Dose-response relationship of in vivo ambulatory load and mechanosensitive cartilage biomarkers: the role of age and tissue health

Osteoarthritis (OA) is a common chronic degenerative joint disease affecting joints such as the hip or the knee. As increased age, obesity and joint injury are major risk factors, worldwide the number of OA affected persons is increasing. Contrary to the misconception that OA is a disease of "wear and tear" of articular cartilage, nowadays OA is understood as a complex multifactorial disease affecting all tissues of the joint. Regardless of the exact OA etiology, in an osteoarthritic joint the chondrocytes – the cells in articular cartilage – were unable to maintain the balance between anabolic and catabolic metabolism. This leads to degenerative changes in articular cartilage, subchondral bone, and synovium. To better understand the mechanisms involved in the OA initiation, cartilage metabolism or cartilage degradation products, so-called articular cartilage biomarkers, were investigated in isolated chondrocytes, in cartilage explants, and in humans. Systemic articular cartilage biomarkers measured in blood have been proposed as surrogate measure of in vivo articular cartilage metabolism. Since chondrocytes can respond metabolically to physical load and normal joint loading contributes to joint health, whereas increased joint loading promotes cartilage degeneration, load-induced changes in cartilage biomarker concentration were studied in healthy, joint injured and osteoarthritic participants to understand the underlying pathologic processes that initiate early or posttraumatic OA.
In healthy participants, the magnitude of load-induced changes in articular cartilage biomarkers is known to be related to ambulatory load magnitude. To date, is unclear if the mechanosensitivity of articular cartilage is altered by the factors age and joint injury. Therefore, the aim of this thesis was to investigate the in vivo dose-response relationship between ambulatory load magnitude and load-induced mechanosensitive articular cartilage biomarker concentration kinetics and to assess the influence of age and anterior cruciate ligament (ACL) injury on this relationship.
We therefore designed and conducted the MechSens study with clinical, biomechanical biological data collection. In brief, younger and older healthy and ACL-injured participants underwent magnetic resonance imaging of both knees and completed a walking stress test on three different days. During this stress test, blood samples were taken before and after walking with either 20% reduced, normal, or 20% increased bodyweight. Using data from a pilot study, we first validated that the load-modification framework used allows us to systematically alter load magnitude without changing joint kinematics or spatiotemporal parameters. We then identified serum cartilage oligomeric matrix protein (sCOMP) and matrix metalloproteinase-3 as articular cartilage biomarkers that respond to the magnitude of ambulatory load with an increase in concentration. With the completion of the MechSens baseline data collection we show that the cartilage composition observed in our ACL-injured participants differs from uninjured knees and confirmed that ACL-injured subjects in the project MechSens have altered cartilage quality. In the last step we show that the load-induced sCOMP concentration change is sensitive to mechanical loading in healthy and ACL-injured participants and that the immediate load-induced change in sCOMP is affected by age but not ACL injury.