Decorin Regulates the Structure and Biomechanical Functions of Articular Cartilage ECM
Thursday, October 1, 2020
2:00 PM-4:00 PM
BIOMED PhD Thesis Defense
Title:
Decorin Regulates the Structure and Biomechanical Functions of Articular Cartilage Extracellular Matrix (ECM) in Health and Disease
Speaker:
Biao Han, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Advisor:
Lin Han, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University
Details:
Osteoarthritis (OA) is the most prevalent musculoskeletal disease that afflicts millions of people worldwide. It is characterized by the irreversible breakdown of the extracellular matrix (ECM) of articular cartilage, a composition of type II collagen fibrils and aggrecan supramolecular network. Currently, the development of effective cartilage regeneration or OA intervention strategies is challenged by the limited understanding of molecular activities that govern the assembly and degradation of the ECM.
The objective of this study is to elucidate the role of decorin, a small leucine rich proteoglycan, in regulating the structure and biomechanical function of normal and osteoarthritic cartilage ECM. In the cartilage of decorin-null murine model, the ECM exhibits substantial reduction in aggrecan, the major proteoglycan that endows cartilage with its load bearing and energy dissipation functions. As a result, decorin-null cartilage develops impaired biomechanical properties, including reduced modulus, increased hydraulic permeability and loss of fluid pressurization induced self-stiffening capabilities. In vitro, loss of decorin does not affect chondrocyte anabolic response to the stimuli of transforming growth factor-β (TGF-β), but decreases the retention of newly synthesized aggrecan within the neo-matrix. Meanwhile, decorin increases the molecular adhesion between aggrecan-aggrecan and aggrecan-collagen II fibrils at the nanoscale. These results demonstrate that decorin plays a crucial structural role in regulating the integrity of aggrecan networks, rather than influencing chondrocyte biosynthesis.
In the destabilization of the medial meniscus (DMM) model of post-traumatic OA, tamoxifen-induced knockout of decorin in mice significantly accelerates the progression of OA, as marked by higher OA Mankin scores, accelerated proteoglycan loss, and increased surface fibrillation. In comparison, such an effect was absent in mice subjected to the knockout of biglycan, another small proteoglycan bearing high structural similarity to decorin. Taken together, these results highlight a crucial role of decorin in mediating the assembly and integrity of cartilage ECM in both healthy and degenerative cartilage. These findings provide a new foundation for developing cartilage regeneration and OA intervention strategies through the modulation of decorin activities.
Contact Information
Natalia Broz
njb33@drexel.edu