the inflammation will settle, leading to resolution of the clinical signs. In addition, physical therapy can be started to prevent muscle atrophy due to disuse of muscles and to improve muscle tone, to maximize afferent sensory input in areas of deficit and to promote a normal range of movement, motion patterns and function. [91] Conservative treatment is best suited for mild cases of IVDD. [92],[93],[94]

Surgical treatment

The decision to treat IVDD patients surgically should be based on several factors, such as the severity of neurological signs, the severity of pain, the type and severity of compressive lesion (s) and the response to conservative therapy. General indications for surgery include clinical signs unresponsive to conservative treatment and the presence of neurological deficits. [90],[92] The aim of surgery is to remove the compressive lesions and structures, such as the herniated IVDD and hypertrophic ligaments, thereby alleviating neural compression. Once the decision has been made that surgery is the optimal treatment option, a wide array of surgical techniques are available to treat IVDD-related compression. Direct decompressive procedures include ventral slot (cervical disc disease), inverted cone slot (CSM), dorsal laminectomy (DLSS) and haemilaminectomy (thoracolumbar disc disease), pediculotomy, corpectomy. [90],[92],[95],[96] Also, curettage or fenestration (nuclectomy) of the diseased disc or adjacent discs which may cause future disease is commonly performed. [92] Indirect decompressive techniques, such as distraction-stabilization/fusion, have also been described as treatment for CSM and DLSS [90],[97] As decompression involves removing essential stabilizing structures, the decompressed segment can also be re-stabilized. A wide variety of techniques, including bone grafts, pins, screws and cages, have been described for this purpose. [96],[97],[98],[99],[100],[101],[102],[103]

Functional repair of the IVDD

The above-described treatments can be regarded as salvage procedures: They are symptomatic and the compressive lesion is removed with or without stabilization of the spinal segment. However, the functionality of the IVDD is not restored. Moreover, these surgical procedures all lead to altered biomechanics of the spinal segment: Decompressive surgery without stabilization results in spinal instability, which may lead to recurrence of clinical signs [104],[105] While stabilization prevents degeneration of the decompressed spinal segment, it is associated with degeneration of the adjacent spinal segments, a phenomenon referred to as adjacent segment disease or the 'domino effect'. [106],[107],[108] These complications have prompted interest in new technologies to restore the functionality of the IVD following decompression.

If IVD degeneration has not progressed beyond repair, the IVD may be repaired by replacing the diseased NP with a NP prosthesis (NPP). [109] A novel, biocompatible, hydrogel NPP has recently been developed. [109],[110],[111] It is implanted in dry form, enabling insertion of the NPP through a small annular opening. After insertion, the prosthesis is allowed to expand in situ and reaches its final dimensions within 18 hours of placement. The prosthesis fills up the entire NP cavity created after nuclectomy (confinement), which is essential to achieve a physiological distribution of stress in the disc and to minimize the risk of implant migration. The NPP consists of an intrinsically radiopaque hydrogel, which makes it optimally visible on X-ray fluoroscopy, computed tomography (CT) and MRI. [109],[110],[111]

The physical-mechanical material properties of this NPP have been assessed by means of swelling and diffusion testing, static and dynamic mechanical testing and creep and fatigue testing. [109],[110],[111] However, before this technique can be used in canine IVD patients, the applicability of the surgical technique in the canine spine and the functionality of this concept need to be investigated.

