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06.01 Intra-articular injection of cadmium protects arthritic joints from inflammation and destruction
  1. Paola Bonaventura1,
  2. Guillaume Courbon2,
  3. Aline Lamboux3,
  4. Fabien Lavocat1,
  5. Hubert Marotte2,
  6. Francis Albarede2,
  7. Pierre Miossec1
  1. 1Immunogenomics and Inflammation research Unit, EA 4130 University of Lyon 1, Hôpital Edouard Herriot Lyon, France
  2. 2Department of Bone and Osteoarticular Biology INSERM U1059 University Jean Monet, University of Lyon, Saint-Etienne, France
  3. 3Geology Laboratory – Department of Earth Sciences, Ecole Normale Supérieure de Lyon and CNRS Lyon, France

Abstract

Background There has been no recent progress in the intra-articular treatment of joint inflammation. Rheumatoid arthritis (RA) synovium hyperplasia is sustained by the secretion of pro-inflammatory cytokines (IL-17/TNF-α), synergistically contributing to chronicity. Since inflammation up-regulates trans-membrane Zinc (Zn) importers, the effects of its binding-competitor Cadmium (Cd) were tested on synoviocytes, synovium explants and in a rat arthritis model in order to reduce hyperplasia and inflammation.

Materials and methods After exposure to IL-17/TNF-α and Cd, Cd-kinetics and Cd-cell content were measured by ICP-MS, while Zn/Cd-transporter gene expression (Zrt-Irt-like protein-8, ZIP-8, importer and metallothioneins-1, MT-1, metal homeostasis regulators) by q-RT-PCR. Synoviocyte viability and apoptosis were measured by neutral red and annexin-V staining. IL-6 levels in synoviocyte and biopsy supernatants were measured by ELISA. Adjuvant induced arthritis rat model was used for in vivo Cd-injection into hind ankle joints. Clinical scores were evaluated. Immune cell recruitment was quantified after H and E staining. Micro-tomography and safarin-O staining were used to measure bone/cartilage loss. The potential Cd-spread was measured in different body reservoirs.

Results After synoviocyte exposure to IL-17/TNF-α combination, ZIP-8 and MT-1s gene expressions increased up to 5.3±3.1 fold and 5.0±0.9 fold respectively, compared to the untreated condition (p<0.05). Combined Cd-cytokine exposure further enhanced MT-1s expression up to 93.3±32.1 fold. Through the transporter enhanced expression, Cd content in inflammatory synoviocytes increased two-fold. RA synoviocytes were sensitised toward apoptosis by exposure to the Cd/cytokine combination with an 80% reduction of cell viability in comparison to control (p<0.01), after 5 days of culture. Moreover, Cd-cytokines association reduced IL-6 production in vitro (up to 83%, after 5 days, p<0.05) and ex-vivo (up to 94%, after 8 days, p<0.01). Intra-articular Cd injection improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p<0.01), inflammatory cell recruitment (up to 50%, p<0.01) and bone/cartilage destruction. The use of 1 ppm of Cd provided the best risk/benefit ratio, without toxic effects on other cell types and organs.

Conclusion The anti-proliferative and anti-inflammatory properties of low-dose Cd may represent a new therapeutic approach for the local treatment of synovitis and hyperplasia in arthritis and other joint diseases.

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