The intrinsic quality of proteoglycans, but not collagen fibres, degrades in osteoarthritic cartilage.

The function of articular cartilage as a load-bearing connective tissue is derived primarily from a balanced interaction between the swelling proteoglycan (PG) matrix and tension-resistant collagen fibrous network. Such balance is compromised during joint disease such as osteoarthritis (OA) due to degradation to PGs and/or collagens. While the PG degradation is generally thought to be related to a loss of protein abundance, the collagenous degradation is more complex as it can be caused independently by a decrease of collagen content, disorganisation of fibrous structure and softening of individual collagen fibrils. A comprehensive understanding of the initial trajectories of degradation of PGs and collagen network can improve our chance of finding potential therapeutic solutions for OA. Here, we developed geometrically, structurally, and compositionally realistic and sample-specific Finite Element (FE) models under the framework of multiphasic mixture theory, from which the elastic moduli of collagen fibres and the PG load-bearing quality in healthy and diseased cartilages were estimated by numerical optimisation of the multi-step indentation stress relaxation force-time curves. We found the intrinsic quality of collagen fibres, measured by their elastic moduli, to stay constant for healthy and diseased cartilages. Combining with previous findings which show unaltered collagen content during early stages of OA, our results suggest the disorganisation of collagen fibrous network as the first form of collagenous degradation in osteoarthritic cartilage. We also found that PG degradation involves not only a loss of protein abundance, but also the quality of the remaining PGs in generating sufficient osmotic pressure for load bearing. This study sheds light on the mechanism of OA pathogenesis and highlights the restoration of collageneous organisation in cartilage as key medical intervention for OA. STATEMENT OF SIGNIFICANCE: Collagen network in articular cartilage consists of individual fibres that are organised into depth-dependent structure specialised for joint load-bearing and lubrication. During osteoarthritis, the collagen network undergoes mechanical degradation, but it is unclear if a loss of content, disorganisation of fibrous structure, or softening of individual fibres causes this degeneration. Using mechanical indentation, Finite Element modelling, and numerical optimisation methods, we determined that individual fibres did not soften in early disease stage. Together with previous findings showing unaltered collagen content, our results pinpoint the disorganisation of collagen structure as the main culprit for early collagenous degradation in osteoarthritic cartilage. Thus, early restoration in cartilage of collagen organisation, instead of individual fibre quality, may be key to slow osteoarthritis development.