Regeneration of the IVDD

The optimal method for restoring IVDD functionality would be to return the IVDD to its healthy state, i.e. regeneration of the degenerated IVD tissue. Regeneration of the IVD involves the prevention, inhibition and/or reversal of degenerative processes by concomitantly stimulating ECM synthesis and decreasing, and ideally reversing, ECM degradation. [112],[113] A prerequisite for IVD regeneration is that the IVD cells and environment still have the capability to produce, and thus restore, a healthy ECM. [112] Different strategies for biological repair of the degenerated IVD can be used, including the use of growth factors and anticatabolic agents, gene therapy and cell-based strategies. [112],[113],[114],[115]

Cell-based therapies and growth factors in lumbar disc degeneration

Both the application of growth factors such as IGF, TGF and bone morphogenetic protein (BMPs) and alternatively replacement of abnormal IVD cells, either by injection of adult mesenchymal stem cells (MSCs) or autologous IVD cells, have been investigated as potential therapeutic agents aimed at regeneration of the IVD matrix. Growth factors are peptides the function of which is to regulate the stimulation of cellular proliferation, differentiation and migration and to stimulate matrix synthesis. In the IVD, specific growth factors such as IGF, TGF and BMP are produced by the chondrocyte-like cells of the NP and act to stimulate matrix synthesis. [116] As loss of IVD matrix composition is a characteristic feature of IVDD, growth factors have been investigated as potential therapeutic agents, aimed at promoting matrix synthesis in the degenerated IVD.

In 2002, BMP was approved as a bone graft substitute for anterior lumbar interbody fusion (ALIF), but in addition to its osteoinductive properties, BMP also demonstrated some potential for the treatment of disc disease. [117] Current human and animal studies have shown upregulation of BMP-2 and -7 in aging discs. [118] This upregulation has been found to have an antiapoptotic effect on the cells of the nucleus pulposus. [117] Also, the introduction of BMP-2 into intervertebral discs has resulted in increased extracellular matrix production. [119] However, the direct introduction of BMP into the intervertebral disc may lead to potential undesired osteogenic effects. In recent years, concerns about the safety of BMP-2 have arisen following reports of adverse reactions attributable to its use in ALIF and its off-label use in other spinal fusions. [120],[121],[122] In 2008, the Food and Drug Administration (FDA) published a public health notification about potentially life-threatening complications associated with use of BMP in cervical spine fusion. [123] To date, the safety of recombinant BMP-2 as a bone graft substitute remains controversial. Recent studies have shown the potential for the drug simvastatin to induce chondrogenesis and the production of Type II collagen and aggrecan through BMP-mediated pathways. [124]

A key factor initiating early degeneration, leading to the transformation of an optimal to a less optimal matrix, involves the disappearance of notochordal cells from the NP. [125],[126],[127] Notochordal cells have been shown to positively influence the activity of surrounding chondrocyte-like cells and their homeostasis [125],[126],[127],[128] and have gained increased attention as a potential NP progenitor cell. [129],[130],[131] Recent animal studies have shown increased extracellular matrix when autologous disc-derived chondrocytes were introduced into a canine disc degeneration model. Furthermore, recent human trial involving the introduction of autologous chondrocytes into postdiscectomy patients has resulted in decreased pain at 2 years compared with controls. Also, there was increased disc hydration at the treated levels and adjacent levels as evidenced by MRI evaluation. [132]

An alternative technique to chrondrocyte transplantation has been the use of adipocyte progenitor cells. The advantage to this technique is the relative abundance of adipose derived stem cell when compared to chondrocytic stem cells. In a rat degenerative disc disease model, transplanted adipose-derived stem cells resulted in increased extracellular matrix production, minimally decreased disc height, and improved discal hydration when compared to controls. [133]

Finally, another promising type of stem cells for future investigation are bone-marrow-derived stem cells. In vitro studies have demonstrated that these cells have similar chondrogenic capacity when compared to nucleu-pulposusderived cells. [134] However, in vivo studies are needed to confirm their potential efficacy, and any strategy involving the introduction of new cells into the human intervertebral disc to induce regeneration would have to account for the increased demand of nutritional supply by the increasing number of cells or the increased activity of previously present cells. [36]

Platelet-rich plasma (PRP) as a strategy for intervertebral disc degeneration repair and regeneration

