The dinitrothiophenol SN-2 reduces osteoclastogenesis and estrogen deficiency-induced bone loss by inhibiting TRAF6 auto-ubiquitination.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42317208.
- Also identified by DOI 10.1016/j.bonr.2026.101923 and PMC identifier 13273726.
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Abstract
Post-menopausal osteoporosis is characterized by overactive bone resorption in response to estrogen withdrawal. As Receptor Activator of NF-κB ligand (RANKL)-induced auto-ubiquitination of TNF receptor-associated factor 6 (TRAF6) on its K124 residue promotes osteoclastogenesis, inhibiting TRAF6<sup>K124</sup> auto-ubiquitination may be a promising therapeutic strategy for post-menopausal osteoporosis. We investigated the impact of the synthetic dinitrothiophenol SN-2 (4-(Dimethylamino)-2,6-bis[[N-[2-[(2-nitrophenyl)dithio]-ethyl]amino]methyl]pyridine) on TRAF6<sup>K124</sup> auto-ubiquitination, osteoclast generation, and osteoporotic bone loss. <i>In vitro</i>, SN-2 inhibited RANKL-induced osteoclast differentiation and osteoclast marker expression in a dose-dependent manner. SN-2 also inhibited RANKL-induced F-actin ring formation and bone resorption <i>in vitro</i>. SN-2 suppressed RANKL-induced TRAF6<sup>K124</sup> auto-ubiquitination (TRAF6-Ub), TRAF6's binding to Transforming Growth Factor Beta-Activated Kinase 1 (TAK1), and TAK1 phosphorylation, thereby inhibiting downstream NF-κB and c-Jun N-terminal Kinase (JNK) signaling pathways critical to osteoclast differentiation. In an ovariectomized mouse model of osteoporosis, SN-2 ameliorated estrogen-deficiency-induced bone loss, improved femoral biomechanical parameters, and inhibited osteoclastogenesis <i>in vivo</i>. SN-2 may show promise as a therapeutic agent in treating bone disorders characterized by RANKL signaling over-activation and excessive bone resorption.