MMP release following cartilage injury leads to collagen loss in intact tissue - a computational study

Abstract

Damage of collagen fibril network in articular cartilage plays a key role in post-traumatic osteoarthritis but the main underlying mechanobiological mechanisms of fibrils degeneration early after injury are not fully understood. This study explores the hypothesis that injurious loading leads to cellular damage that triggers the release of matrix metalloproteinases (MMPs), resulting in loss of collagen content in cartilage. To investigate this, we developed a computational mechano-signaling model simulating spatial collagen loss in bovine cartilage. In the model, the injurious loading causes excessive shear strains in tissue matrix, leading to cell damage and subsequent release of MMPs. The model was compared to ex vivo cartilage explant experiments over 12 days post-injury where collagen content was assessed via Fourier-transform infrared microspectroscpy. By day 12, the simulated collagen loss aligned with our experimental findings along most of tissue depth ([~]30% bulk average loss in the model vs. [~]35% in the experiment). The results suggest that injury-related cell damage and the downstream MMP activity could partly explain the depth-wise collagen content loss in early days after ex vivo cartilage injury. Ultimately, combining the current approach with joint-level computational models could enhance the prediction of the onset and progression of cartilage degeneration. Author SummaryKnee injuries can initiate an irreversible degeneration of articular cartilage which can later lead to the development of post-traumatic osteoarthritis over the years. Currently, there is no cure or effective intervention to repair degenerated cartilage or halt disease progression. Yet, opportunities for intervention depend on a thorough understanding of mechanisms that govern the very early changes in cartilage tissue composition such as the collagen fibrils. In this work, we developed a finite element computational modeling framework to simulate cartilage following injurious loading, focusing on the early loss of collagen content. The model aims to capture the role of injury-induced cellular damage in elevating proteolytic activity within the tissue, which could rapidly degrade collagen fibrils and result in significant collagen loss. This model framework offers a tool for studying the degradation of the collagen fibril network, testing hypotheses involving cell-driven mechano-signalling pathways and evaluating potential treatment interventions aimed at preventing collagen loss.