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Downregulation of the Inflammatory Response by CORM-3 Results in Protective Effects in a Model of Postmenopausal Arthritis

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Abstract

CO-releasing molecules (CORMs) are a new class of drugs able to release small amounts of CO in biological systems. We have shown previously that one of these molecules, CORM-3, exerts anti-inflammatory effects in animal models. The aim of this study was to assess the effects of CORM-3 on bone metabolism in a model of postmenopausal rheumatoid arthritis osteoporosis. Ovariectomy was followed by collagen-induced arthritis in female DBA-1/J mice. Animals showing arthritis on day 22 after immunization were then randomized into control and treatment groups. CORM-3 was administered at 10 mg/kg, intraperitoneally, once a day. Alendronate was administered at 100 μg/kg, orally, once a day. On days 36 and 50 after immunization, animals were killed and tissues analyzed. The arthritic score was significantly reduced by CORM-3 but not by alendronate treatment. Histopathological analyses indicated that both compounds reduced cellular infiltration and cartilage degradation. Local bone erosion and reduction in TNFα levels were seen for CORM-3 on day 50 and for alendronate on day 36. Serum levels of COMP, IL-6, MMP-3, CTX-I, alkaline phosphatase, and osteocalcin were decreased by both treatments, whereas TNFα levels were reduced by CORM-3 and TRAP-5b by alendronate. Micro-computed tomographic analysis showed protective effects on trabecular bone, which were more prominent for CORM-3 on day 36 and for alendronate on day 50. Our results suggest that CORMs represent a novel anti-inflammatory strategy to counteract joint bone erosion with partial protective effects on systemic bone loss in postmenopausal rheumatoid arthritis.

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Acknowledgments

This study was supported by grants SAF2010-22048 and RETICEF RD06/0013/2001 (Ministerio de Economía y Competitividad, ISCIII, FEDER) and Prometeo2010-047 (Generalitat Valenciana). L. I. is the recipient of an FPI fellowship (Ministerio de Economía y Competitividad). The authors thank Prof. Brian Mann for the synthesis of CORM-3.

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Authors and Affiliations

  1. Department of Pharmacology, University of Valencia, Av. Vicent Andres Estelles s/n, 46100, Burjassot, Valencia, Spain

    Lidia Ibáñez, Maria José Alcaraz, Nuria Maicas & Maria Luisa Ferrándiz

  2. Trabeculae S.L., 32900, San Cibrao das Viñas, Ourense, Spain

    David Guede

  3. Santiago de Compostela University Hospital, 15706, Santiago de Compostela, Spain

    José Ramón Caeiro

  4. INSERM, U955 Equipe 3, Université Paris Est, Faculté de Médecine, 94010, Creteil, France

    Roberto Motterlini

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  1. Lidia Ibáñez
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  2. Maria José Alcaraz
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  7. Maria Luisa Ferrándiz
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Correspondence to Maria Luisa Ferrándiz.

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Ibáñez, L., Alcaraz, M.J., Maicas, N. et al. Downregulation of the Inflammatory Response by CORM-3 Results in Protective Effects in a Model of Postmenopausal Arthritis. Calcif Tissue Int 91, 69–80 (2012). https://doi.org/10.1007/s00223-012-9612-7

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  • DOI: https://doi.org/10.1007/s00223-012-9612-7

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