Translational Models in Rheumatology

Figure 2. Nordic Bioscience explant model vivo system model mimics rheumatic diseases

By excising cartilage or synovial membranes from human or bovine knees, an explant model system can be set up to mimic rheumatological diseases (Figure 2). Depending on the specific experimental setup and stimulations, catabolic and anabolic treatment effects on cartilage and synovium can be investigated by measuring the translational Nordic ProteinFingerPrint™ biomarkers.

Figure 3. showcases how compounds with different MoA’s affect joint remodeling differently using the ARG, C2M, and nordicPRO-C2™ (PRO-C2) biomarkers, quantifying aggrecan degradation and type II collagen degradation and formation. Stimulating human cartilage with proinflammatory cytokines (Figure 3A+B) induces increased aggrecan and type II collagen degradation. Increasing concentrations of an ADAMTS5 inhibitor (Figure 3A) or Fostamatinib, a SYK inhibitor, (Figure 3B) significantly reduces cartilage destruction. Additionally, the biomarker NordicPRO-C2 allowed the assessment of cartilage formation in explants stimulated with Sprifermin, a recombinant human FGF18, (Figure 3C).

Figure 3. Nordic Bioscience tissue destruction and formation biomarkers

Figure 4. Extracellular matrix remodeling in-vitro Scar-in-a-Jar model

The prolonged Scar-in-a-Jar is a novel model that employs macro-molecular crowding to promote extracellular matrix formation, maturation, and deposition in vitro (Figure 4). The extracellular matrix plays a crucial role in providing structural support to cells and regulating tissue repair and regeneration by acting as a reservoir for growth factors and cytokines. Understanding the extracellular matrix dynamics is vital for developing therapeutic strategies, even in rheumatoid diseases where patients can present with a fibrotic endotype. Using macromolecular crowding, the model becomes more 3D-like and increases complexity, making it a suitable translational model.

By stimulating fibroblast-like-synoviocytes with pro-fibrogenic cytokines, we can model joint fibrosis in vitro and evaluate the efficacy of treatment using the Nordic ProteinFingerPrint™ biomarkers. Thus, we can determine efficacy by measuring collagen formation in the supernatants, allowing direct translation to clinical settings.

As shown in Figure 5., we can induce fibrogenesis with profibrotic stimuli and subsequently inhibit fibrogenesis by increasing anti-fibrotic or anti-inflammatory treatment concentrations. Measuring the nordicPRO-C3™ (PRO-C3) and nordicPRO-C6™ (PRO-C6) biomarkers, reflecting type III and VI collagen formation, allowed for the quantification of the anti-fibrotic effects of an ALK5 inhibitor (Figure 5A), nintedanib (Figure 5B), and tofacitinib (Figure 5C).

Figure 5. Fibrogenesis profibrotic stimuli on antifibrotic and anti-inflammatory treatment

Various in vivo models mimicking RA or OA, such as the collagen-induced-arthritis model, represent important translational tools to study arthritis in vivo. By collecting blood from these animals, joint remodeling can be evaluated using the Nordic ProteinFingerPrint™ biomarkers to assess drug efficacy and pharmacodynamic effects in preparation for clinical trials.

The graph (Figure 6.) showcases increased synovial tissue destruction quantified with the C1M and C3M biomarkers in a rodent collagen-induced arthritis model.

Figure 6. Nordic Bioscience in-vivo arthritic models with the biomarkers C1M and C3M