Regulators of Inflammation in Arthritic Disease Pathogenesis.
is a major cause of cartilage destruction and leads to the imbalance of catabolic and
anabolic activities in the arthritic joint. Our aim was to investigate both positive and
negative regulators of inflammation involved in arthritic joint disease. As a positive
regulator, pigment epithelium derived factor (PEDF) has been reported to have both pro-
and anti-inflammatory ... read moreactivities in various cell types and shown to be upregulated in
the arthritic joint, but its role in joint destruction is unclear. We investigated its
role in cartilage degeneration under inflammatory conditions using ectopic PEDF
expression in primary human articular knee chondrocytes, explant bone cultures from
PEDF-deficient and wild type mice and the monosodium iodoacetate (MIA) inflammatory
joint destruction animal model in PEDF-deficient and wild type mice. We showed that PEDF
protein expression was higher in human osteoarthritis samples compared to normal
samples. We demonstrated that ectopic PEDF expression in primary human articular knee
chondrocytes exacerbated catabolic gene expression in the presence of interleukin 1 beta
(IL-1β). In whole bone organ cultures, IL-1β induced the expression of
matrix metalloproteinase 13 (MMP-13) and caused significant cartilage matrix loss.
Interestingly, PEDF-deficient bones from 29 week old animals, but not 10 week old
animals, showed reduced MMP-13 protein expression and matrix loss compared to their wild
type counterparts. In addition, PEDF-deficiency in 29 week old animals preserved matrix
integrity and protected against cell loss in the MIA joint destruction model in vivo. We
conclude that PEDF exacerbates cartilage degeneration in an age-dependent manner under
an inflammatory setting. As a negative regulator, azithromycin (AZM) has exhibited
anti-inflammatory activity in various systems and a sister compound, erythromycin,
demonstrated chondroprotective effects in an animal model of joint destruction. However,
the role of azithromycin in joint destruction has not been investigated. We investigated
its role in cartilage degeneration using the MIA inflammatory joint destruction animal
model and primary human articular knee chondrocyte cultures in the presence of
IL-1β. We found that azithromycin preserved cartilage matrix in vivo and inhibited
IL-1β-mediated catabolic gene expression in vitro. We conclude that AZM has
therapeutic potential to treat inflammatory joint disease. Altogether, these findings
broaden our understanding of both positive and negative regulators of inflammation in
arthritic disease pathogenesis.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Li Zeng.
Committee: Heber Nielsen, John Castellot, and John Leong.
Keyword: Cellular biology.read less