Invited critical reviewMMPs and ADAMTSs in intervertebral disc degeneration
Introduction
Low back pain is a chronic, expensive, common medical problem in the world. It is the most common cause of disability in people younger than 45 years of age. Over 80% of adults will experience low back pain during their lifetimes [1]. At present, low back pain has become the second most frequent cause for visits to the hospital. There is growing evidence that the majority of low back pain is associated with intervertebral disc (IVD) degeneration (IDD) [2]. IDD constitutes the pathological foundation of most musculoskeletal disorders of the spine, including spinal stenosis, instability, disc herniation, radiculopathy and myelopathy. Despite the pathogenesis of IDD has not been completely understood, the predominant changes to IDD are characterized by in active cell number reduction, extracellular matrix (ECM) degradation, altered phenotype of normal disc cells, and presence of inflammation [3], [4]. Current treatment for IDD includes conservative management (bed rest, nonsteroidal anti-inflammatory drugs and physical therapy) and surgical procedures (laminectomy, corpectomy and fusion). If conservative treatment fails, then surgical fusion is commonly considered. All of these therapeutic methods are limited to treat the symptoms but do nothing to slow down or reverse the course of IDD. Thus, a greater understanding of IDD pathology is urgent to optimize treatment strategies and develop novel anti-IDD drugs.
The major ECM components within the discs are collagens and proteoglycans. In healthy discs, the rates of synthesis and breakdown of ECM are in equilibrium because of intricate regulation by growth factors and catabolic cytokines. When catabolism of ECM prevails over its anabolism, IDD often occurs. It is well established that loss of collagens and proteoglycans play a critical role in the development of disc degeneration [5]. Matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTSs) are primary enzymes that cleave collagens and proteoglycans. It has been already reported that many members of MMPs and ADAMTSs are highly expressed in degenerative IVD tissue and cells, and these enzymes are deeply implicated in ECM breakdown and IDD progression [6]. Moreover, inactivation or knockdown of MMPs and ADAMTSs has shown enormous potential in promoting ECM repair and retarding disc regeneration [7]. In this review, we summarize the expression patterns and roles of MMPs and ADAMTSs in IDD, and describe recent progress regarding their inhibition as a promising biological therapeutic approach for disc degeneration.
Section snippets
Structure and function of IVDs
The IVD is an important component of the spinal column and forms a shock absorber between each vertebra, allowing bending, flexion and torsion of the spine. Normal IVD is a complicated structure that contains three morphologically distinct regions: nucleus pulposus (NP), annulus fibrosus (AF) and cartilaginous end plates. The cartilaginous end plates are localized to the cranial and caudal aspects of each disc and contain the peripheral vasculature that nourishes the disc [8].
As a thick, dense
Etiology of IDD
Although the exact pathophysiology of IDD has not been completely understood, the environmental and genetic factors are thought to be the main contributors to IDD. Occupational exposures such as vibration [14], mechanical influences including heavy lifting and weight [15], lifestyle factors such as lack of exercise [16], and the long use of non-Japanese cars [17] are known to promote IVD degeneration. Injuries associated with lifting or trauma [18], [19] and tobacco use [20], [21] have been
Matrix synthesis and degradation during disc degeneration
In healthy discs, the rates of synthesis and breakdown of the ECM are in equilibrium. When ECM breakdown prevails over its synthesis, IDD usually occurs. In the early stage of degeneration, collagen synthesis, in general, is increased. Especially, a clear increase in Col II content is seen within the NP, possibly signifying an attempted repair mechanism [7]. With more advanced degeneration, Col II content markedly decreases, resulting in a reduced ratio of Col II to Col I. Moreover, the
MMPs
MMPs, also called matrixins, are a very large family of calcium-dependent, zinc-containing endopeptidases. There are 24 MMP genes identified in humans to date, among which MMP-23 gene includes two genetic duplications. Thus, humans have 23 MMPs. MMPs are traditionally divided into six categories depending on their substrate specificity, protein structure and subcellular localization: collagenases, gelatinases, stromelysins, matrilysins (minimal domain), membrane-type MMPs, and unclassified
Disc MMP expression
MMP expression in normal IVD tissue is low and even devoid. In infant and preadolescent IVDs, MMP-1, MMP-2, MMP-3 and MMP-9 cannot be detected using immunohistochemistry; however, MMP-1 and MMP-3 appear in adult IVDs [35]. Le Maitre et al. have demonstrated that MMP-3 and MMP-13 expression is absent but a minimal expression of MMP-1 exists in non-degenerative discs [36]. In porcine discs, the level of MMP-1 mRNA increased with aging [37]. In contrast, the greatest expression of MMP-19 is
Roles of MMPs and ADAMTSs in IDD
The initiation and development of IDD is a multifactorial and complex process, and the involved mechanisms are not fully elucidated. The disruption of ECM is a major hallmark of disc degeneration. Given the key role of MMPs and ADAMTSs in ECM degradation, it is not surprising that these enzymes are involved in the pathology of IDD (Fig. 1). The effects of MMPs and ADAMTSs on IDD progression will be discussed in detail below. Simultaneously, agents that affect the course of IDD by regulating the
Therapeutic potential of targeting MMPs and ADAMTSs in IDD
Existing therapy options for IDD are restricted to treat the symptoms, and does not target its pathophysiology, highlighting the urgent need to develop biological therapeutic approaches. Since excessive ECM disruption is thought to the primary cause of IDD, delaying or stopping the characteristic ECM loss in disc degeneration has been suggested as a novel strategy which aims to restore matrix homeostasis by enhancing anabolism or reducing catabolism [99]. Considering the key role of MMPs and
Conclusions and future directions
It is clear that IDD primarily results from an imbalance between catabolism and anabolism of disc ECM components, especially Col II and aggrecan. As the primary mediators of Col II and aggrecan degradation, the majority of MMPs and ADAMTSs are highly expression in degenerative IVD tissue and cells, and play a crucial role in ECM breakdown and IDD progression. Despite the fact that inhibition of MMPs and ADAMTSs has shown efficacy and therapeutic potential in promoting ECM repair and preventing
Disclosure
The authors have declared no conflict of interest.
Acknowledgment
The authors gratefully acknowledge the financial support from the Natural Science Foundation in Hunan Province, China (2015JJ5003).
References (124)
- et al.
Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration
Spine J.
(2013) - et al.
Gene therapy for intervertebral disk degeneration
Orthop. Clin. North Am.
(2011) - et al.
The role of polymorphisms of genes encoding collagen IX and XI in lumbar disc disease
Neurol. Neurochir. Pol.
(2014) - et al.
Spine degeneration in a murine model of chronic human tobacco smokers
Osteoarthr. Cartil.
(2012) - et al.
The genetics of intervertebral disc degeneration. Familial predisposition and heritability estimation
Joint Bone Spine
(2008) Membrane-type matrix metalloproteinases: their functions and regulations
Matrix Biol.
(2015)- et al.
Matrix metalloproteinases: they're not just for matrix anymore!
Curr. Opin. Cell Biol.
(2001) A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family
Int. J. Biochem. Cell Biol.
(2004)Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics
Matrix Biol.
(2015)- et al.
Quantitative analysis of gene expression in a rabbit model of intervertebral disc degeneration by real-time polymerase chain reaction
Spine J.
(2005)