Notochordal Cell-Derived Therapeutic Strategies for Discogenic Back Pain

摘要

An understanding of the processes that occur during development of the intervertebral disk can help inform therapeutic strategies for discogenic pain. This article reviews the literature to identify candidates that are found in or derived from the notochord or notochordal cells and evaluates the theory that such factors could be isolated and used as biologics to target the structural disruption, inflammation, and neurovascular ingrowth often associated with discogenic back pain. A systematic review using PubMed was performed with a primary search using keywords “(notochordal OR notochord) And (nerves OR blood vessels OR SHH OR chondroitin sulfate OR notch OR CTGF) NOT chordoma.” Secondary searches involved keywords associated with the intervertebral disk and pain. Several potential therapeutic candidates from the notochord and their possible targets were identified. Studies are needed to further identify candidates, explore mechanisms for effect, and to validate the theory that these candidates can promote structural restoration and limit or inhibit neurovascular ingrowth using in vivo studies. Keywords: notochordal cells, notochord, sonic hedgehog, Semaphorin 3A, chondroitin sulfate, Notch, CTGF, intervertebral Concepts and factors important during development of the spine may be useful as therapeutic agents to address intervertebral disk (IVD) degeneration (IDD). The notochord patterns all regions of the IVD during development secreting several ligands (e.g., sonic hedgehog [SHH], connective tissue growth factor [CTGF], chondroitin sulfate [CS], Noggin, Chordin, and Semaphorin 3A) with the capacity to influence cell differentiation, inflammation, angiogenesis, and axonal growth. 1 , 2 , 3 , 4 A shift in nucleus pulposus (NP) cellular phenotype from predominantly notochordal cells (NCs) to predominantly small nucleus pulposus cells (SNPCs) is associated with maturation, and the loss of NCs has been speculated to initiate the onset of IDD in humans. 5 , 6 NCs secrete soluble factors that are essential for patterning and maintaining the healthy avascular and aneural IVD; hence loss of such factors during growth and aging may contribute to disease progression. Seminal work by Aguiar et al demonstrated increased proteoglycan synthesis of NP cells when cocultured with NCs, as a first demonstration of the therapeutic potential of NC-derived factors, and this was followed by studies examining NC-derived factors on mature human NP and mesenchymal stem cells (MSCs) in vitro. 7 , 8 , 9 NCs also influence annulus fibrosus (AF) cells and may have potential to suppress the expression of proinflammatory cytokines. 10 Therefore, NCs may secrete “candidate” factors that could be harnessed for therapeutic effect to limit or reduce the symptom-causing pathologies of IDD. Structural disruption of the IVD is commonly reported morphologically and with imaging. 11 , 12 Ingrowth of nociceptive nerve fibers deep within the IVD has also been reported in the painful degenerate human IVD and has been suggested to be one of the sources of discogenic pain. 13 , 14 “Targets” for these factors therefore include structural disruption, inflammation, and neurovascular ingrowth, which may all interact at different stages of degeneration. The purpose of this systematic literature review is to identify possible candidates and explore the hypothesis that candidates found in or derived from the notochord or NCs can address targets in IDD. We also highlight the concept of a cocktail treatment that focuses on both structural restoration and also symptoms associated with discogenic back pain and a need for screening in in vivo animal models for validation of such candidates.