title: Wide bandwidth nanomechanical assessment of murine cartilage reveals protection of aggrecan knock-in mice from joint-overuse.
abstract: Aggrecan loss in human and animal cartilage precedes clinical symptoms of osteoarthritis, suggesting that aggrecan loss is an initiating step in cartilage pathology. Characterizing early stages of cartilage degeneration caused by aging and overuse is important in the search for therapeutics. In this study, atomic force microscopy (AFM)-based force-displacement micromechanics, AFM-based wide bandwidth nanomechanics (nanodynamic), and histologic assessments were used to study changes in distal femur cartilage of wildtype mice and mice in which the aggrecan interglobular domain was mutated to make the cartilage aggrecanase-resistant. Half the animals were subjected to voluntary running-wheel exercise of varying durations. Wildtype mice at three selected age groups were compared. While histological assessment was not sensitive enough to capture any statistically significant changes in these relatively young populations of mice, micromechanical assessment captured changes in the quasi-equilibrium structural-elastic behavior of the cartilage matrix. Additionally, nanodynamic assessment captured changes in the fluid-solid poroelastic behavior and the high frequency stiffness of the tissue, which proved to be the most sensitive assessment of changes in cartilage associated with aging and joint-overuse. In wildtype mice, aging caused softening of the cartilage tissue at the microscale and at the nanoscale. Softening with increased animal age was found at high loading rates (frequencies), suggesting an increase in hydraulic permeability, with implications for loss of function pertinent to running and impact-injury. Running caused substantial changes in fluid-solid interactions in aggrecanase-resistant mice, suggestive of tissue degradation. However, higher nanodynamic stiffness magnitude and lower hydraulic permeability was observed in running aggrecanase-resistant mice compared to running wildtype controls at the same age, thereby suggesting protection from joint-overuse.
authors.affiliation: School of Engineering, College of Science and Engineering, San Francisco State University, San Francisco, CA 94132, United States; Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States. Electronic address: Azadi@sfsu.edu.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Azadi
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Cambridge, MA 02139, United States.
authors.forename: Hadi Tavakoli
authors.initials: HT
authors.lastname: Nia
authors.affiliation: University of Melbourne Department of Pediatrics & Murdoch Children׳s Research Institute, Parkville, Australia.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Gauci
authors.affiliation: Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Ortiz
authors.affiliation: University of Melbourne Department of Pediatrics & Murdoch Children׳s Research Institute, Parkville, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fosang
authors.affiliation: Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Grodzinsky
mesh_terms: D053674:Aggrecans / Q000235:genetics* / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002356:Cartilage / Q000378:metabolism*; D002417:Cattle; D010450:Endopeptidases / Q000378:metabolism; D005269:Femur / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D055595:Mechanical Phenomena; D051379:Mice; D018625:Microscopy, Atomic Force; D036103:Nanotechnology; D010003:Osteoarthritis / Q000378:metabolism; D010539:Permeability
chemical_list: D053674:Aggrecans; D010450:Endopeptidases; C083641:aggrecanase