A multi-switch mechanism underlying mechanical force regulation of aggrecan degradation in osteoarthritic cartilage

To elucidate the molecular mechanism by which mechanical forces regulate aggrecan degradation in osteoarthritic cartilage. Steered molecular dynamics simulations were conducted using an all-atom model of ADAMTS-5 complexed with an aggrecan peptide encompassing the Glu373-Ala374 cleavage site. External forces ranging from 10 to 1000 pN were applied to evaluate the effects of mechanical loading on peptide conformation and enzyme-substrate binding. Non-bonded interaction energies and hydrogen bond distributions were analyzed to identify force-dependent binding states. As external force increased, the aggrecan peptide elongated monotonically, but binding stability between ADAMTS-5 and aggrecan alternated between destabilization and re-stabilization. Stable binding states were identified at 0, 100, 400, and 900 pN, each mediated by distinct sets of hydrogen bonds and salt bridges concentrated near the cleavage site. Between these levels, binding weakened, indicating transitions between states. Mechanical force regulates ADAMTS-5-aggrecan interactions through a multi-switch mechanism involving multiple stable binding conformations. This molecular mechanism explains how different loading regimes alternately suppress or promote extracellular matrix degradation, and yields experimentally testable predictions showing that moderate loading preserves cartilage, whereas overload accelerates its degradation in osteoarthritis.