Dietary Scopoletin Ameliorates Diabetes-Associated Impairment of Bone Turnover via Activation of Bone Morphogenetic Protein-2 Pathway

Abstract

Abstract Objectives Diabetes induces bone deteriorateion leading to osteopenia, increased risk of fracture and osteoporosis. Thus, diabetes-induced bone fragility has been recently recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on osteoclastogenesis and osteoblastogenesis remain unclear. Scopoletin, a coumarin family, is naturally found at notably high concentrations in chicory, leaves of stinging nettle, passion flower and noni. The purpose of this study was to identify that scopoletin was capable of preventing diabetic impairment of bone remodeling through BMP-2 pathway. Methods The in vitro study employed osteoblastic MC3T3-E1 cells that were exposed to 33 mM glucose in the presence of 1–20 μM scopoletin. In addition, murine macrophage Raw 264.7 cells were incubated with RANKL for differentiation to multi-nucleated osteoclasts and treated with 33 mM glucose for 5 days in the presence of 1–20 μM scopoletin. The in vivo study was conducted with the db/db mice that were orally administrated 10 mg/kg scopoletin daily for 10 weeks. Results High glucose diminished TRAP activity and bone resorption in RANKL-differentiated osteoclasts, indicating that osteoclast activation may be impaired under diabetic conditions. In contrast, scopoletin elevated osteoclastic differentiation and activation reduced by glucose. On the other hand, high glucose attenuated the ALP activity of osteoblastic cells, which was enhanced by treating 1–20 μM scopoletin to cells. Oral administration of scopoletin elevated plasma levels of osteoprotegerin, RANKL and osteocalcin reduced in diabetic mice, and increased trabecular bone formation and ephiphyseal disc thickness of growing bone. Finally, scopoletin enhanced the induction of Runx2 and BMP-2 in osteoblasts dampened by high glucose. Conclusions Scopoletin improved aberrant bone remodeling in diabetic osteoblasts and osteoclasts through induction of Runx2 and BMP-2. These findings suggest the possibility that scopoletin could be a potential agent for the treatment of diabetes-associated bone diseases. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2019R1A2C1003218), and was supported by Basic Science Research Program through NRF funded by the Ministry of Education (2020R1A6A3A0110009611).