Understanding Osteoarthritis as a Biological and Biomechanical Disease
Hui Mingalone, Carrie.
Osteoarthritis (OA), a degenerative joint condition characterized by progressive loss of
articular cartilage and other joint tissue changes, is the most common cause of
disability in the United States. OA is a disease with multifactorial etiology resulting
in heterogeneous disease onset and progression, but the same ending of joint
degeneration. Current treatment options are focused... read moreon managing OA symptoms,
specifically pain, but do not treat the underlying cause of disease. A major hurdle for
better therapies is the lack of understanding of OA disease initiation and progression,
especially at early stages of prior to clinical symptoms. This thesis present two
independent projects seeking to understand the roles of biochemical and biomechanical
factors in OA development. In the field of OA research, biochemical changes are
understood to occur in early OA. There is an increase in cartilage metabolism and a
decrease in catabolism, which contributes to cartilage loss and other joint tissue
changes. Inflammation is thought to be a major driver of these biochemical changes
underlying structural changes. One aspect of this thesis focuses on understanding
inflammatory dynamics driven by master transcriptional regulator NFκB and how it
may be related to cartilage structural changes. Results from this study showed that
NFκB driven inflammation, visualized via bioluminescence imaging, peaks early in a
post-traumatic OA (PTOA) mouse model and that structural modifications, visualized as
collagen fiber thickness and orientation changes through second harmonic generation
imaging, also occur in early OA across different cartilage layers. The second project of
this thesis is focused on understanding the interplay between biochemical (specifically
glucose) and biomechanical factors in OA progression utilizing a novel ex vivo joint
culturing system, the Joint-in-Motion 1 (JM1) device. In this study, whole mouse knee
joints were cultured in media solutions with variable glucose and osmolarity with
dynamic input. While joint spatial orientation, cell numbers, and extracellular matrix
collagen II was preserved, proteoglycan was lost only in joints cultured in high glucose
with dynamic movement. This study revealed the synergistic effects of biomechanical and
biomechanical factors in OA development and highlights a possible role for glucose in
priming the joint for damage via biomechanical
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Li Zeng.
Committee: Heber Nielsen, Gary Sahagian, and Linden Hu.
Keyword: Biology.read less