Type V Collagen Orchestrates Initial Matrix Templating in Developing Articular Cartilage & Meniscus

Monday, April 22, 2024

1:00 PM-3:00 PM

BIOMED PhD Thesis Defense

Title:
Type V Collagen Orchestrates the Initial Matrix Templating in Developing Articular Cartilage and Meniscus

Speaker:
Bryan Kwok, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
 
Advisor:
Lin Han, PhD
Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
The articular cartilage and meniscus in the knee joint are critical for painless movement, but these tissues’ have low regeneration capacities, rendering them vulnerable to injury and osteoarthritis (OA), the most prevalent musculoskeletal disease that afflicts more than 27 million people in the US. Successful regeneration in articular cartilage and meniscus is challenged by the limited understanding of how these two tissues and their extracellular matrices (ECMs) initially form. This thesis queries the early molecular events that govern the assembly of the initial primitive matrix in the embryonic cartilage and meniscus. Using wild-type embryonic murine knee joint as the model system, we found that the primitive matrix of cartilage and meniscus initiates with a pericellular matrix (PCM)-like template that matures into the specialized PCM and bulk ECM regions. In this early phase, articular cartilage and meniscus developed molecular characteristics signifying distinct matrix templating during initial formation. Also, from embryonic to neonatal development, the micromodulus of cartilage and meniscus matrices stiffen exponentially, with a daily modulus increase rate of ≈ 36% and ≈ 20%, respectively. These results together highlighted the rapid and distinct development traits of the primitive matrices for these two tissues, providing the foundation for determining the molecular mechanisms governing the early matrix templating, and for developing novel tissue engineering strategies to recapitulate the native ECM formation.

Building on these findings, we examined the role of type V collagen, a minor fibril-forming collagen, in regulating the initial matrix templating of both tissues. Although collagen V is usually considered as a co-initiator of collagen I fibrillogenesis, we found pronounced expression in both collagen I-based meniscus and collagen II-rich articular cartilage at embryonic stage. In the joint-specific Col5a1 knockout model (Col5a1f/f/Gdf5Cre, or Col5a1cKO), we found substantial matrix defects in newborn tissues, including reduced meniscus size, flattened cartilage, thickened collagen fibrils and reduced tissue modulus.

Despite these changes, single-cell RNA-sequencing did not yield clear phenotype in cell phenotype or signaling, supporting a direct role of collagen V in initial matrix templating. Such impaired matrix templating results in disrupted postnatal growth. In 1-month-old Col5a1cKO joints, we found decreased meniscus size, an absent meniscus inner zone with much reduced Col2a1 expression, and reduced proteoglycan content in cartilage. These changes further progressed to marked signs of OA-like cartilage and meniscus degeneration by 3 months of age, as well as aberrant formation of osteophytes and subchondral bone remodeling, which are signs of advanced OA, by 8 months of age. Together, these results show that collagen V is an essential constituent of the initial matrix templating of both articular cartilage and meniscus. Targeting molecular activities of collagen V could hold the potential of improving the regeneration of these two structurally distinct tissues to treat OA and joint injury.

Contact Information

Natalia Broz
njb33@drexel.edu