Blockade of NLRP3 alleviates systemic lupus erythematosus-induced osteoporosis through dual modulation of osteogenesis and osteoclastogenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42699060.
- Also identified by DOI 10.1016/j.bonr.2026.101942 and PMC identifier 13543794.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease frequently associated with accelerated bone loss and osteoporosis. Emerging evidence implicates the NLRP3 inflammasome as a pivotal mediator of inflammation-driven bone remodeling dysregulation in SLE. This study investigates the therapeutic potential of targeting NLRP3 inhibition for SLE treatment using both a synthetic NLRP3 inhibitor (MCC950) and a natural NLRP3 inhibitor-oridonin, for its potential clinical translation. Using a combination of <i>in vitro</i> and <i>in vivo</i> approaches, we demonstrate that NLRP3 activation by lipopolysaccharide (LPS) promotes osteoclast differentiation and inhibits osteogenic differentiation through distinct molecular mechanisms. In RAW264.7 macrophages, LPS-induced NLRP3 activation upregulates autophagy-related genes (LC3B, p62) and osteoclastogenesis- related genes (TRAF6, c-Jun, NFATc1), which are effectively suppressed by MCC950 intervention. In mesenchymal stem cells, LPS exposure impairs osteogenic differentiation by reducing Runx2 and OCN gene expression while increasing pyroptosis-related genes (GSDMD, Caspase-11), these effects that are significantly ameliorated by oridonin intervention. In an SLE murine model (MRL/lpr mice), 12 weeks of NLRP3 inhibition with either MCC950 or oridonin both restore bone microstructure, enhance trabecular bone density, improve biomechanical properties, and normalize serum biomarkers of bone turnover. This study provides compelling evidence that targeting NLRP3 signaling represents a promising therapeutic strategy for SLE-associated osteoporosis. The osteogenic effect of oridonin, a naturally occurring compound with established clinical safety, highlights its potential as a promising agent for treating bone loss in SLE patients. These findings underscore the importance of inflammasome targeting in managing SLE-induced bone remodeling disorders.