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Interferon-ß modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patientsJacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA
Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA
Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA
Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA
Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA
Department of Statistics, University of Alabama, Birmingham, AL, USA
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, USA, Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA, murali{at}acsu.buffalo.edu
Purpose Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone home-ostasis in response to interferon-ß-1a (IFN-ß-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-
Methods In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 µg IFN-ß-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1 Results IFN-ß-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1ß (MIP-1ß), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-ß resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. Conclusions IFN-ß treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.
Key Words: bone • gene expression • interferons • multiple sclerosis • osteoporosis • pharmacodynamics
Multiple Sclerosis, Vol. 12, No. 5,
541-550 (2006) This article has been cited by other articles:
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B (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). 
/ß expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-ß-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. 
