TY - JOUR
T1 - Bovine lactoferricin induces TIMP-3 via the ERK1/2-Sp1 axis in human articular chondrocytes
AU - Yan, Dongyao
AU - Chen, Di
AU - Hawse, John R.
AU - van Wijnen, Andre J.
AU - Im, Hee Jeong
N1 - Funding Information:
This work was supported by NIH NIAMS R01 grants (to HJI) from AR053220 and AR062136 , and R01 grant from the National Institute of Dental and Craniofacial Research : DE014036 (to JRH). We thank the Gift of Hope Organ Tissue Donor Network and Dr. Margulis for making human tissues available, and we also extend our appreciation to the tissue donor families who made it possible. We thank Dr. Gabriella Cs-Szabo and David Gerard for their time and efforts in OA tissue acquisition.
PY - 2013/3/15
Y1 - 2013/3/15
N2 - Bovine lactoferricin (LfcinB) is a heparan sulfate-binding peptide with multiple bioactivities. In human articular cartilage, LfcinB antagonizes interleukin-1 β (IL-1β) and fibroblast growth factor 2 (FGF-2) in proteoglycan metabolism, catabolic protease expression, and induction of pro-inflammatory mediators. LfcinB specifically activates ERK1/2, p38 and Akt, but whether these signaling pathways control the expression of LfcinB target genes remained unknown. In this report, we characterized a novel aspect of LfcinB-mediated genetic response in human articular chondrocytes, tissue inhibitor of metalloproteinase 3 (TIMP-3) induction. Inhibition of individual signaling pathways revealed that ERK1/2 functions as the major pathway in TIMP-3 expression, whereas Akt plays a minor role. Further investigation identified Sp1 as a critical transcriptional activator in TIMP-3 regulation, and Sp1 activity is modulated by ERK1/2, not Akt. Comparative quantification indicates that significant downregulation of TIMP-3 occurs in OA chondrocytes, suggesting a beneficial role of LfcinB in OA pathogenesis. Our results collectively provide new insights into the mechanism of action of LfcinB, and support the candidacy of LfcinB as a chondroprotective agent.
AB - Bovine lactoferricin (LfcinB) is a heparan sulfate-binding peptide with multiple bioactivities. In human articular cartilage, LfcinB antagonizes interleukin-1 β (IL-1β) and fibroblast growth factor 2 (FGF-2) in proteoglycan metabolism, catabolic protease expression, and induction of pro-inflammatory mediators. LfcinB specifically activates ERK1/2, p38 and Akt, but whether these signaling pathways control the expression of LfcinB target genes remained unknown. In this report, we characterized a novel aspect of LfcinB-mediated genetic response in human articular chondrocytes, tissue inhibitor of metalloproteinase 3 (TIMP-3) induction. Inhibition of individual signaling pathways revealed that ERK1/2 functions as the major pathway in TIMP-3 expression, whereas Akt plays a minor role. Further investigation identified Sp1 as a critical transcriptional activator in TIMP-3 regulation, and Sp1 activity is modulated by ERK1/2, not Akt. Comparative quantification indicates that significant downregulation of TIMP-3 occurs in OA chondrocytes, suggesting a beneficial role of LfcinB in OA pathogenesis. Our results collectively provide new insights into the mechanism of action of LfcinB, and support the candidacy of LfcinB as a chondroprotective agent.
KW - Articular cartilage
KW - Bovine lactoferricin
KW - Chondrocyte
KW - Osteoarthritis
KW - Tissue inhibitor of metalloproteinase
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U2 - 10.1016/j.gene.2013.01.001
DO - 10.1016/j.gene.2013.01.001
M3 - Article
C2 - 23313877
AN - SCOPUS:84873524215
SN - 0378-1119
VL - 517
SP - 12
EP - 18
JO - Gene
JF - Gene
IS - 1
ER -