Background/Purpose: The knee menisci are essential elements in joint biomechanics and meniscus damage is a driver of cartilage destruction and knee osteoarthritis. Meniscus damage and associated changes in innervation are also an important source of knee pain.

As early molecular and cellular changes and mechanisms that mediate the onset of tissue damage and mechanisms of progression are poorly understood, there are no approaches to prevent or delay onset or stop progression of meniscus destruction. The goal of this study is to discover genes and mechanisms of meniscus aging and osteoarthritis at early and late stages.

Methods: This study used a unique collection of human knees from organ donors across the age spectrum, including 11 young normal donors (36 ± 12.0 years; 3 female; 8 male), 5 aged normal (71 ± 7.6 years; 3 female; 2 male), 7 aged donors with mild OA (64 ± 12.6 years; 2 female; 5 male) and 12 patients with severe OA (70 ± 11.8 years; 9 female; 3 male undergoing total knee arthroplasty (TKA). Knees from organ donors were graded for OA on all cartilage surfaces and classified based on these cartilage OA scores. The menisci were scored macroscopically and for histopathological changes. Bulk RNA-sequencing was performed to profile transcriptomic changes and differentially expressed genes (DEGs) were interrogated for mechanisms of aging, tissue damage and pain.

Results: The aged OA group had higher histopathology scores, and compared to the young normal group there were 84 downregulated genes (DRGs) and 413 upregulated genes (URGs) (adj p < 0.05 and baseMean > 1). Metascape analysis revealed the biological processes (BPs) regulated by the DRGs were macroautophagy, Endoplasmic-reticulum-associated protein degradation (ERAD), protein folding and NABA core matrisome (IGFBP6, LAMA2, MFGE8, OMD). The URGs were also enriched for biological processes related to extracellular matrix (ECM), including several collagens, but also for processes related to neuronal and sensory system remodeling.

The comparison of the TKA with the young normal group revealed 577 DRGs and 2680 URGs (adj p < 0.05 and log₂FC > |1|). THE DRGs were enriched for several metabolic pathways and protective biological processes related to response to amino acid deficiency and antimicrobial defense. The URGs were strongly enriched for matrisome and ECM and also for neuronal system, synaptic transmission and sensory organ development. There were several URGs related to pain, including NGF, and ANK3 which has been linked to pain phenotype. Further, several genes encoding for voltage-gated sodium channels (SCN2B, SCN5A, SCN8A and SCN10A) and transient receptor potential cation channels (TRPV4 and TRPV6) were upregulated in TKA meniscus.

Conclusion: These results indicate that early or mild stages of OA are primarily characterized by disruption of cellular homeostasis and defense mechanisms and a relatively low level of ECM process activation. These same processes are more enriched in the late-stage OA group which also has a marked enhancement of processes related to neuronal remodeling and pain.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-meniscus-histopathological-and-transcriptomic-changes-at-early-and-advanced-stages-of-knee-osteoarthritis/