Coumarin Ameliorates Impaired Bone Turnover by Inhibiting the Formation of Advanced Glycation End Products in Diabetic Osteoblasts and Osteoclasts

Accumulating evidence demonstrates that the risk of osteoporotic fractures increases in patients with diabetes mellitus. Thus, diabetes-induced bone fragility has recently been recognized as a diabetic complication. As the fracture risk is independent of the reduction in bone mineral density, deterioration in bone quality may be the main cause of bone fragility. Coumarin exists naturally in many plants as phenylpropanoids and is present in tonka beans in significantly high concentrations. This study investigated whether coumarin ameliorated the impaired bone turnover and remodeling under diabetic condition. The in vitro study employed murine macrophage Raw 264.7 cells differentiated to multinucleated osteoclasts with receptor activator of nuclear factor-κΒ ligand (RANKL) in the presence of 33 mM glucose and 1-20 μM coumarin for five days. In addition, osteoblastic MC3T3-E1 cells were exposed to 33 mM glucose for up to 21 days in the presence of 1-20 μM coumarin. High glucose diminished tartrate-resistant acid phosphatase activity and bone resorption in RANKL-differentiated osteoclasts, accompanying a reduction of cathepsin K induction and actin ring formation. In contrast, coumarin reversed the defective osteoclastogenesis in diabetic osteoclasts. Furthermore, high glucose diminished alkaline phosphatase activity and collagen type 1 induction of osteoblasts, which was strongly enhanced by submicromolar levels of coumarin to diabetic cells. Furthermore, coumarin restored the induction of RANK and osteoprotegerin in osteoclasts and osteoblasts under glucotoxic condition, indicating a tight coupling of osteoclastogenesis and osteoblastogenesis. Coumarin ameliorated the impaired bone turnover and remodeling in diabetic osteoblasts and osteoclasts by suppressing the interaction between advanced glycation end product (AGE) and its receptor (RAGE). Therefore, coumarin may restore optimal bone turnover of osteoclasts and osteoblasts by disrupting the hyperglycemia-mediated AGE-RAGE interaction.

Keywords: advanced glycation end-product; bone remodeling; bone turnover; coumarin; glucose; osteoblasts; osteoclasts.