β-Catenin-Deficient Intervertebral Disc Cells Reduce Chemotactic Transcription and Myeloid Cell Recruitment to Injured Discs of Mice
Abstract
Aging exacerbates the incidence of discogenic chronic low back pain by excessive inflammation and immune cell presence. Aging reduces intervertebral disc (IVD) Wnt signaling, which is associated with IVD cell differentiation, IVD cell proliferation and anti-inflammatory signaling. However, it is unclear how in vivo Wnt signaling-absent IVD cells, which model aged IVD cells, regulate chemotactic signaling and immune cell recruitment. We hypothesized that Wnt signaling-absent IVD cells attenuate chemotactic transcription and immune cell recruitment to naive IVD and in response to IVD injury. First, because aging reduces Wnt signaling in all IVD cells, we deleted β-catenin using the AcanCreERT2. β-catenin deletion reduced monocyte chemoattractant protein-1 (MCP1/CCL2) Ccl2 in male and female IVDs by 58% and 79%, respectively (n = 5-6/sex). Using positron emission tomography/computed tomography (PET/CT) imaging of myeloid cells in 5-month-old mice (n = 4 IVD/sex/grp), deletion of β-catenin reduced myeloid-derived cell burden in naive IVD by 79% and attenuated IVD injury-induced recruitment by 48%. Next, because nucleus pulposus (NP) cells begin losing Wnt signaling early in life, we deleted β-catenin using the ShhCreERT2. Compared to RNA-sequencing of WT IVD post injury (n = 3/grp), deletion of β-catenin in NP cells impaired the activation of immune cell pathways, such as MCP1/CCL2. Together, the chemotactic transcriptomic response and myeloid cell accumulation due to IVD injury…
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