A novel flavonoid isolated from the steam-bark of Ulmus Wallichiana Planchon stimulates osteoblast function and inhibits osteoclast and adipocyte differentiation

(2S,3S)-Aromadendrin-6-C-β-d-glucopyranoside (AG) is a novel flavonol isolated from the extract of Ulmus wallichiana (Himalayan Elm). Extract of U. wallichiana is used as a traditional medicine for rapid fracture repair in India. We characterized the mechanism of action of AG in mouse bone cells by investigating its effect on the precursors of osteoblasts, osteoclasts and adipocytes. At nanomolar concentrations, AG increased differentiation of preosteoblasts obtained from neonatal mouse calvaria. The gene expression of osteogenic markers, including runt-related transcription factor 2 (Runx-2), bone morphogenetic protein-2 (BMP-2), type I collagen and osteocalcin were elevated in the preosteoblasts. The extracellular matrix mineralization was higher in preosteoblast and bone marrow cells when AG was present in the medium. Furthermore, AG protected the differentiated osteoblasts from serum deprivation-induced apoptosis, and increased the expression of the anti-osteoclastogenic cytokine, osteoprotegerin. It inhibited osteoclast differentiation of bone marrow precursor cells to osteoclasts in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and monocyte/macrophage-colony stimulating factor (M-CSF). Additionally, in 3T3-L1 preadipocytes, AG decreased the expression of genes involved in adipogenesis, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element binding protein (SREBP) and CCAAT/enhancer-binding protein alpha (CEBP/α), and induced apoptosis of differentiated adipocytes. Induction of adipogenic differentiation was also inhibited in the presence of AG. AG exhibited no estrogenic/antiestrogenic effect. Together, our data show that AG has potent osteogenic, anti-osteoclastogenic and anti-adipogenic effects, which may translate to a better skeletal outcome in postmenopausal osteoporosis.

Graphical Abstract(2S,3S)-Aromadendrin-6-C-β-d-glucopyranoside (AG) is a novel compound isolated from Ulmus wallichiana (Himalayan Elm) that is used for rapid fracture repair in ethno-traditional practice in India. Our data show that AG, while pushing osteoprogenitors along the osteoblastic differentiation pathway, prevents them from detouring onto adipocyte pathway and at the same time reducing osteoclast generation directly as well as indirectly by stimulating osteoblastic cells to express the anti-osteoclastogenic cytokine, osteoprotegerin. AG via multiple beneficial effects on bone cells may have better skeletal impact in postmenopausal osteoporosis by inhibiting the process of bone resorption and stimulating bone formation.Figure optionsDownload high-quality image (78 K)Download as PowerPoint slide