Background/Purpose: Intervertebral disc (IVD) degeneration and facet joint (FJ) osteoarthritis (OA) often co-exist, and both are major contributors to lower back pain (LBP). Despite their clinical relevance, the shared mechanisms of tissue damage in these anatomically and functionally linked tissues remain poorly understood. The objective of this study was to perform histological analyses and omics profiling of FJs and IVDs from the same young and aged human donors. Data were analyzed for molecular and cellular alterations linked to tissue damage and LBP.

Methods: IVDs and FJs were harvested from the L3/L4 of 5 young, healthy (aged 23-37) and 10 aged (aged 67–81) donors. IVD and FJ sections were stained with Safranin O and histologically graded using the Thompson system for nucleus pulposus (NP), annulus fibrosus (AF), vertebral body (VB), and cartilaginous end plate (CEP) and OARSI systems for FJ sections. Bulk RNA sequencing was performed on all tissues using SMARTseq.

Results: Histological grading revealed significantly higher overall scores in IVDs from aged donors as compared to normal donors. Sub-compartment scores of VB, NP, AF, and CEP were also elevated in the aged group. Similarly, OARSI scores were significantly higher in FJ cartilage from aged donors compared to young healthy. Transcriptomic analysis identified 38, 161, 615, 2262, and 500 differentially expressed genes (DEGs) in AF, NP, CEP, VB, and FJ, respectively (A). Gene Set Enrichment Analysis (GSEA) revealed upregulation of cartilage and bone development pathways, along with extracellular matrix (ECM) remodeling in aged AF. In aged NP, ER-associated degradation (ERAD) and unfolded protein response (UPR) pathways were prominently enriched. GSEA in degenerated CEP highlighted enrichment of stress responses and hypoxia-related pathways. In VB, pathways related to oxygen transport, adipogenesis, and neurovascular regulation were enriched. In FJ cartilage, GSEA revealed upregulation of UPR, integrated stress response, and circadian rhythm pathways (B). Notably, stress responses and UPR pathways were consistently upregulated across degenerated NP, CEP, and FJ (highlighted in B). Additionally, we investigated the molecular overlap between knee OA pathways and spine degeneration by assessing whether OA-associated genes identified in knee articular cartilage were upregulated in the cartilaginous components of the spine specifically, the CEP and FJ cartilage (C). While transcriptomic profiles of CEP and FJ cartilage showed considerable similarity to each other, overlap with the knee OA gene set was limited, with only 6–8 of the 134 OA-associated genes commonly upregulated. KCNN4, upregulated across CEP, FJ, and OA gene sets, is linked to cartilage homeostasis and mechanotransduction.

Conclusion: The strong correlation between IVD and FJ degeneration, along with shared upregulation of stress-related pathways particularly the UPR and integrated stress response suggests common molecular mechanisms driving IVD and FJ degeneration. These findings highlight the importance of targeting cellular stress response and UPR pathways to develop more effective, system-level therapeutic strategies to address structural damage to IVD and FJ and associated LBP.

(A) Differentially expressed genes (DEGs) identified as upregulated or downregulated in nucleus pulposus (NP), annulus fibrosus (AF), vertebral body (VB), cartilage endplate (CEP), and facet joint (FJ) cartilage. (B) Gene set enrichment analysis (GSEA) highlighting the top 10 enriched pathways in normal versus aged FJ cartilage. (C) Venn diagram illustrating the overlap of DEGs among CEP, FJ cartilage, and a curated osteoarthritis (OA) gene set.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multi-tissue-molecular-and-histopathological-profiling-of-facet-joints-and-intervertebral-discs/