Researchers have found a new avenue for approaching spinal disc degeneration and published their work in Aging Cell.
A very common problem
Back problems in the elderly are widely known to be caused by a deteriorating spine. Some of these problems are due to the vertebrae themselves losing cohesion, such as in osteoporosis, but the soft discs between the vertebrae also wear out. This condition, intervertebral disc degeneration (IDD), makes discs less elastic, decreasing their ability to bear loads and hold the spine together [1].
Previous work has found that cellular senescence is a major part of disc degeneration, as the SASP has been linked to the degradation of the nucleus pulposus (NP) cells responsible for maintaining spinal discs [2]. Some recent work has directly contradicted other recent work in the mechanisms behind IDD; one paper concluded that the senescence-related STING pathway is responsible for it [3], while another concluded that it is not [4].
This paper, however, does not focus on STING. Instead, it focuses on BRD4, a compound that regulates transcription and gene expression. Previous work has found that BRD4 is directly related to the degradation of NP cells and thus IDD in diabetic patients [5], and these researchers have previously found that inhibiting BRD4 suppresses IDD in rats [6].
However, that prior study did not go into precisely why this is the case. Therefore, the researchers took a very close look at the biochemistry involved, discovering a mechanistic pathway that had not been previously described.
Confirming the target
In their first experiment, the researchers examined cells derived from IDD patients, including pathway analysis. They found that BRD4 indeed spurs senescence in NP cells, including upregulation of the well-known senescence inducer NF-κB. Senescence and severity are strongly correlated in IDD; patients with merely Grade II IDD had far less than patients with Grade V IDD, whose discs had become yellowed and solidified.
The researchers then turned to their rat population. Wild-type Sprague-Dawley rats naturally develop IDD over time in much the same way as humans; 2-month-old rats had no signs of it, while 9-month-old rats began to develop it and 20-month-old rats had notable degeneration. As expected, the SASP and other senescence biomarkers increased over time in these animals’ NP cells. Here, too, BRD4 was directly linked to this increase.
The researchers confirmed this link by cultivating NP cells and driving them senescent by either TNF-α or repeated replication. In both cases, the cells’ BRD4 increased alongside their SASP production. Overexpressing BRD4 caused these maintenance-focused cells to secrete compounds that break down the extracellular matrix (ECM); inhibiting BRD4 caused them to build the ECM instead.
Fundamental mechanisms
An examination of biochemical pathways found that the gene MAP2K7 is expressed alongside BRD4. Previous work has found this gene to be related to the well-known MAPK signaling pathway [7]. Knocking down BRD4 also knocked down MAP2K7, confirming that MAP2K7 is downstream of BRD4 and suggesting that it plays a role in cellular senescence.
Directly upregulating and downregulating MAP2K7 had the same effects as in BRD4, with overexpression leading to cellular senescence and ECM deterioration; similarly, inhibition led to a decrease in senescence and an increase in ECM construction.
Similar work on MAP2K7 and BRD4 found yet another downstream target, PGF. In cells derived from IDD patients, the expression of all three of these genes increased alongside disease severity and cellular senescence. Rat tissues were found to have similar results. Once more, direct upregulation and downregulation of PGF had the same effects as in BRD4 and in MAP2K7. These effects were confirmed in rats; in an IDD model induced by needle puncture, rats with BRD4 knocked down through a silencing lentivirus had reduced levels of both MAP2K7 and PGF, along with reduced senescence and better disc and ECM healing, compared to a control group.
Regulating these three components differently had interesting and sometimes contradictory effects. Downregulating BRD4 while upregulating MAP2K7 decreased senescence but also decreased ECM construction. Doing the reverse seemed to be beneficial, decreasing senescence and increasing ECM construction. Overexpressing MAP2K7 while inhibiting PGF also led to benefits in fighting senescence and improving ECM construction, while doing the reverse of this also reduced senesence but harmed construction.
Overall, the researchers concluded that BRD4, MAP2K7, and PGF form a signaling axis that modulates senescence and ECM maintenance in NP cells. They suggest that the components of this axis are potentially druggable targets, and focusing on this area may lead to effective therapies for age-related back pain and disc deterioration.
Literature
[1] Azril, Huang, K. Y., Hobley, J., Rouhani, M., Liu, W. L., & Jeng, Y. R. (2023). Correlation of the degenerative stage of a disc with magnetic resonance imaging, chemical content, and biomechanical properties of the nucleus pulposus. Journal of Biomedical Materials Research Part A, 111(7), 1054-1066.
[2] Gao, J. W., Shi, H., Gao, F. P., Zhou, Z. M., Peng, X., Sun, R., … & Wu, X. T. (2025). Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 80(2), glae204.
[3] Wang, P., Zhang, S., Liu, W., Lv, X., Wang, B., Hu, B., & Shao, Z. (2024). Bardoxolone methyl breaks the vicious cycle between M1 macrophages and senescent nucleus pulposus cells through the Nrf2/STING/NF-κB pathway. International Immunopharmacology, 127, 111262.
[4] Ottone, O. K., Kim, C. J., Collins, J. A., & Risbud, M. V. (2022). The cGAS-STING pathway affects vertebral bone but does not promote intervertebral disc cell senescence or degeneration. Frontiers in immunology, 13, 882407.
[5] Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., … & Zhang, X. (2019). BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. The FASEB Journal, 33(10), 11555-11566.
[6] Zhang, G. Z., Chen, H. W., Deng, Y. J., Liu, M. Q., Wu, Z. L., Ma, Z. J., … & Kang, X. W. (2022). BRD4 inhibition suppresses senescence and apoptosis of nucleus pulposus cells by inducing autophagy during intervertebral disc degeneration: an in vitro and in vivo study. Oxidative Medicine and Cellular Longevity, 2022(1), 9181412.
[7] Zhang, H., Shao, Y., Yao, Z., Liu, L., Zhang, H., Yin, J., … & Bai, X. (2022). Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7. Annals of the rheumatic diseases, 81(5), 676-686.
