Chow L, Contino E, Seabaugh K, Goodrich L, McIlwraith CW, Impastato R, Singer J, Das S, Dow S, Pezzanite LM.
Abstract
Objective
To determine differential gene expression in synovial tissues following injection of IA 2.5% polyacrylamide hydrogel (2.5% iPAAG), a biocompatible nondegradable synthetic polymer, to treat osteoarthritis (OA).
Methods
Osteoarthritis was induced in 1 middle carpal joint of 16, 2- to 5-year-old horses (7 mares and 9 geldings) via surgical osteochondral fragment creation in combination with exercise on a high-speed treadmill; the contralateral limb underwent a sham operation. Horses were exercised 5 days per week, beginning on day 16 postoperatively. The osteochondral fragment joint was injected with 2 mL 2.5% iPAAG or saline at day 14 (n = 8 horses/group). Synovial biopsies (days 0 and 70) and synovial fluid (SF) were obtained (days 0, 14, 28, 42, 56, and 70). The RNA was extracted from synovium and SF cells and subjected to transcriptomic sequencing to determine differentially expressed genes and enriched pathways. The in vivo portion of the study was performed from July to October 2024.
Results
Transcriptomic analysis of 2.5% iPAAG–treated versus saline-treated synovium (day 70) revealed upregulation of innate immune activation pathways and reduced metabolic, cell cycle, and growth factor signaling pathways. The 2.5% iPAAG treatment had the most pronounced effect on the transcriptome of SF cells longitudinally at day 28 (14 days post-treatment), with downregulation of inflammatory tumor necrosis factor-α pathways and T-cell/lymphocyte signaling pathways.
Conclusions
2.5% iPAAG treated synovium may lead to upregulation of immune and cell cycle regulatory pathways in synovium, with suppression of some inflammatory pathways in SF cells. Limitations include assessment in an acute, experimentally induced model.
Clinical Relevance
Transcriptomic analysis suggests that one downstream mechanism of action of 2.5% iPAAG involves modulation of immune and cellular signalling pathways following integration into the synovial membrane, supporting the potential benefit of earlier intervention in the disease process.
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