Role of collagen VI and IX in mechanotransduction in the cartilage microenvironments: A multiscale in silico examination.

Background/objectives: Chondrocytes are mechanosensitive cells involved in the biosynthesis and maintenance of articular cartilage. Histologically, these cells are surrounded by a pericellular matrix (PCM) characterized by a relatively high concentration of collagen VI and a low concentration of collagen IX in the junction area with the extracellular matrix (ECM). However, the impact of PCM composition and its interaction with the ECM, such as alteration of collagen content (VI, IX), on chondrocyte mechanics is largely unknown. This study aimed to develop a multiscale model to investigate the role of collagens VI and IX in regulating cellular and tissue-level cartilage mechanics. Methods: A poro-hyperelastic multi-scale finite element cartilage model was developed to connect aggregate tissue-level load to cellular mechanics. The cell-enriched cartilage model included anatomical cell distributions and collagen types II, VI, and IX, representing the building block network of the ECM and PCM, respectively. An unconfined compression test was simulated under normal and perturbed collagen VI and IX nonlinear properties. Cellular- and tissue-level mechanics were simulated simultaneously using an explicit coupling approach. Results: At the aggregate level, cartilage reaction force varied substantially with alteration of collagen VI, while it was largely unaffected by changes in collagen IX properties within the range of variations considered. Furthermore, alterations in collagen VI and IX stiffness were associated with changes in cellular volume, supported load, and the mechanical microenvironment of the cells. Conclusion: These findings indicate that minor collagen networks can modulate the cellular mechanical environment while exerting a limited effect on the macroscopic cartilage response. Delineating this association will likely improve understanding of cellular function under conditions in which collagens VI and IX are compromised, such as focal injuries or enzymatic degradation. Translational potential statement: This study demonstrates that alterations in minor collagen networks (types VI and IX) can modulate chondrocyte mechanotransduction, positioning them as potential mechanobiological markers in understanding the onset and progression of degenerative joint diseases such as osteoarthritis. The realistic multiscale cartilage model offers a physiologically relevant framework that, when integrated with joint-level simulations, could predict cell-level loading during daily physical activities-informing diagnostics, therapeutic strategies, and biomaterial design.