Identification of synovial fluid proteins that are associated with early osteoarthritis treatment failure: the search for novel markers leads us back to matrix metalloproteinases (MMPs)

Hulme, C.H.; Wilson, E.; Fuller, H.R.; Roberts, S.; Richardson, J.B.; Gallacher, P.; Peffers, M.J.; Shirran, S.L.; Botting, C.H.; Wright, K.T.

Abstract

Introduction: Autologous chondrocyte implantation (ACI) is a cell therapy used to treat cartilage defects and early osteoarthritis. During initial surgery (Stage I), healthy cartilage is harvested from the joint. Chondrocytes are isolated and culture-expanded before being implanted into the defect site (Stage II). An alternative cell-based therapy uses patients’ bone marrow (BM), which is collected without cartilage harvest at Stage I; subsequently culture-expanded BM-mesenchymal stromal cells (MSCs) are implanted at Stage II. 20% of ACI-treated patients demonstrate no clinical benefit. We aim to better understand why these individuals fail.

Materials and Methods: Two proteomic techniques (isobaric tag for relative and absolute quantitation and label-free quantitative liquid chromatography tandem mass spectrometry) were used to comprehensively profile the proteome of knee synovial fluid (SF) samples. Fourteen ACI responders’ and 13 non-responders’ SFs collected at Stages I and II were analysed. ACI response was determined by change in functional knee score at 12 months. Proteins showing differential levels were validated using Quantikine® immunoassays in this cohort and a further independent group of patients which included those treated with BM-MSCs (ie, no cartilage harvest procedure).

Results: Proteomic analyses highlighted that MMPs 1 and 3 demonstrate increased abundance at Stage II compared to Stage I, only in the ACI failure group (MMP-1 increased 2.7-fold; MMP-3 increased 2.9-fold). These observations were validated by immunoassay (MMP-1, Stage I: 800 ± 889 pg/mL, Stage II: 7741 ± 8065 pg/mL, P = 0.006; MMP-3, Stage I: 34 ± 17 ng/mL, Stage II: 61 ± 17 ng/mL, P = 0.002, Mann-Whitney U test). In the independent cohort, MMP-1 (n = 31) and MMP-3 (n = 47) were increased at Stage II compared to Stage I, only in the patients who underwent a cartilage harvest procedure during Stage I (P < 0.0001; Wilcoxon matched pairs).

Discussion: This study suggests that there may be an acute catabolic response in the knee to the cartilage harvest procedure in ACI only in individuals who do not respond well clinically. Further study is required to determine whether the cartilage harvest procedure itself is damaging in these patients or whether this response to cartilage injury is indicative of a poor innate capacity for cartilage repair.

Citation

Hulme, C., Wilson, E., Fuller, H., Roberts, S., Richardson, J., Gallacher, P., …Wright, K. (2018, July). Identification of synovial fluid proteins that are associated with early osteoarthritis treatment failure: the search for novel markers leads us back to matrix metalloproteinases (MMPs). Poster presented at Matrix Biology Europe – July 2018 Meeting Celebrating 50 years of Federation of European Connective Tissue Societies Meetings, Manchester, United Kingdom

• Presentation Conference Type: Poster
• Conference Name: Matrix Biology Europe – July 2018 Meeting Celebrating 50 years of Federation of European Connective Tissue Societies Meetings
• Conference Location: Manchester, United Kingdom
• Start Date: Jul 21, 2018
• End Date: Jul 24, 2018
• Deposit Date: Jun 23, 2023
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1111/iep.12294