Bioactive Therapies for Degenerative Disc Disease: Microenvironmental Foundations of Disease

Intervertebral disc (IVD) degeneration is a common source of back pain. The IVD is a complex structure that consists of an outer annular ring, an inner nucleus pulposus, and flanking cartilaginous endplates, which together allow for daily mobility by distributing loads and acting as a flexible segment within the spine. Both age and mechanical overload can drive the development of a pathologic disc microenvironment that includes alterations in mechanics, solute transport, and inflammation. Such changes in the disc have negative consequences on resident cells that promote their senescence, apoptosis, and contribution to furthering disc degeneration through mitochondrial dysfunction and the release of reactive oxygen species, proteases, and cytokines. This crosstalk between IVD cells and their microenvironment creates a feedback loop that eventually manifests into such clinical conditions as disc height loss, herniations, and total IVD collapse. Developing a holistic understanding of how this feedback loop is initiated and may be halted will enable the development of novel therapeutics that not only provide analgesic benefit but also help rebuild the deteriorated disc.