PRP contains a variety of proteins and growth factors that are expected to serve as a therapeutic growth factor cocktail, playing a pivotal role in regulating the tissue microenvironment, improving cellular functions and promoting the regeneration of damaged tissues. PRP has been clinically applied for its healing properties, [135] and now is widely applied in many therapeutic areas. The concept that PRP application would promote IVDD regeneration is based on the role of platelets in wound healing. When activated, platelets can secrete a variety of growth factors, including PDGF, IGF-1, TGF-β, VEGF, bFGF, EGF and CTGF, among others. [136],[137] All these growth factors might play significant roles in promoting the proliferation of tissues. Platelets also contain antibacterial and bactericidal proteins that may influence the process of inflammatory responses by inducing the synthesis of some molecules, such as integrins, interleukins and chemokines. [138] Last but not least, platelets may serve as a biological sponge because they can absorb, store and transfer some small molecules that regulate tissue regeneration. [139] PRP represents a new biotechnology in tissue engineering and has become a popular clinical treatment for various tissue healing applications without any immune rejections. Chen and colleagues [140] demonstrated that PRP could promote nucleus pulposus regeneration and resulting in increased levels of messenger ribonucleic acids (mRNAs) involved in chondrogenesis and matrix accumulation.

Gene therapy in lumbar disc degeneration

Transduction of genes that have the potential to interfere with disc degeneration or even induce disc regeneration is a concept recently applied to IVDD by researchers. This strategy requires identification of relevant genes that play a role in the disc degeneration cascade, as well as ways of delivering those potentially therapeutic genes into disc cells. This can be obtained by so-called gene vector systems, which include a variety of viral and, more recently, non-viral vectors. [141],[142],[143]

Genetic material can be delivered into host cells by vectors via one of two methods in vivo or ex vivo. In vivo refers to the direct injection or inhalation of the vector. Ex vivo is the process where host cells are removed and the vector is applied in vitro, and then the modified cells are returned to the host. There are two classifications of vectors which can be used in gene therapy: Viral or non-viral vectors. Viral vectors can be further subdivided into two categories: Genome incorporating, which include retroviruses and lentiviruses and non-genome incorporating viruses, such as herpes viruses, adenoviruses and adeno-associated viruses. Viral vectors are genetically modified viruses which have been engineered to lack the genetic material which makes them pathogenic while retaining the genetic information which enables insertion of their genes into host cells. Additionally, a copy of the therapeutic gene is inserted into the viral vector so that it may be transferred into the host cell.

The first gene with potentially beneficial effects on disc degeneration to be experimentally delivered to the IVDD in an animal model was TGF-β1. [144] A similar approach of initial transduction of a marker gene was taken by Moon et al. to deliver genes into human IVD cells. [145]

Additionally, other growth factors, [146] inhibitors of metalloproteinases [147] and also a transcription factor, Sox-9, [148] have received consideration as possible targets for gene therapy for IVDD. Following identification of ADAMTS5 as a contributor to cartilage degradation in a mouse model, [149] ADAMTS5 small interference RNA was successfully used in a rabbit model to suppress degradation of NP tissue. [150] A similar approach was used to target caspase 3, a main executor of apoptosis, in a rabbit model [151] Future in vivo studies linking theoretical benefits of any of these gene therapy approaches to situations possibly encountered in clinical practice are desirable [152] and comprise the long-term perspective of applying gene therapy as a strategy to treat the underlying mechanism of disc degeneration.

In summary, the IVD is an essential stabilizing and mobilizing component of the spine. IVDD involves numerous cellular, biochemical and biomechanical processes. The diagnosis and treatment of IVD degenerative disease can be refined further, thereby facilitating early diagnosis and early treatment of IVDD patients, which could lead to better outcomes and improved quality of life. Preventing the loss of IVD matrix composition would ideally be used in conjunction with an approach aimed at regenerating the IVD matrix in order to begin reversing the matrix composition. Therefore, regeneration of the degenerated IVD matrix must be considered as an additional and equally important factor in the treatment of IVDD. However, much still needs to be learned about the fundamental processes involved in IVD degeneration, knowledge which may aid our understanding of the degenerative process and facilitate the development of novel strategies to regenerate the IVD.

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