Summary

Age at surgery was associated with higher concentrations of pro-inflammatory biomarkers and lower concentrations of anti-inflammatory biomarkers in the synovial fluid prior to meniscus surgery, suggesting an age-related intensification of the pro-inflammatory response and inhibition of the anti-inflammatory response that may contribute to long-term functional decline observed in older patients.

Abstract

Purpose

Meniscal injuries trigger an acute inflammatory response mediated by intra-articular cytokines, which can accelerate cartilage degradation and subchondral bone changes, contributing to post-traumatic osteoarthritis (PTOA). The role of age in this inflammatory response is unclear. The current study investigates age-dependent variation in cytokine types and concentrations in knee synovial fluid following meniscal injury.

Methods

Patients undergoing arthroscopic knee surgery for isolated meniscal injury were prospectively enrolled between July 2011 and April 2024. Synovial fluid was aspirated from the operative knee and concentrations of 10 biomarkers of interest (RANTES, IL-6, MCP-1, MIP-B, VEGF, TIMP-1, TIMP-2,IL-1RA, MMP-3, and bFGF) were measured. Those at least 9 years following surgery were invited to complete VAS Pain, Lysholm, Tegner, and KOOS-PS patient-reported outcome (PRO) surveys. Multivariable linear regression assessed pairwise relationships between age at surgery, log-normalized biomarker concentrations, and PROs, while adjusting for covariates of sex, body mass index (BMI), symptom duration, and baseline Outerbridge grade. Conditional process analysis was used to further explore age-biomarker relationships with symptom duration as a moderator and baseline Outerbridge grade as a mediator.

Results

The study included 160 patients (86 males and 74 females) for biomarker analysis with a mean age of 50.2 years ± 12.5. Mean follow up was 10.2 ± 1.3 years. Regression revealed positive associations between age and log-normalized concentration of pre-operative IL-6. Moderator analysis found age to be positively associated with IL-6, VEG-F, and IL-1Ra in chronic meniscal injuries. Mediator analysis via baseline Outerbridge grade found an indirect positive relationship between age and MIP-B, VEGF, and MMP-3, and an indirect negative relationship between age and TIMP-1 and TIMP-2. Pre-operative TIMP-1 was positively associated with 10-year KOOS-PS and elevated in treatment responders.

Conclusion

Age at surgery was associated with higher concentrations of several pro-inflammatory biomarkers (IL-6, VEGF, MIP-B, and MMP-3) and lower concentrations of two key anti-inflammatory biomarkers (TIMP-1 and TIMP-2) in the synovial fluid prior to meniscus surgery. Anti-inflammatory markers were associated with improved long-term PROs. These findings suggest an age-related intensification of the pro-inflammatory response and inhibition of the anti-inflammatory response that may contribute to long-term functional decline observed in older patients after meniscus surgery. There is potential for age-specific immunomodulatory therapeutic strategies to manage inflammation and mitigate the progression toward post-traumatic osteoarthritis in older patients.