Molecular Determinants of Neutrophil Extracellular Vesicles That Drive Cartilage Regeneration in Inflammatory Arthritis.

Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs.

Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer-induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group).

Neutrophil elastase and its inhibitors-overlooked players in osteoarthritis.

Cartilage homeostasis is maintained by a delicate balance between anabolism and catabolism. In osteoarthritis, pathological biomechanics or injury triggers cartilage breakdown, nonresolving synovial inflammation, and bone changes, causing reduced joint mobility and incapacitating pain. Undoubtedly, the most important cartilage degrading collagenase during osteoarthritis, matrix metalloproteinase (MMP)-13, is activated by an unlikely player: neutrophil elastase.

Novel anti-inflammatory and chondroprotective effects of the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride and human melanocortin MC3 receptor agonist PG-990 on lipopolysaccharide activated chondrocytes.

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 (α-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp]-γ-MSH, PG-990) receptors and C-terminal peptide α-MSH(KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins.

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates.

We hypothesized that exudates collected at the beginning of the resolution phase of inflammation might be enriched for tissue protective molecules; thus an integrated cellular and molecular approach was applied to identify novel chondroprotective bioactions. Exudates were collected 6 h (inflammatory) and 24 h (resolving) following carrageenan-induced pleurisy in rats. The resolving exudate was subjected to gel filtration chromatography followed by proteomics, identifying 61 proteins.

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury.

Introduction: Mechanical injury can greatly influence articular cartilage, propagating inflammation, cell injury and death - risk factors for the development of osteoarthritis. Melanocortin peptides and their receptors mediate anti-inflammatory and pro-resolving mechanisms in chondrocytes. This study aimed to investigate the potential chondroprotective properties of α-MSH and [DTRP(8)]-γ-MSH in mechanically injured cartilage explants, their ability to inhibit pro-inflammatory and stimulate anti-inflammatory cytokines in in situ and in freshly isolated articular chondrocytes.

Analyses on the mechanisms that underlie the chondroprotective properties of calcitonin.

Introduction: Calcitonin (CT) has recently been shown to display chondroprotective effects. Here, we investigate the putative mechanisms by which CT delivers these actions.

Methods: Immortalized C-28/I2 cells or primary adult human articular chondrocytes (AHAC) were cultured in high-density micromasses to investigate: (i) CT anabolic effects using qPCR and immuhistochemistry analysis; (ii) CT anti-apoptotic effects using quantitation of Bax/Bcl gene products ratio, TUNEL assay and caspase-3 expression; (iii) CT effects on CREB, COL2A1 and NFAT transcription factors.

Resolution of inflammation: examples of peptidergic players and pathways.

Appreciation for the resolution of inflammation has increased in recent years, with the detailing of specific mediators and pathways and the identification of (receptor) targets that could be exploited for innovative anti-inflammatory drug discovery programmes. Thus, acute inflammation resolves by the intervention of endogenous anti-inflammatory mediators that reduce white blood cell recruitment and promote removal of migrated leukocytes by apoptosis and phagocytosis by resident 'cleaners', such as the macrophages, resulting ultimately in the repair of the inflamed or injured tissue. Here, we explore a selection of pro-resolving proteinaceous mediators and targets, such as melanocortins and galectins.

Chondroprotective and anti-inflammatory role of melanocortin peptides in TNF-α activated human C-20/A4 chondrocytes.

Background And Purpose: Melanocortin MC(1) and MC(3 ) receptors, mediate the anti-inflammatory effects of melanocortin peptides. Targeting these receptors could therefore lead to development of novel anti-inflammatory therapeutic agents. We investigated the expression of MC(1) and MC(3) receptors on chondrocytes and the role of α-melanocyte-stimulating hormone (α-MSH) and the selective MC(3) receptor agonist, [DTRP(8) ]-γ-MSH, in modulating production of inflammatory cytokines, tissue-destructive proteins and induction of apoptotic pathway(s) in the human chondrocytic C-20/A4 cells.