Investigating Sex Differences in Knee Osteoarthritis: Meniscus Models Under Simulated Microgravity

• Author / Creator

  Ma, Zhiyao

• Knee osteoarthritis (KOA) is a degenerative joint disease that impacts all structures within the knee joint, often leading to chronic pain and disability. The meniscus, a crucial fibrocartilaginous structure within the knee, plays a key role in joint biomechanics. It is well established that damage or degeneration of the meniscus significantly contributes to the progression of KOA. Additionally, recent studies have shown that the meniscus is one of the first structures to be affected in the early stages of KOA. This early involvement underscores the meniscus's importance in KOA research. Despite well-documented differences in KOA prevalence and severity between males and females, the molecular mechanisms behind these sex-specific differences are not well understood. This gap in knowledge hinders the development of targeted therapies that can more effectively address the unique aspects of KOA in each sex. To address this, studies in this thesis use simulated microgravity (SMG) to induce KOA-like changes in meniscus models. SMG effectively mimics mechanical unloading, a condition known to exacerbate osteoarthritic changes by disrupting normal biomechanical stimuli. By employing SMG, this thesis aims to investigate the sex-specific molecular mechanisms that contribute to the development and progression of KOA in various meniscus models, with in-depth tissue level and bioinformatics analysis elucidating the key molecules, pathways, and regulatory networks involved.
  Chapter 1 provides a comprehensive review of the mechanical environment of the knee meniscus, examining how various forms of mechanical stimuli influence meniscus cell phenotype and extracellular matrix production. It also introduces SMG as an emerging method to study the effects of mechanical unloading on engineered meniscus models, setting the stage for experimental investigations in subsequent chapters. Building on this, Chapter 2 focuses on the short-term responses of primary meniscus fibrochondrocytes seeded on 3D type I collagen scaffolds to SMG, presenting a detailed transcriptome study that tracks molecular pathways and signaling networks over time. Significant gene expression changes are identified, with JUN highlighted as a potential marker for sex differences. Extending these findings, Chapter 3 examines the long-term effects of SMG on engineered meniscus models to understand the broader impact of prolonged mechanical unloading and investigates tissue-level differences. Additionally, it explores the effects of cyclic hydrostatic pressure (CHP) to study mechanical loading. Chapter 4 builds on the SMG study from Chapter 3, using the same engineered meniscus models, to provide a deeper focus on the transcriptome profile. This chapter identifies the cell surface marker CD36 as an indicator of higher osteoarthritis development propensity in a subgroup of females. Finally, Chapter 5 investigates the role of CD36 in sex differences related to KOA using human total knee arthroplasty meniscus samples and a CD36 knockout mice model. The findings indicate that CD36 plays a significant role in mediating meniscus calcification and hypertrophic differentiation, with notable sex-specific differences. Chapter 6 summarizes the thesis and suggests future research directions.
  The findings of this thesis provide valuable insights into the sex-specific molecular responses of meniscus models to mechanical unloading induced by SMG, using both human and mouse models. Understanding these differences is crucial for developing targeted therapeutic strategies for KOA, given the varying prevalence and severity of the disease between sexes. This research enhances our knowledge of the molecular mechanisms behind KOA and sex differences. It underscores the effectiveness of SMG as a platform for inducing KOA-like changes and screening potential biomarkers, such as CD36, to identify individuals with a higher propensity for osteoarthritis development. These insights can aid in developing suitable therapeutic targets for managing KOA.

• Subjects / Keywords

  • Osteoarthritis
  • sex-dependent difference
  • simulated microgravity
  • bioinformatics

• Graduation date

  Fall 2024

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-yk7p-yk21

• License

  This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.