Age-Dependent Variation in Cytokine Type and Concentration in Knee Synovial Fluid After Meniscal Injury

Abstract

Background:

Meniscal injuries trigger a local inflammatory response mediated by intra-articular mediators. Proinflammatory cytokines and chemokines can lead to cartilage degradation and subchondral bone changes, contributing to posttraumatic osteoarthritis. The role that age plays in this inflammatory response is unclear.

Purpose:

To investigate age-dependent variation in cytokine types and concentrations in knee synovial fluid after meniscal injury.

Study Design:

Cohort study; Level of evidence, 3.

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 were measured. Patients at least 9 years after surgery were invited to complete patient-reported outcome (PRO) surveys. Multivariable linear regression assessed pairwise relationships between age at surgery, log-normalized biomarker concentrations, and PROs, while adjusting for relevant covariates. Conditional process analysis was used to explore age-biomarker relationships, with symptom duration as a moderator and baseline Outerbridge grade as a mediator.

Results:

The study included 160 patients for biomarker analysis with a mean ± SD age of 50.2 ± 12.5 years. Forty-seven patients who reached a minimum 9 years of follow-up completed PRO surveys. Mean follow-up was 10.2 ± 1.3 years. Regression analysis revealed positive associations between age and log-normalized concentration of preoperative IL-6. Moderator analysis found age to be positively associated with IL-6, VEG-F, and IL-1Ra in chronic meniscal injuries. Mediator analysis 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. Preoperative TIMP-1 was positively associated with 10-year Knee injury and Osteoarthritis Outcome Score–Physical Function Short Form score and elevated in treatment responders.

Conclusion:

Age at surgery was associated with higher concentrations of proinflammatory biomarkers and lower concentrations of anti-inflammatory biomarkers in the synovial fluid before meniscal surgery. Anti-inflammatory markers were associated with improved long-term PROs. These findings suggest an age-related intensification of the proinflammatory response and inhibition of the anti-inflammatory response that may contribute to long-term functional decline in older patients after meniscal surgery. There is potential for age-specific immunomodulatory therapeutic strategies to manage inflammation and mitigate the progression toward posttraumatic osteoarthritis in older patients.