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2015 ; 23
(2
): 308-18
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Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen
type I biosynthesis
#MMPMID25464168
Wu L
; Petrigliano FA
; Ba K
; Lee S
; Bogdanov J
; McAllister DR
; Adams JS
; Rosenthal AK
; Van Handel B
; Crooks GM
; Lin Y
; Evseenko D
Osteoarthritis Cartilage
2015[Feb]; 23
(2
): 308-18
PMID25464168
show ga
OBJECTIVE: Articular cartilage is a highly specialized tissue which forms the
surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or
microfracture surgery heal via the formation of fibrotic tissue characterized by
a high content of collagen I (COL I) and subsequent poor mechanical properties.
The goal of this study is to investigate the molecular mechanisms underlying
fibrosis after joint injury. DESIGN: Rat knee joint models were used to mimic
cartilage defects after acute injury. Immunohistochemistry was performed to
detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow
stromal cells (BMSCs) were used to study the influence of the lipid
lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and
immunohistochemistry were performed to evaluate the production of COL I. Chemical
inhibitors were used to block LPA signaling both in vitro and in vivo. RESULTS:
After full-thickness cartilage injury in rat knee joints, stromal cells migrating
to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX);
intact articular cartilage in rat and humans expressed negligible levels of ATX
despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in
COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and
PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly
reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage
defects in rats in favor of the collagen II-enriched normal state. CONCLUSION:
Taken together, these results identify an attractive target for intervention in
reducing the progression of post-traumatic fibrosis and osteoarthritis.
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