The epigenetic underpinnings of lower back pain

Abstract

Lower back pain is a leading cause of disability in western countries, and about 20% of those affected by lower back pain develop a chronic condition. 1 In addition to the personal impact, the loss of productivity associated with chronic lower back pain causes a large socioeconomic burden for western society. Chronic lower back pain is caused by intervertebral disc degeneration (IVDD) characterized by the breakdown of one or more of the discs that separate the spinal vertebrae. Current treatments for IVDD focus on relieving the symptoms of back pain but often do not address the underlying molecular mechanisms of disc degeneration. Therefore, an important focus of current research is to identify the various factors responsible for disc degeneration, as well as strategies for regeneration. Intervertebral discs are multi-component structural tissues composed of an inner hydrated gel-like nucleus pul-posus (NP) surrounded by an outer fibrous region and a cartilaginous endplate, which together normally provide cushioning between vertebrae and absorb pressure put on the spine. Under compressive loads, the NP distributes hydraulic pressure within each disc in all directions. The NP consists of collagen fibrils, proteoglycan aggrecans, and NP cells (NPCs). NPCs reside in an environment with limited vasculature and generate energy through anaerobic glycolysis. These cells synthesize colla-gen and secrete chemokines, matrix proteases, cytokines, and growth factors. 2 The pathophysiology of IVDD is not fully understood; however, environmental and genetic factors are reported to contribute to NPC senescence that leads to increased catabolism of the extracellular matrix, loss of proteoglycan and water content in the NP, and failure of the intervertebral disc biomechanical properties. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. A recent report from Li et al. reveals a new mechanism for how altered epigenetic mechanisms contribute to NPC senescence and IVDD (Figure 1). 3 Epigenetic mechanisms regulate heritable gene expression patterns without affecting the underlying DNA sequence. Decades of research suggests these mechanisms are responsible, at least in part, for the aging process. Age related variations of epigenetic mechanisms such as DNA methylation, noncoding RNAs, chromatin remodeling and histone posttranslational modification produce transcriptional changes responsible for many aging-related diseases such as cancer and heart failure. By comparing gene expression from NPCs isolated from normal or degenerated discs, the authors found that IVDD was associated with a gene expression signature of NPC senescence. Significantly, the expression of the ALKBH5 gene, a N 6-methyladenosine (m 6 A) demethylase, was found to be enriched in senescent NPCs and expression of senescent markers was determined to be dependent on ALKBH5 expression and activity. The authors determined that the histone lysine demethylase KDM4A was increased in senescent NPCs and bound to the promoter region of the ALKBH5 gene, causing a decrease in his-tone H3 lysine 9 trimethylation at the ALKBH5 promoter, which promoted increased ALKBH5 expression. In addition , the authors found that the DNMT3B mRNA half-life was shorter in ALKBH5 knockdown cells. The m 6 A peak of DNMT3B was enriched in the 3′UTR region of DNMT3B mRNA, and by RNA pull down it was revealed that YTHDF2 bound to this m 6 A site in the DNMT3B mRNA. In both normal and senescent NPCs, YTHDF2 inhibition increased the stability and expression of DNMT3B mRNA. These results suggest that in senescent NPCs increased Clin. Transl. Med. 2022;12:e868. wileyonlinelibrary.com/journal/ctm2 1 of 3 https://doi.