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Urokinase Plasminogen Activator System in Synovial Fibroblasts from Osteoarthritis Patients: Modulation by Inflammatory Mediators and Neuropeptides

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Abstract

Plasminogen activators are specific proteolytic enzymes implicated in a variety of basic biological processes. The expression of the urokinase plasminogen activator system components is increased in some human diseases, including osteoarthritis. We sought to study the effect of two components of the inflamed synovial microenvironment on this system, IL-1β and fibronectin fragments, elucidating whether corticotropin-releasing factor (CRF) and vasoactive intestinal peptide (VIP) neuropeptides modulate it, and analyzing the physiological consequences in joint destruction by measuring matrix metalloproteinases-9 and metalloproteinases-13 levels in osteoarthritis fibroblast-like synoviocytes. We showed that IL-1β and fibronectin fragments stimulated urokinase system contributing to the perpetuation of the destructive cascade in joint. VIP modulated, even at constitutive level, this system, also counteracting the effect of both inflammatory stimuli. However, CRF seemed to be ineffective in controlling the production of these proteinases. Moreover, VIP was able to reduce the constitutive expression of matrix metalloproteinase-13 and the levels of both matrix metalloproteinases after stimulation with the pro-inflammatory stimuli. Our results suggest that the presence of early and later inflammatory mediators, such as IL-1β and fibronectin fragments, increases the urokinase system and the matrix metalloproteinases levels. Whereas CRF did not affect this system, VIP counteracts these actions supporting its therapeutic potential for the treatment of osteoarthritis.

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Acknowledgments

This work was supported by Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (PI11/00195, PI12/00758, PI11/00505, RETICS RD08/0075, and RD12/0009/0002, RIER) within VI PNDE I+D+I by FEDER funds from EU and SII10/BMD-2350 from Comunidad Autónoma de Madrid (CAM). By grants from ISCIII to RJ, MC, and a predoctoral fellowship (SPG) from the Ministerio de Educación, Cultura y Deporte.

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Authors and Affiliations

  1. Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, José Antonio Novais n°2, Ciudad Universitaria, 28040, Madrid, Spain

    Selene Pérez-García, Mar Carrión, Rebeca Jimeno, Rosa P. Gomariz & Yasmina Juarranz

  2. Servicio de Reumatología, Hospital Universitario de la Princesa. Instituto de Investigación Sanitaria la Princesa, Madrid, Spain

    Ana M. Ortiz & Isidoro González-Álvaro

  3. Servicio de Traumatología, Hospital Universitario de la Princesa. Instituto de Investigación Sanitaria la Princesa, Madrid, Spain

    Julián Fernández

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  1. Selene Pérez-García
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  2. Mar Carrión
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  3. Rebeca Jimeno
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  4. Ana M. Ortiz
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  5. Isidoro González-Álvaro
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  6. Julián Fernández
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  7. Rosa P. Gomariz
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  8. Yasmina Juarranz
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Correspondence to Rosa P. Gomariz or Yasmina Juarranz.

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The last two authors share senior authorship.

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Pérez-García, S., Carrión, M., Jimeno, R. et al. Urokinase Plasminogen Activator System in Synovial Fibroblasts from Osteoarthritis Patients: Modulation by Inflammatory Mediators and Neuropeptides. J Mol Neurosci 52, 18–27 (2014). https://doi.org/10.1007/s12031-013-0189-z

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