Thelephoric acid, p-terphenyl, induces bone-forming activities in pre-osteoblasts

Abstract

• Thelephoric acid is a p-terphenyl compound isolated from the mushrooms of Polyozellus multiplex. • Thelephoric acid enhances ALP enzymatic activities in pre-osteoblasts. • Thelephoric acid enhances bone matrix mineralization in pre-osteoblasts. • Thelephoric acid enhances nuclear RUNX2 expression and accumulation via Smad1/5/8 phosphorylation. • Thelephoric acid enhances cell adhesion and migration in osteoblast differentiation. • Thelephoric acid is a potentially beneficial compound for prevention and treatment in bone diseases. Polyozellus multiplex , a wild mushroom belonging to Thelephoracea, is distributed in Korea, Japan, and China. Thelephoric acid (Thel), a terphenylquinone found in P. multiplex , reportedly exhibits beneficial effects, including antioxidant, anticancer, and neuroprotective activities. Herein, we extracted Thel from P. multiplex (>95.8% purity) and examined its osteogenic effects on pre-osteoblasts. Thel exerted no cytotoxicity in pre-osteoblasts. Based on alkaline phosphatase staining and activity, Thel promoted osteoblast differentiation and bone matrix mineralization. Biochemical investigations revealed that Thel enhanced nuclear runt-related transcription factor 2 (RUNX2) expression and accumulation via Smad1/5/8 phosphorylation, while exhibiting synergistic activities following cotreatment with bone morphogenetic protein 2 or fibroblast growth factor 2 in pre-osteoblast cultures. Thel increased cell adhesion and migration in differentiating osteoblasts by upregulating matrix metalloproteinase 13 (MMP13). Collectively, these findings indicate that Thel induced osteogenic properties by regulating RUNX2 and MMP13 expression, suggesting that Thel could be further developed to treat bone disorders.