Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttraumatic Inflammatory and Chondrodegenerative State

Abstract

Objective: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury.

Design: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of 1129 proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired t test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini post hoc analysis.

Results: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 (P = 0.08, standardized response mean [SRM] = 1.00), MMP-3 (P = 0.05, SRM = 0.90), ADAM12 (P = 0.03, SRM = 1.31), aggrecan (P = 0.08, SRM = 1.13), and CTX-II (P = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways.

Conclusions: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury.

Trial registration: ClinicalTrials.gov NCT01692756.

Keywords: anterior cruciate ligament; biomarker; osteoarthritis; pathway analysis; proteome.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Second look arthroscopy of a patient not involved in the current study performed 4 weeks after anterior cruciate ligament (ACL) reconstruction. After ACL injury, the patient showed a subacute inflammatory response in the surrounding synovium that can be strictly localized as shown in (A). The synovial inflammation is sharply demarcated along the base of the medial meniscus in a patient 4 weeks after ACL injury. Some patients develop more severe synovitis that is often accompanied by pain and stiffness. In those patients, the chronic inflammatory state may result in a pannus-like synovial response that can cover the condyle like a vascularized membrane (B). The membrane covers normal articular cartilage and can easily be stripped with an arthroscopic hook. The underlying cartilage, while appearing normal, appears softer and less light reflective than normal articular cartilage during arthroscopy (C).