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Osteoarthritis (OA) is a multifactorial degenerative pathology, whose progression is exacerbated by pro-inflammatory cytokines signaling. Among the changes triggered in chondrocytes during inflammation, modified expression of tiny epigenetic regulators as microRNAs was shown having deleterious implications for articular cartilage. Aim of the present study was to identify differentially expressed microRNAs in human OA cartilage and to determine their relevance to pathological progression. An OA model based on inflammatory stimulation of a chondrocytic human cell line was used to analyze microRNAs deregulation, and results revealed miR-149 severely down-regulated by IL1β and TNFα. Real-time PCR analysis of miR-149 was exerted also in human primary chondrocytes isolated from cartilage of OA donors and postmortem from subjects with no known history of OA, confirming down-regulation in osteoarthritis. Moving on a functional study, miR-149 regulatory effect on tumor necrosis factor alpha ( TNFα), interleukin 1 beta ( IL1β) and interleukin 6 ( IL6) 3′UTRs was evaluated by luciferase assays, and chondrocytes production of TNFα upon miR-149 transfection was measured by enzyme-linked immuno sorbent assay. We found that miR-149 is down-regulated in OA chondrocytes, and this decrease seems to be correlated to increased expression of pro-inflammatory cytokines such as TNFα, IL1β and IL6. OA is a multifactorial disease and we think that our results give new insights for understanding the complex mechanisms of osteoarthritic pathogenesis. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is one of the most common degenerative joint disease for which there is no cure. It is treated mainly with non-steroidal anti-inflammatory drugs to control the symptoms and some supplements, such as glucosamine and chondroitin sulphate in order to obtain structure-modifying effects. Aim of this study is to investigate the effects of l-carnitine, a molecule with a role in cellular energy metabolism, on extracellular matrix synthesis in human primary chondrocytes (HPCs). Dose-dependent effect of l-carnitine on cartilage matrix production, cell proliferation and ATP synthesis was examined by incubating HPCs with various amounts of molecule in monolayer (2D) and in hydromatrix scaffold (3D). l-Carnitine affected extracellular matrix synthesis in 3D in a dose-dependent manner; moreover, l-carnitine was very effective to stimulate cell proliferation and to induce ATP synthesis, mainly in 3D culture condition. In conclusion, l-carnitine enhances cartilage matrix glycosaminoglycan component production and cell proliferation, suggesting that this molecule could be useful in the treatment of pathologies where extracellular matrix is degraded, such as OA. To our knowledge, this is the first study where the effects of l-carnitine are evaluated in HPCs. [ABSTRACT FROM AUTHOR]

The aim of this pilot study was to analyze the effects of glucosamine (GlcN) and its N-acetyl-phenylalanine derivative (NAPA) in Vitamin A model of osteoarthritis (OA) in rabbits. GlcN or NAPA or saline solution was intra-articularly administered in rabbit OA knees. Histological analysis revealed that treatment with GlcN or NAPA was associated with more homogeneous chondrocyte cellularity, absence of fissures and fragmentation and more intense staining of the matrix with Alcian Blue compared to the articular surfaces of the knees treated with saline solution. Comparative in vitro study performed on rabbit primary chondrocytes revealed that GlcN and NAPA were also able to counteract the IL-1β-upregulation of genes coding for metalloproteases and inflammatory cytokines. Our preliminary in vivo and in vitro studies suggest that GlcN and NAPA could play a disease-modifying protective role in OA by an anti-catabolic effect and an anti-inflammatory activity on chondrocytes. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), the most prevalent degenerative joint disease, still lacks a true disease-modifying therapy. The involvement of the NF-κB pathway and its upstream activating kinases in OA pathogenesis has been recognized for many years. The ability of the N-acetyl phenylalanine glucosamine derivative (NAPA) to increase anabolism and reduce catabolism via inhibition of IKKα kinase has been previously observed in vitro and in vivo. The present study aims to confirm the chondroprotective effects of NAPA in an in vitro model of joint OA established with primary cells, respecting both the crosstalk between chondrocytes and synoviocytes and their phenotypes. This model satisfactorily reproduces some features of the previously investigated DMM model, such as the prominent induction of ADAMTS-5 upon inflammatory stimulation. Both gene and protein expression analysis indicated the ability of NAPA to counteract key cartilage catabolic enzymes (ADAMTS-5) and effectors (MCP-1). Molecular analysis showed the ability of NAPA to reduce IKKα nuclear translocation and H3Ser10 phosphorylation, thus inhibiting IKKα transactivation of NF-κB signalling, a pivotal step in the NF-κB-dependent gene expression of some of its targets. In conclusion, our data confirm that NAPA could truly act as a disease-modifying drug in OA. [ABSTRACT FROM AUTHOR]