期刊
OSTEOARTHRITIS AND CARTILAGE
卷 26, 期 12, 页码 1733-1743出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2018.08.012
关键词
FGFR1; Peptide; Osteoarthritis; Mice
资金
- Special Funds for Major State Basic Research Program of China (973 program) [2014CB942904]
- National Natural Science Foundation of China [81530071, 81472074]
- State Key Laboratory of Trauma, Burn and Combined Injury, China [201601]
Objective: We previously reported that genetic ablation of (Fibroblast Growth Factors Receptors) FGFR1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice, which suggests that FGFR1 is a potential targeting molecule for osteoarthritis (OA). Here, we identified R1-P1, an inhibitory peptide for FGFR1 and investigated its effect on the pathogenesis of OA in mice induced by destabilization of medial meniscus (DMM). Design: Binding ability between R1-P1 and FGFR1 protein was evaluated by enzyme-linked immuno sorbent assay (ELISA) and molecular docking. Alterations in cartilage were evaluated histologically. The expression levels of molecules associated with articular cartilage homeostasis and FGFR1 signaling were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC). The chondrocyte apoptosis was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay. Results: R1-P1 had highly binding affinities to human FGFR1 protein, and efficiently inhibited extracellular signal-regulated kinase (ERK) 1/2 pathway in mouse primary chondrocytes. In addition, R1-P1 attenuated the IL-1 beta induced significant loss of proteoglycan in full-thickness cartilage tissue from human femur head. Moreover, this peptide can significantly restore the IL-1 beta mediated loss of proteoglycan and type II collagen (Col II) and attenuate the expression of matrix metalloproteinase-13 (MMP13) in mouse primary chondrocytes. Finally, intra-articular injection of R1-P1 remarkably attenuated the loss of proteoglycan and the destruction of articular cartilage and decreased the expressions of extracellular matrix (ECM) degrading enzymes and apoptosis in articular chondrocytes of mice underwent DMM surgery. Conclusions: R1-P1, a novel inhibitory peptide for FGFR1, attenuates the degeneration of articular cartilage in adult mice, which is a potential leading molecule for the treatment of OA. (c) 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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