Aging Disc Cells Lose a Key Signal That Calls Immune Cells to Heal Injured Spines

Chronic low back pain is one of the most common and costly medical complaints on the planet, and its leading driver is the slow, often silent degeneration of the intervertebral discs that cushion the spine. Yet one of the strangest features of disc disease has long defied explanation: degeneration visible on an MRI scan does not always hurt, and debilitating pain can strike people whose discs look structurally fine. A new study in mice, published in Aging Cell, offers a fresh clue to this puzzle by showing that when disc cells lose a critical molecular signaling pathway as they age, they stop sending out the chemical distress calls that summon immune cells to an injury site. The finding reframes age-related back pain not simply as a matter of tissue breakdown, but as a failure of the inflammatory conversation between damaged discs and the immune system.

The pathway in question is Wnt signaling, a master regulator of cell identity, proliferation, and repair that operates in nearly every tissue of the body. Its central messenger, a protein called β-catenin, shuttles from the cell’s cytoplasm into the nucleus when the pathway is active, where it teams up with transcription factors known as TCF and LEF to switch on target genes. In the intervertebral disc, Wnt signaling helps maintain the youthful, gel-filled nucleus pulposus cells that produce the disc’s abundant extracellular matrix. Previous work from the same group showed that deleting β-catenin from disc cells weakens the disc’s compressive stiffness, while stabilizing β-catenin makes discs stiffer and more resistant to deformation. Aging, meanwhile, is known to strip Wnt signaling from disc cells, pushing them toward a more mature, cartilage-like state that produces less matrix.

What remained unclear was whether this age-related loss of Wnt signaling changes how disc cells behave during injury, specifically whether it alters their ability to recruit immune cells to the damaged tissue. To find out, the researchers engineered mice in which β-catenin could be deleted from disc cells in adulthood, using a tamoxifen-activated Cre system targeted to aggrecan-producing cells throughout the disc, or more selectively to nucleus pulposus cells using a Sonic hedgehog-driven driver. Because the deletion was induced at four months of age, well after spinal development was complete, the researchers could isolate the effect of losing Wnt signaling without the confounding systemic inflammation that accompanies natural aging. They then injured the discs mechanically using a tail compression device that applies a precisely calibrated load, roughly equivalent to the change in pressure a human disc experiences when standing up from a chair.

The first surprise came from the genetic confirmation itself. Deleting β-catenin reduced Wnt reporter activity in the annulus fibrosus of male mice by 62 percent, and the deletion cut β-catenin gene expression by 65 percent in male discs and a striking 90 percent in female discs. But the most consequential change was in a single chemokine: Ccl2, also known as MCP-1, the monocyte chemoattractant protein that acts as a beacon guiding monocytes and macrophages toward inflamed tissue. Its expression plummeted by 58 percent in male discs and 79 percent in female discs after β-catenin deletion. Intriguingly, other inflammatory genes responded differently by sex: male discs upregulated the pro-inflammatory cytokine Il1b nearly fivefold and the activated-neutrophil marker S100a9 threefold, while female discs showed no such changes.

To track immune cell recruitment in living animals rather than inferring it from gene expression alone, the team deployed an elegant imaging strategy. They injected mice with PERFECTA-HDL nanoparticles, high-density lipoprotein-like particles that are preferentially taken up by myeloid cells, radiolabeled with zirconium-89, and then scanned the animals with PET/CT before and after disc injury. The results were dramatic. In wild-type mice, disc injury increased tracer signal in the injured region by more than 800 to 1000 percent, reflecting a massive influx of myeloid cells. In mice lacking β-catenin in their disc cells, baseline myeloid accumulation was already reduced by roughly 76 to 79 percent, and the injury-induced surge was blunted by about half. Immunohistochemical staining for the pan-myeloid marker CD11b corroborated the imaging, showing that β-catenin deletion attenuated injury-induced myeloid infiltration by 30 percent in males and 42 percent in females.

