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J. P. Gratton, M. Morales-Ruiz, Y. Kureishi,, D. Fulton, K. Walsh and W. C. Sessa, “Akt down-regulation of p38 signalling provides a novel mechanism of vascular endo-thelial growth factor-mediated cytoprotection in endothelial cells,” The Journal of Biological Chemistry, Vol. 276, No. 32, 2001, pp. 30359-30365.

has been cited by the following article:

• TITLE: Osteoprotegerin Secretion by Mevastatin via p38MAPK and NF-kB

  AUTHORS: Helen Smith

  KEYWORDS: Osteoprotegerin; Osteoporosis; Statin; Mevastatin

  JOURNAL NAME: Open Journal of Rheumatology and Autoimmune Diseases, Vol.2 No.2, May 7, 2012

  ABSTRACT: Osteoprotegerin (OPG) is a protein produced by many cell types that has the remarkable property of inhibiting bone loss. It does this by binding to the key bone resorptive cytokine, receptor activator of NF-kB ligand (RANKL). This cytokine is produced mainly by osteoblastic cells and is instrumental in osteoclast differentiation. If the ratio of RANKL:OPG increases, bone resorption increases and results in bone loss in diseases such osteoporosis, rheumatoid arthritis and hypercalcaemia of malignancy. Hence, if drugs can be found that increase OPG, this will decrease the activity of osteoclasts and therefore bone resorption. Statins are cholesterol lowering drugs that have recently been shown to increase bone formation in rodents. It was hypothesised from this finding that this could be due to an increase in OPG production. If these commonly prescribed drugs could be used to prevent bone loss or to increase bone formation then this may prove a useful means of reducing fracture risk in patients. Treating Saos-2 osteoblast-like cells in vitro with mevastatin increased OPG production and secretion through the mevalonate pathway. A failure of geranylgeranylation of Rho and/or farnesylation of Ras proteins leads to an increase in PI-3K activation then AKT activation leading to several different signaling pathways such as MAPK’s and NF-kB. NF-kB and p38MAPK inhibitors prevented the statin stimulation of OPG but not the decrease in cell number, suggesting that statins regulate OPG secretion via PI-3K, p38MAPK and NF-kB.