Molecular therapy for disk degeneration and pain

Abstract

The nucleus pulposus of the intervertebral disk contains high amounts of the proteoglycan aggrecan, which confers the disk with a remarkable ability to resist compression. Other molecules such as collagens and noncollagenous proteins in the extracellular matrix are also essential for function. During disk degeneration, aggrecan and other molecules are lost due to proteolysis. This can result in loss of disk height, which can ultimately lead to pain. Biological therapy of intervertebral disk degeneration aims at preventing or restoring primarily aggrecan content and other molecules using therapeutic molecules. The purpose of the article is to review recent advances in biological repair of degenerate disks and pain.

Keywords: Link N; biological repair; growth factor; intervertebral disk degeneration; pain.

Fig. 1

Schematic views of the human intervertebral disk, vertebrae, and vasculature in the fetal (26 weeks), juvenile (10 years), and adult (50 years) human. The figure shows the disk with the nucleus pulposus (NP) surrounded by the annulus fibrosus (AF) and separated from the vertebral bodies by the end plate (EP). The thickness and diameter of the end plate, the vascularity of the disk, and the abundance of notochordal cells in the nucleus pulposus decline with age. Mesenchymal cells gradually replace notochordal cells in the nucleus pulposus, and the consistency of the nucleus pulposus changes from fluid to more gelatinous because of decreased proteoglycan content.

Fig. 2

The disk cell is a master of its destiny. The figure depicts the disk cell responsible for synthesizing matrix molecules such as aggrecan and collagen as well as degrading the matrix through the action of proteases. In a healthy disk there is a balance between synthesis and degradation.

Fig. 3

Therapeutic molecules used in disk repair: transforming growth factor (TGF), bone morphogenetic protein (BMP), growth differentiation factor (GDF), cartilage-derived morphogenetic protein (CDMP), Sma-Mad (Smad) proteins, Sox 9, LIM mineralization protein-1 (LMP-1), tissue inhibitor of matrix metalloproteinase (TIMP), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and Link N.

Fig. 4

Signal transduction pathways in the disk cell by the TGF-β superfamily of ligands, Link N and Wnt. TGF-β superfamily includes BMPs. Typically, TGF-β superfamily activates its type II receptor, which recruits and phosphorylates a type I receptor. TGF-ßs are mediated by SMAD2 and SMAD3 that form complexes with SMAD4 and translocate to the nucleus, and BMPs and Link N are mediated by SMAD1 and SMAD5. The canonical Wnt pathways are initiated when Wnt protein bind to receptors of the Frizzled family and the LRP5/6 co-receptor. The signal is further mediated by Dishevelled family of proteins and leads to β − catenin cytoplasm accumulation followed by entering in the nucleus where it modulates gene expression. Abbreviations: BMP, bone morphogenetic protein; EGF, epidermal growth factor; FGF, fibroblast growth factor; GDF-5, growth differentiation factor 5; IGF, insulin-like growth factor; IL-1, interleukin-1; LMP-1, LIM mineralization protein-1; TGF, transforming growth factor; TIMP-1, tissue inhibitors of matrix metalloproteinase-1; Wnt, Wnt/b-catenin.

Fig. 5

Axial and nonaxial back pain. Back pain is an intricate amalgam of conditions that includes both axial and radicular (nonaxial) pain. Axial back pain is defined as spontaneous or movement- evoked pain or discomfort localized to the spine and low back region. Nonaxial, referred to as radicular pain or sciatica, usually follows the trajectory of the sciatic nerve. Abbreviations: AF, annulus fibrosus; IL-1β, interleukin-1β; IVD, intervertebral disk; NGF, nerve growth factor; NP, nucleus pulposus; TNFα, tumor necrosis factor-α.