Small molecule-based treatment approaches for intervertebral disc degeneration: Current options and future directions

Abstract

Low back pain (LBP) is a major reason for disability, and symptomatic intervertebral disc (IVD) degeneration (IDD) contributes to roughly 40% of all LBP cases. Current treatment modalities for IDD include conservative and surgical strategies. Unfortunately, there is a significant number of patients in which conventional therapies fail with the result that these patients remain suffering from chronic pain and disability. Furthermore, none of the current therapies successfully address the underlying biological problem - the symptomatic degenerated disc. Both spinal fusion as well as total disc replacement devices reduce spinal motion and are associated with adjacent segment disease. Thus, there is an unmet need for novel and stage-adjusted therapies to combat IDD. Several new treatment options aiming to regenerate the IVD are currently under investigation. The most common approaches include tissue engineering, growth factor therapy, gene therapy, and cell-based treatments according to the stage of degeneration. Recently, the regenerative activity of small molecules (low molecular weight organic compounds with less than 900 daltons) on IDD was demonstrated. However, small molecule-based therapy in IDD is still in its infancy due to limited knowledge about the mechanisms that control different cell signaling pathways of IVD homeostasis. Small molecules can act as anti-inflammatory, anti-apoptotic, anti-oxidative, and anabolic agents, which can prevent further degeneration of disc cells and enhance their regeneration. This review pursues to give a comprehensive overview of small molecules, focusing on low molecular weight organic compounds, and their potential utilization in patients with IDD based on recent in vitro, in vivo, and pre-clinical studies.

Keywords: degeneration; discogenic pain; inflammation; intervertebral disc; small molecules.

Figure 1

The intervertebral disc structure and the hallmarks of IVD degeneration (IDD). (A) The structure of the IVD and its anatomical location in the vertebral column. (B) Compared to healthy IVD, inflammation, blood vessel and neuronal ingrowth escalated in the degenerated disc. Moreover, the disorganization of collagen fibers and increasing of the interlamellar distances between collagen bundles in the annulus fibrosus were usually observed during the degeneration process that often results in disc bulging. During IDD, the number of apoptotic disc cells dramatically increased as well as the cell-cluster formation of nucleus pulposus (NP) cells. The calcification of the cartilage endplate and osteophyte formation occur in advanced degeneration. IVD degeneration is diagnosed when the degenerated IVD in the spine becomes symptomatic and causes discogenic pain. Additionally, the degenerated IVD (protrusion, bulging etc.) presses on spinal nerves, often producing radicular pain.

Figure 2

The modulatory effect of small molecules on inflammation, anabolic and catabolic processes and their impacts on IDD. Pro-inflammatory cytokines including IL-1 and TNF-a, are the key cytokines triggering IVD matrix degeneration through activation of NF-κB and P38/MAPK pathways. Moreover, these cytokines activate MMPs and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs) which finally will elevate ECM degradation. Small molecules can prevent IDD progression by inhibiting the activity of pro-inflammatory cytokines and the subsequent factors (NF-κB and P38/MAPK), or modulating the anabolic, catabolic and even some alternative pathways such as BMP-2 or Wnt pathways. IL: interleukin; ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs; MMPs: matrix metalloproteinase; CBD: cannabidiol; ECGC: Epigallocatechin gallate; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK: MAP Kinase; UA: urolithin A, TGF-β: transforming growth factor-beta; Cox: cyclooxygenase; PGE2: prostaglandin E2; IFN-γ: interferon-gamma; TNF-α: tumor necrosis factor-alpha.

Figure 3

The effect of small molecules on programmed cell death (apoptosis) and oxidative stress in degenerated IVD cells. Both intrinsic and extrinsic pathways of apoptosis are playing critical roles in IVD cell degeneration. Small molecules can increase the expression level of Bcl-2, leading to inhibition of the intrinsic pathway by its inhibitory effect on BAX and BAK1. BAX and BAK1 control the release of cytochrome C from mitochondria to cytosol or bind to Apaf-1, leading to inhibition of caspase 9 activity. Several small molecules can also decrease the expression level of caspase 3 in disc cells and subsequently inhibit apoptosis. Inflammatory cytokines and oxidative stresses can also increase the number of apoptotic cells in degenerated IVD cells by activating the ROS-mediated PI3K/Akt pathway. Production of ROS and the expression level of related products such as iNOS can be suppressed by different small molecules. TNF-α: tumor necrosis factor-alpha; IL: interleukin; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK: MAP Kinase; Bcl2: B-cell lymphoma 2; Bax: BCL-Associated X; BAK1: BRI1-associated receptor kinase 1; PI3K: phosphatidylinositol 3-kinase; Akt: Protein Kinase B; ROS: reactive oxygen species; iNOS: inducible nitric oxide synthase; CBD: cannabidiol.

Figure 4

The in vivo and clinical studies focused on the role of small molecules on IVD regeneration. ''n'' denotes the number of in vivo or clinical studies, Abbreviation; IP: intraperitoneal injection; ID: intradiscal injection/delivery; CBD: cannabidiol; EGCG: epigallocatechin 3-gallate.

Figure 5

Conventional diagnostic approaches and a proposed diagnostic method for detection of IDD. (A) Frequently used diagnostic methods in several in vivo studies for the diagnosis of IVD degeneration and evaluation of treatment responses. (B) Specific antibodies (Ab) may be locally injected into disc areas through the proposed method to attach with the ECM neoepitopes (NE); which produced during early degeneration processes. Then, the whole body animal bioluminescence could be used to track the Abs-neoepitopes complex (rat tail IDD model). PCR: polymerase chain reaction; WB: western blot; MRI: magnetic resonance imaging; IHC: immunohistochemistry; HIVD: healthy intervertebral disc; DIVD: degenerated intervertebral disc; SMs: small molecules; Ab: antibody; NE: neo-epitope; ECM: extracellular matrix; DC: disc cell; MMPs: matrix metalloproteinases.