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A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κB activity and c-Fos expression.

Abstract：

AIMS:Osteoclasts, the unique bone-resorbing polykaryons, are responsible for many bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Hence, the regulation of osteoclast formation is considered a potential therapeutic approach for these diseases. In this study, we investigated the effect of a novel small compound, C(25)H(32)N(4)O(4)S(2) (NecroX-7) on osteoclast formation. MAIN METHODS:We analyzed the effects of NecoX-7 on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in vitro and LPS-induced bone loss in vivo. KEY FINDINGS:We observed that NecroX-7 suppressed osteoclast formation from primary bone marrow macrophages (BMMs) in a dose-dependent manner. NecroX-7 significantly inhibited the NF-κB signaling pathway without affecting the activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK in response to RANKL. In addition, NecroX-7 strongly attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are crucial transcription factors for osteoclast differentiation. Mirroring the down-regulation of c-Fos and NFATc1, the expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was also reduced by the addition of NecroX-7. Furthermore, confirming the in vitro anti-osteoclastogenic effect, NecroX-7 inhibited lipopolysaccharide (LPS)-induced bone loss in vivo. SIGNIFICANCE:Our data imply that NecroX-7 is useful as a therapeutic drug for the treatment of bone resorption-associated diseases.

journal_name

Life Sci

journal_title

Life sciences

authors

Kim HJ,Yoon KA,Lee MK,Kim SH,Lee IK,Kim SY

doi

10.1016/j.lfs.2012.09.009

subject

Has Abstract

pub_date

2012-11-02 00:00:00

pages

928-34

issue

19-20

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(12)00508-5

journal_volume

91

pub_type

杂志文章

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