Therapeutic potential of growth differentiation factors in the treatment of degenerative disc diseases

Abstract

Intervertebral disc (IVD) degeneration is a major contributing factor to chronic low back pain and disability, leading to imbalance between anabolic and catabolic processes, altered extracellular matrix composition, loss of tissue hydration, inflammation, and impaired mechanical functionality. Current treatments aim to manage symptoms rather than treat underlying pathology. Therefore, IVD degeneration is a target for regenerative medicine strategies. Research has focused on understanding the molecular process of degeneration and the identification of various factors that may have the ability to halt and even reverse the degenerative process. One such family of growth factors, the growth differentiation factor (GDF) family, have shown particular promise for disc regeneration in in vitro and in vivo models of IVD degeneration. This review outlines our current understanding of IVD degeneration, and in this context, aims to discuss recent advancements in the use of GDF family members as anabolic factors for disc regeneration. An increasing body of evidence indicates that GDF family members are central to IVD homeostatic processes and are able to upregulate healthy nucleus pulposus cell marker genes in degenerative cells, induce mesenchymal stem cells to differentiate into nucleus pulposus cells and even act as chemotactic signals mobilizing resident cell populations during disc injury repair. The understanding of GDF signaling and its interplay with inflammatory and catabolic processes may be critical for the future development of effective IVD regeneration therapies.

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

“…As mentioned previously, interest has been paid to the potential of growth factors 72,73 and cells 7,9 for regeneration of the IVD. Wnt3a and wnt5a are crucial factors for the maintenance and induction of cells to a chondrogenic phenotype and thus hold promise as tools in treatment of IVD degeneration.…”

Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc

“…While current treatment options for DDD, including oral analgesics and surgery, solely aim to reduce the symptoms, researchers have made extensive efforts over the past decade to develop novel therapeutic approaches that target the underlying pathophysiological mechanisms, i.e., degeneration, inflammation, and enhanced apoptosis (Fernandez-Moure et al, 2018;Tendulkar et al, 2019). A wide range of approaches has been tested which are described in detail elsewhere (Krupkova et al, 2018;Smith et al, 2018;Clouet et al, 2019;Hodgkinson et al, 2019;Loibl et al, 2019), ranging from autologous disc cell therapy, growth factors, biologics, gene transfection, and biomaterials to CRISPR/Cas9 genome engineering, as well as the use of mesenchymal stem cells (MSCs). However, none of these concepts have been successfully incorporated yet into daily clinical practice.…”

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

“…However, use of these factors is linked with concerns that their use may cause unwanted nerve and blood vessel ingrowth, accelerating IVD degeneration. Therefore, members of the growth differentiation factor (GDF) family, the receptors for which are not expressed by invading blood vessels within degenerate discs [ 9 ], have emerged as promising candidates [ 10 ]. However, what remains unknown is whether degenerate cells can respond to GDF stimuli in a manner that reverses the cascade of degeneration affecting the disc as an organ.…”