Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-κB activated pyroptosis pathways. (December 2021)

• Record Type: Journal Article
• Authors: Tao, Huaqiang; Li, Wenming; Zhang, Wei; Yang, Chen; Zhang, Chun; Liang, Xiaolong; Yin, Juan; Bai, Jiaxiang; Ge, Gaoran; Zhang, Haifeng; Yang, Xing; Li, Hongxia; Xu, Yaozeng; Hao, Yuefeng; Liu, Yu; Geng, Dechun
• Is Part Of: Pharmacological research. Volume 174(2021)
• Publication Date: 2021-12
• Subjects: OP osteoporosis -- UA urolithin a -- Micro-CT micro-computed tomography -- RANKL receptor activator for nuclear factor-κB ligand -- OVX ovariectomized -- CMC-Na sodium carboxymethyl cellulose -- BMD bone mineral density -- BV bone volume -- BV/TV bone volume per tissue volume -- Tb N Trabecular number -- Tb Sp trabecular separation -- Ct Th cortical thickness -- PCR polymerase chain reaction -- PBS phosphate buffered saline -- IL-1β interleukin-1β -- NF-κB nuclear factor kappaB -- MAPK mitogen-activated protein kinase -- PI3K phosphatidylinositol 3-kinase -- ET ellagitannins -- EA ellagic acid -- LPS Lipopolysaccharide -- M-CSF macrophage colony stimulating factor -- TRAcP tartrate-resistant acid phosphatase -- OSCAR osteoclast associated receptor -- TNF tumor necrosis factor -- H&E hematoxylin and eosin -- CTSK Cathepsin K -- NFATc1 nuclear factor of activated T cells 1 -- Acp5 acid phosphatase 5 -- CTX-1 C-terminal telopeptide of type I collagen -- NOD nucleotide binding oligomerization domain -- NLRP3 NOD-like receptor pyrin domain containing 3 -- Caspase 1 cysteinyl aspartate specific proteinase 1; Urolithin A -- Osteoporosis -- Osteoclast -- Inflammation -- Pyroptosis; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105967
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Osteoporosis (OP) is characterized by decreased trabecular bone volume and microarchitectural deterioration in the medullary cavity. Urolithin A (UA) is a biologically active metabolite generated by the gut microbiota. UA is the measurable product considered the most relevant urolithin as the final metabolic product of polyphenolic compounds. Considering that catabolic effects mediated by the intestinal microbiota are highly involved in pathological bone disorders, exploring the biological influence and molecular mechanisms by which UA alleviates OP is crucial. Our study aimed to investigate the effect of UA administration on OP progression in the context of estrogen deficiency-induced bone loss. The in vivo results indicated that UA effectively reduced ovariectomy-induced systemic bone loss. In vitro, UA suppressed Receptor Activator for Nuclear Factor-κB Ligand (RANKL)-triggered osteoclastogenesis in a concentration-dependent manner. Signal transduction studies and sequencing analysis showed that UA significantly decreased the expression of inflammatory cytokines (e.g., IL-6 and TNF-α) in osteoclasts. Additionally, attenuation of inflammatory signaling cascades inhibited the NF-κB-activated NOD-like receptor signaling pathway, which eventually led to decreased cytoplasmic secretion of IL-1β and IL-18 and reduced expression of pyroptosis markers (NLRP3, GSDMD, and caspase-1). Consistent with this finding, an NLRP3 inflammasome inhibitor (MCC950) was employed to treat OP, and modulation of pyroptosis was found to ameliorate osteoclastogenesis and bone loss in ovariectomized (OVX) mice, suggesting that UA suppressed osteoclast formation by regulating the inflammatory signal-dependent pyroptosis pathway. Conceivably, UA administration may be a safe and promising therapeutic strategy for osteoclast-related bone diseases such as OP. Graphical Abstract: ga1