Abstract
Intervertebral disk (IVD) degeneration is often associated with severity of lower back pain. IVD core is an avascular, highly hydrated tissue composed of type II collagen, glycosaminoglycans, and proteoglycans. The disk degeneration is not only a destruction of IVD structure but also is related to a disorder of the turnover of the disk matrix, leading the jelly-like IVD core to be replaced by fibrous components. Here we present a disease-modifying strategy for IVD degenerative diseases by direct regulation of the cells in the IVD using mRNA medicine, to alter the misbalanced homeostasis during disk degeneration. When mRNA encoding a cartilage-anabolic transcription factor, runt-related transcription factor-1, was administered to a rat model of coccygeal disk degeneration using a polyplex nanomicelle composed of polyethylene glycol-polyamino acid block copolymers and mRNA, the disk height was maintained to a significantly higher extent (≈81%) compared to saline control (69%), with prevention of fibrosis in the disk tissue. In addition, the use of nanomicelles effectively prevented inflammation, which was observed by injection of naked mRNA into the disk. This proof-of-concept study revealed that mRNA medicine has a potential for treating IVD degenerative diseases by introducing a cartilage-anabolic factor into the host cells, proposing a new therapeutic strategy using mRNA medicine.
Highlights
Lower back and neck pain are frequently associated with intervertebral disk (IVD) degeneration, and imaging studies have found an association between prevalent IVD degeneration and severity of lower back pain.[1,2] The IVD is composed of a central hydrophilic proteoglycan-rich gelatinous core, the nucleus pulposus (NP), which is surrounded by a multilamellar collagenous ring, the annulus fibrosus, and cartilaginous and bony endplates that separate the disk from the vertebrae.[3]
In this study, we demonstrated the therapeutic effects of RUNX1 mRNA injected into the IVD using nanomicelles
Local Inflammation Induced by RUNX1 mRNA Was Reduced by Nanomicelles the inflammatory responses at the injection site were evaluated, because, as shown in Figure 4, a number of cells might be infiltrated in the disk tissue, especially for the naked RUNX1 mRNA group
Summary
Lower back and neck pain are frequently associated with intervertebral disk (IVD) degeneration, and imaging studies have found an association between prevalent IVD degeneration and severity of lower back pain.[1,2] The IVD is composed of a central hydrophilic proteoglycan-rich gelatinous core, the nucleus pulposus (NP), which is surrounded by a multilamellar collagenous ring, the annulus fibrosus, and cartilaginous and bony endplates that separate the disk from the vertebrae.[3] The IVD core is an avascular, highly hydrated tissue due to the extracellular matrix (ECM) surrounding nucleus pulposus cells, which are composed of type II collagen, glycosaminoglycans (GAGs), and proteoglycans such as aggrecan.[4,5] The IVD is a dynamic tissue, in which the ECM undergoes continuous turnover.[6] Disk disease is a destruction of IVD structure and is related to a disorder of the turnover, due to the shortage of factors involved in the homeostasis of the disk matrix.[7] Even when anabolic and catabolic activities of cells in the IVD are normally maintained, excessive mechanical stress or other stimuli can alter the homeostasis and initiate the degenerative cascade
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