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Abstract

The synthetic triterpenoid TP-222 inhibits RANKL stimulation of osteoclastogenesis and matrix metalloproteinase-9 expression.

Roy A Fava, Sarah Elliott, Lauren Raymond, Jessica Mollmark, Ezra Hays, Tadashi Honda, Gordon W Gribble, Michael B Sporn and Matthew P Vincenti
The Journal of Rheumatology May 2007, 34 (5) 1058-1068;
Roy A Fava
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Sarah Elliott
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Lauren Raymond
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Jessica Mollmark
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Ezra Hays
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Tadashi Honda
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Gordon W Gribble
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Michael B Sporn
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Matthew P Vincenti
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Abstract

OBJECTIVE: Receptor activator of nuclear factor-kappaB ligand (RANKL) promotes osteoclast differentiation from monocyte precursors by inducing a cohort of genes, including tartrate-resistant acid phosphatase (TRAP) and matrix metalloproteinase-9 (MMP-9). A family of synthetic triterpenoids with antiinflammatory and pro-apoptotic properties was described to modulate differentiation in monocytic cell lineages. We therefore investigated the ability of the potent and bioavailable synthetic triterpenoid TP-222 to inhibit RANKL-induced osteoclast formation and MMP-9 expression from monocytic precursor cells. METHODS: Osteoclast formation was assayed by staining for TRAP-positive multinucleated cells. MMP-9 expression was measured by quantitative RT-PCR, Western blot, immunohistochemistry, and gel zymography. In vivo effects of TP-222 were assessed by daily intraperitoneal injection of 4-week-old mice for 7 days followed by measurement of osteoclast number and MMP-9 expression at the cartilage/bone junction of the epiphyseal growth plate. RESULTS: RANKL promoted and TP-222 (300 nM) inhibited osteoclast formation in cultures of RAW264.7 cells or bone marrow-derived monocytes. RANKL also induced MMP-9 expression in RAW264.7 cells and this was reduced by concurrent or subsequent addition of TP-222. TP-222 treatment significantly reduced the mean number of osteoclasts present at the cartilage/bone interface compared to vehicle-injected control mice. Morphometric analyses of tissue sections showed that TP-222 treatment reduced the amount of immunoreactive MMP-9 present in both mononucleated pre-osteoclasts and osteoclasts. CONCLUSION: Our data demonstrate that TP-222 inhibits osteoclast formation and MMP-9 expression in vitro and in vivo, and suggest that triterpenoids may be useful compounds for modulating bone resorption diseases.

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The Journal of Rheumatology
Vol. 34, Issue 5
1 May 2007
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The synthetic triterpenoid TP-222 inhibits RANKL stimulation of osteoclastogenesis and matrix metalloproteinase-9 expression.
Roy A Fava, Sarah Elliott, Lauren Raymond, Jessica Mollmark, Ezra Hays, Tadashi Honda, Gordon W Gribble, Michael B Sporn, Matthew P Vincenti
The Journal of Rheumatology May 2007, 34 (5) 1058-1068;

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The synthetic triterpenoid TP-222 inhibits RANKL stimulation of osteoclastogenesis and matrix metalloproteinase-9 expression.
Roy A Fava, Sarah Elliott, Lauren Raymond, Jessica Mollmark, Ezra Hays, Tadashi Honda, Gordon W Gribble, Michael B Sporn, Matthew P Vincenti
The Journal of Rheumatology May 2007, 34 (5) 1058-1068;
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