Bulk RNA sequencing of injured discs revealed just how profoundly β-catenin shapes the transcriptional response to damage. In wild-type discs, injury upregulated nearly 3,000 gene ontology pathways, and 60 percent of the top twenty were immune-related, including the positive regulation of MCP-1 production itself. Genes like saa3, nos2, il1b, and the neutrophil chemotactic pair cxcl2-cxcr2 were strongly induced, painting a picture of an aggressive early innate immune response dominated by neutrophils and inflammatory macrophages. In β-catenin-deficient discs, that immune signature was largely absent. Instead, injury pushed the transcriptome toward pathways of cell cycle progression, reverse transcription, and developmental biology, with upregulation of genes like twist2, pole, and myog that hint at progenitor-like differentiation programs rather than inflammatory mobilization.

Among the most striking findings was what happened to two anti-inflammatory regulators. In β-catenin-deficient injured discs, five of the seven most downregulated genes relative to wild-type injured discs were inflammation-related, including the serpinA1 family, which encodes alpha-1 antitrypsin, a potent inhibitor of neutrophil elastase that normally restrains tissue degradation and modulates cytokine production. The enzyme ephx2, which metabolizes anti-inflammatory eicosanoids called EETs, was also suppressed. The researchers suggest that losing these brakes on inflammation may paradoxically impair proper inflammatory resolution, allowing neutrophil elastase to chew up the extracellular matrix while the disc fails to mount the coordinated immune response needed for genuine repair.

To connect the engineered deletion back to real aging, the team compressed the tail discs of mice at five, twelve, and twenty-four months of age and measured inflammatory gene expression. Aging reproduced the pattern seen in β-catenin-deficient discs: the injury-induced upregulation of Il6 was attenuated in old female mice, and the regulation of serpinA1a shifted with age in ways that mirrored the knockout phenotype. This corroboration strengthens the central claim that the Wnt-deficient young disc is a legitimate model of the aged disc’s impaired chemotactic signaling, and that the immune recruitment failure observed in the knockouts reflects what actually happens in aging tissue.

The study also surfaced a notable sex difference. Male mice showed a far larger myeloid cell influx after disc injury than females, and β-catenin deletion suppressed that response more dramatically in males. The authors note this may relate to the higher incidence of chronic low back pain among young-adult men compared with young-adult women, while the elevated prevalence in older women may have different, menopause-related origins. It is a reminder that inflammatory biology in the spine, as in so many tissues, is not one-size-fits-all.

The implications reach beyond basic biology. If aged, Wnt-deficient disc cells under-recruit immune cells after injury, they may fail to trigger the acute neutrophil response that recent human pain research has linked to protection against chronic pain, potentially explaining why some degenerating discs become persistently painful while others do not. At the same time, the loss of anti-inflammatory regulators like alpha-1 antitrypsin suggests that simply damping inflammation with NSAIDs, the current mainstay of treatment, may be precisely the wrong approach for aged discs. The authors argue that effective therapies for age-related discogenic pain will need to strike a careful balance, restoring enough chemotactic signaling to permit proper immune-mediated healing without amplifying the chronic, excessive inflammation that drives tissue destruction. It is a subtle prescription, but one that this study, for the first time, grounds in a concrete molecular mechanism.

Subject of Research: The role of Wnt/β-catenin signaling in intervertebral disc cells in regulating chemotactic gene expression and myeloid cell recruitment during disc injury and aging

Article Title: β‐Catenin‐Deficient Intervertebral Disc Cells Reduce Chemotactic Transcription and Myeloid Cell Recruitment to Injured Discs of Mice

Article References: Kroon, T. M., Munitz, J., Ranzenigo, A., Umali, M., Wang, W., Huang, J. J., Teunissen, A. J. P., & Holguin, N. (2026). β‐Catenin ‐Deficient Intervertebral Disc Cells Reduce Chemotactic Transcription and Myeloid Cell Recruitment to Injured Discs of Mice. Aging Cell, 25(10), Article e70740. https://doi.org/10.1111/acel.70740

Image Credits: AI Generated

DOI: 10.1111/acel.70740

Keywords: intervertebral disc, Wnt signaling, beta-catenin, chronic low back pain, disc degeneration, myeloid cells, inflammation, chemokines, Ccl2, PET imaging, aging, nucleus pulposus