The Development of a Progressive In Vitro Cell-Based Model of Osteoarthritis.
Osteoarthritis (OA) of the knee, characterized by knee pain and eventual loss of joint
function remains a significant unmet medical need worldwide. Treatment of both pain and
structural damage progression are challenging, with current pain therapies providing
inconsistent benefit and treatments to halt or slow loss of structural integrity
nonexistent. Although the facets of OA are ... read morenot well understood, it is clear that the
disease represents a complex combination of metabolic processes affecting the cartilage,
underlying bone, synovium, and surrounding tissues of articular joints. This complexity
makes it difficult to develop accurate models. Given the cost, time, and complexity
associated with performing in vivo studies, preliminary study of disease biology as well
as identification, validation, and testing of potential therapeutic targets can benefit
greatly from studies initially performed in vitro in well-designed models ideally
translatable to both in vivo research and clinical settings. A human cell-based model of
osteoarthritis progressing from early to late-stage OA was developed. This work included
the combination of synovial fibroblasts and monocytes as a model of synovium. In culture
with the synovium component, mesenchymal stem cell (MSC) pellets were used as the
cartilage component. At early time points, the model produced many cytokines and
degradative enzymes present in clinical OA. Glycosaminoglycan (GAG) was released from
the cartilage component. Also, the cartilage component mounted a repair response as
measured by an increase in aggrecan gene expression. These three criteria were evidence
of a model of early stage OA. At later time points, the cartilage component continued to
lose GAG. The repair response was lost. Finally, the production of degradative enzymes,
specifically matrix metalloproteinase 1 and 3 (MMP-1 and MMP-3), was diminished. These
criteria were evidence of a progression to late stage OA. Understanding the full
progression of OA could lead to the development of new targets and new therapeutics and
having a realistic in vitro model is one step in that
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Biomedical Engineering.
Advisor: David Kaplan.
Committee: Catherine Kuo, Li Zeng, and Gloria Matthews.
Keyword: Biomedical engineering.read less