University of California, San Diego San Diego, CA, United States
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Nathan Argel1, Sina Stücker2, Adnan Cutuk3, Robert Meyer3, Nancy Lane4, Jessica Bertrand2, Monica Guma3 and Jessica Murillo-Saich1, 1Department of Medicine, University of California San Diego, La Jolla, CA, 2Department of Orthopaedic Surgery, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany, 3San Diego VA Healthcare Service, La Jolla, CA, 4University of California, Hillsborough, CA
Background/Purpose: Emerging research suggests that synovial inflammation and metabolic alterations are involved in the progression of osteoarthritis (OA). Additionally, the presence of calcium-containing crystals (CC), such as basic calcium phosphate (BCP) and calcium pyrophosphates (CPP) crystals, has been implicated in the development of OA, potentially contributing to inflammatory responses and pain. However, our understanding of the impact of CC on synovial tissue (ST) in OA remains limited. Therefore, the aim of this study is to investigate the relationship between synovial CC, histological composition, pain as well as the synovial metabolic profile in OA.
Methods: A total of 28 ST samples were collected from patients diagnosed with OA during total joint replacement surgeries. The ST samples were either fixed in formalin for subsequent histological analysis, or snap-frozen for metabolomic analysis. The histological assessment of ST samples was performed using the Krenn histopathological synovitis score, which categorized the samples into two groups: inflammation grade 0-I and inflammation grade II-III. Synovial CD68 positive cells and synovial area containing CC (%Ca++) were assessed by immunohistochemistry and Von Kossa staining respectively, and semi-quantified using Image J. The severity of OA disease was evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Nuclear Magnetic Resonance (NMR) spectra of the ST samples were acquired using a 600 MHz Bruker Avance III spectrometer with 1H-NMR. The Chenomx NMR Suite 8.5 professional software was employed for metabolite identification and quantification(μM). For statistical analysis, MetaboAnalyst 5.0, SPSS v26, and R Studio software were utilized.
Results: 13 samples with inflammation grade 0-I and 15 samples with inflammation grade II-III samples were included. There were no significant differences observed in the synovial area containing CC (%Ca++) between the two inflammation groups (p=0.48). Furthermore, no correlation was found between %Ca++ and CD68 expression (p=0.84). However, WOMAC scores showed a positive correlation with %Ca++ (Figure 1A-B). Regarding metabolites associated with %Ca++, we observed a positive association between pyruvate and %Ca++ (r=0.43, p=0.02) and a tendency for a positive correlation between succinate and %Ca++ (r=0.30, p=0.13). However, metabolites such as choline and glucose did not show any correlation with %Ca++ in ST (Figure 2A). Interestingly, we also found positive correlations between %Ca++ and citrate (r=0.62, p< 0.01), creatinine (r=0.67, p< 0.01), dimethylamine (r=0.77, p< 0.01), and sn-glycero-3-phosphocholine (r=0.43, p=0.02) (Figure 2B).
Conclusion: Our findings provide evidence supporting the association between synovial CC and the pain phenotype in OA. Although no direct correlation between inflammation and %Ca++ was observed, our results suggest that these crystals may contribute to metabolic alterations in the ST. Further investigations are warranted to elucidate whether the presence of CC in OA triggers pain and to identify the underlying metabolic pathways.
Figure 1. A) Scatter plot showing Pearson correlation between %Ca++ in synovial tissue and total WOMAC. B) Pearson correlation between the %Ca++ in synovial tissue and age, painDETECT and WOMAC scores.
Figure 2. Scatter plot showing Pearson correlation between %Ca++ in synovial tissue and A) metabolites associated to inflammation and B) other metabolites statistically significant.
N. Argel: None; S. Stücker: None; A. Cutuk: None; R. Meyer: None; N. Lane: None; J. Bertrand: None; M. Guma: Genentech, 5, Gilead, 5, Novartis, 5, Pfizer, 5; J. Murillo-Saich: None.
