期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 872, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2020.172971
关键词
Anti-inflammatory; Apoptosis; Chemokines; Chondroprotective; Melanocortins; Matrix metalloproteinases
资金
- University of Naples
Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (alpha-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp(8)]-gamma-MSH, PG-990) receptors and C-terminal peptide alpha-MSH11-43 (KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 mu g/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp(8)]-gamma-MSH. Prophylactic and therapeutic regimes of [DTrp(8)]-gamma-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs - 1,-3 and -13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment.
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