Abstract: Regeneration of articular cartilage remains a key challenge in musculoskeletal healthcare. One major obstacle is the incomplete understanding of molecular activities that govern the assembly, maintenance and degeneration of cartilage extracellular matrix (ECM). We discovered that decorin, a small leucine-rich proteoglycan (SLRP), plays a critical role in regulating cartilage ECM biomechanics and mechanobiology. In cartilage ECM, decorin provides “physical linkages” to increase the molecular adhesion of aggrecan and collagen fibril networks. As a result, the decorin-strengthened collagen fibril network and decorin-mediated aggrecan adhesion can increase the retention of aggrecan by limiting its diffusive loss from the ECM. In decorin-null mice, knee cartilage develops substantial reduction of aggrecan content, contributing to impaired cartilage biomechanics, including reduced elastic modulus and elevated hydraulic permeability. In turn, this decorin loss-induced aggrecan reduction leads to impaired cartilage pericellular matrix at the microscale, resulting in demoted chondrocyte intracellular Ca2+ signaling in situ. When decorin expression is ablated upon the destabilization of the medial meniscus (DMM) surgery in inducible knockout mice, joints develop more severe osteoarthritis (OA), marked by the reduced modulus, accelerated aggrecan depletion and pronounced surface fibrillation. In addition, in aged mice, targeted cartilage-specific deletion of decorin leads to progressive cartilage erosion, impaired chondrocyte Ca2+ signaling and aggravated surface fibrillation. Furthermore, single cell-RNA sequencing revealed infiltration of cells from adjacent joint tissues, and these cells are highly metabolically active, resulting in the formation of a dense collagen I-rich fibrous layer on femoral cartilage surface. Thus, deletion of decorin aggravates the loss of hyaline matrix traits and irreversible damage of cartilage during aging. Together, our results underscore the indispensable role of decorin-mediated physical linkages in the overall structural integrity and mechanobiology of cartilage ECM in post-natal growth, maintenance, and disease progression. This function of decorin is distinct from its canonical roles in regulating the assembly of collagen fibrils or mediating TGF-β signaling. Modulation of decorin activities could provide a novel path to improve the quality of engineered cartilage and attenuate the degeneration of cartilage in disease and aging.
Bio: Dr. Lin Han is a professor in the School of Biomedical Engineering, Science and Health Systems at Drexel University. He obtained Ph.D. degree at MIT in 2007. His Ph.D. thesis focused on the molecular, cellular and tissue nanomechanics of cartilage. He later worked as a post-doctoral associate at MIT, where he continued the exploration of nanostructure and nanomechanics of soft and hard biological tissues. His current research focuses on understanding the structural and mechanobiological roles of extracellular matrix collagens and proteoglycans, as well as their applications in tissue regeneration and disease treatment. Specifically, his lab studies the roles of small proteoglycan, decorin, and regulatory fibril-forming collagens, types V and XI, in the formation, degeneration and regeneration of cartilage, meniscus and temporomandibular joint.
Host: Jill Middendorf