A Human Osteochondral Tissue Model Mimicking Cytokine-Induced Key Features of Arthritis In Vitro

Abstract

Adequate tissue engineered models are required to further understand the (patho)physiological mechanism involved in the destructive processes of cartilage and subchondral bone during rheumatoid arthritis (RA). Therefore, we developed a human in vitro 3D osteochondral tissue model (OTM), mimicking cytokine-induced cellular and matrix-related changes leading to cartilage degradation and bone destruction in order to ultimately provide a preclinical drug screening tool. To this end, the OTM was engineered by co-cultivation of mesenchymal stromal cell (MSC)-derived bone and cartilage components in a 3D environment. It was comprehensively characterized on cell, protein, and mRNA level. Stimulating the OTM with pro-inflammatory cytokines, relevant in RA (tumor necrosis factor α, interleukin-6, macrophage migration inhibitory factor), caused cell- and matrix-related changes, resulting in a significantly induced gene expression of lactate dehydrogenase A, interleukin-8 and tumor necrosis factor α in both, cartilage and bone, while the matrix metalloproteases 1 and 3 were only induced in cartilage. Finally, application of target-specific drugs prevented the induction of inflammation and matrix-degradation. Thus, we here provide evidence that our human in vitro 3D OTM mimics cytokine-induced cell- and matrix-related changes—key features of RA—and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup.

Advances in Engineered Three-Dimensional (3D) Body Articulation Unit Models

“…To this end, the in vitro 3D models have presented great potential as a preclinical testing platform for drug development and addressing the limitations of 2D monolayer testing tools. 136–139 These 3D models of dense cell masses with reproducible sizes, morphology, and necrotic core formation, are typically prepared through different tissue engineering strategies to simulate natural tumors and show higher invasiveness and drug resistance than ordinary 2D culture. Although the 3D models for drug screening offer apparent advantages over the traditional 2D models and animal models, they still suffer from certain limitations in terms of morphological and functional attributes.…”

“… 141 In a case, a 3D model was prepared to understand the pathological and physiological mechanisms involved in the destruction of cartilage and subchondral bone during rheumatoid RA, simulating cytokine-induced cell and matrix-related changes and leading to cartilage degradation, as well as bone destruction to ultimately provide preclinical drug screening tools. 136 In vitro toxicological analysis can significantly benefit from the bioprinting approach as the small molecules (drugs) can be assessed with higher efficiency in a drastically shorter time. In several instances, researchers applied the bioprinting approach to producing cartilage structures that could be used for in vitro drug screening using an expandable “tissue chain” bioprinting model.…”

“…To this end, the in vitro 3D models have presented great potential as a preclinical testing platform for drug development and addressing the limitations of 2D monolayer testing tools. [136][137][138][139] These 3D models of dense…”

Optimization of a Tricalcium Phosphate-Based Bone Model Using Cell-Sheet Technology to Simulate Bone Disorders

“…Cells were used until passage 6. MSC characterization was performed as described previously in detail [37,59].…”

“…In a previous study, we used a scaffold-based model and seeded MSCs on the biodegradable β-TCP scaffold to mimic cancellous bone [37]. We could demonstrate that these MSCs showed osteogenic properties in vitro, evidenced by the high expression of collagen type 1 (COL1A1), osteocalcin (OC), osteonectin (ON), and bone formation via µCT analysis.…”