PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

Objectives To define how peroxisome proliferator-activated receptor (PPAR) β/δ expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPARβ/δ interacts with factors such as nuclear factor-kappa B (NF-κB) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPARβ/δ on MSC immunosuppressive properties. Methods We either treated human MSCs (hMSCs) with the irreversible PPARβ/δ antagonist (GSK3787) or derived MSCs from mice deficient for PPARβ/δ (PPARβ/δ−/− MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays. Results Modulation of PPARβ/δ expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPARβ/δ−/− MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPARβ/δ+/+ MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPARβ/δ−/− MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPARβ/δ+/+ MSCs. The enhanced NO2 production by PPARβ/δ−/− MSCs was due to the increased retention of NF-κB p65 subunit on the κB elements of the inducible nitric oxide synthase promoter resulting from PPARβ/δ silencing. Conclusions Our study is the first to show that the inhibition or knockdown of PPARβ/δ in MSCs primes their immunoregulatory functions. Thus, the regulation of PPARβ/δ expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype

Environmental arginine controls multinuclear giant cell metabolism and formation

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Beta ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling. Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases

PPARβ/δ expression orchestrates the immunosuppressive effect of mesenchymal stem cells via NF-κB signalling

International audienc

PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis

International audienc

Wnt Inhibitory Factor 1 Deficiency Uncouples Cartilage and Bone Destruction in Tumor Necrosis Factor alpha-Mediated Experimental Arthritis

Item does not contain fulltextOBJECTIVE: Wnt signaling plays a pivotal role in skeletal development and in the control of cartilage and bone turnover. We have recently shown that the secreted Wnt antagonist Wnt inhibitory factor 1 (WIF-1) is mainly expressed in the upper layers of epiphyseal and articular cartilage and, to a lesser extent, in bone. Nevertheless, WIF-1(-/-) mice develop normally. In light of these findings, we undertook this study to analyze the role of WIF-1 in arthritis. METHODS: Expression analyses for WIF-1 were performed by real-time reverse transcription-polymerase chain reaction (RT-PCR). WIF-1(-/-) and tumor necrosis factor (TNF)-transgenic mice were crossbred, and the progression of arthritis in TNF-transgenic WIF-1(-/-) mice and littermate controls was evaluated. Structural joint damage was analyzed by histologic staining, histomorphometry, and micro-computed tomography. Wnt/beta-catenin signaling was investigated by real-time RT-PCR and immunofluorescence on primary chondrocytes. RESULTS: WIF-1 expression was repressed by TNFalpha in chondrocytes and osteoblasts and down-regulated in experimental arthritis and in articular cartilage from patients with rheumatoid arthritis. WIF-1 deficiency partially protected TNF-transgenic mice against bone erosion and loss of trabecular bone, probably as a result of less osteoclast activity. In contrast, arthritis-related cartilage damage was aggravated by WIF-1 deficiency, while overexpression of WIF-1 attenuated cartilage degradation in TNF-transgenic mice. In chondrocytes, TNFalpha stimulated canonical Wnt signaling, which could be blocked by WIF-1, indicating a direct effect of TNFalpha and WIF-1 on Wnt signaling in this system. CONCLUSION: These data suggest that WIF-1 may take part in the fine-tuning of cartilage and bone turnover, promoting the balance of cartilage versus bone anabolism

12/15-lipoxygenase counteracts inflammation and tissue damage in arthritis.

Contains fulltext : 81781.pdf (publisher's version ) (Closed access)Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A(4) (LXA(4)). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA(4) within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA(4), which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-alpha. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis

Qualitätskriterien im Umfeld von AAL.

Die demografische Entwicklung in Europa geht mit dem Wunsch eines gesunden und unabhängigen Lebens bis ins hohe Alter einher. Dies kann durch entsprechende altersgerechte Assistenzsysteme erreicht werden, welche die Interaktion zwischen technischen und sozialen Systemen verbessern. Im Rahmen der Förderinitiative „Altersgerechte Assistenzsysteme für ein gesundes und unabhängiges Leben – AAL“ des BMBF wird der Entwicklung entsprechender Assistenzsysteme Rechnung getragen. Die Arbeitsgruppe Qualitätskriterien hat sich zum Ziel gesetzt, dieses gemeinsame Verständnis zu fördern. Hierzu hat die Arbeitsgruppe das vorliegende Whitepaper aufgestellt. Es dient dem direkten Anwender und den privaten sowie öffentlichen Dienstleistern von AAL-Produkten zur Orientierung bei relevanten Qualitätskriterien für den Aufbau einer AAL-Umgebung. Hersteller und Kostenträger erfahren, welche Qualitätskriterien im besonderen Umfeld von AAL von Bedeutung sind