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

Abstract

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.

In Vitro Macrophage Immunomodulation by Poly(ε-caprolactone) Based-Coated AZ31 Mg Alloy

“…Consistent with the microscopic results, our data on the quantification of the TRAP-positive multinucleated cells and TRAP activity showed significant differences between the analysed samples, with the Mg-PCL-CM exhibiting the highest levels. This result is in line with data reported by Lee et al [ 138 ] showing that CM promoted the formation of TRAP-positive multinucleated cells. Noteworthy, the co-presence of ZnO nanoparticles in the PCL-CM and PCL-CM coatings induced the most significant decrease in the mentioned two osteoclast-specific markers.…”

“…Given the known anti-inflammatory activity of ZnO nanoparticles, studies have reported their dose-and size dependent effects on the inflammatory response of RAW 264.7 cells, with lower doses and smaller sized nanoparticles (30 nm) having the most beneficial effect [134][135][136]. Even though the anti-inflammatory activities of different CM compounds have been reported in several studies [50,[136][137][138][139] here, the extraction media obtained from the PCL-CM coated sample exhibited a more pronounced pro-inflammatory response close to the TCPS sample but two-fold lower than the bare alloy, a feasible explanation being the lower amount of CM released from the PCL-CM coating (15 µg mL −1 ) in comparison to the PLC-CM-ZnO coating (26 µg mL −1 ).…”

Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption

“…These cytokines were shown to induce the formation and activation of osteoclasts. Hyperglycemia also enhances RANKL expression [ 42 , 51 , 52 , 53 ]. Hyperglycemia was shown to directly alter the expression of osteoblast-related genes, such as osteocalcin, and to affect osteoblast differentiation in vitro [ 54 , 55 ].…”

Coumarin’s Anti-Quorum Sensing Activity Can Be Enhanced When Combined with Other Plant-Derived Small Molecules

“…They are showed anti-ulcerogenic [ 5 ], antiparasitic [ 6 ], anti-inflammatory [ 7 , 8 , 9 , 10 , 11 ], and other properties [ 12 , 13 , 14 ]. They are also antioxidant [ 15 ], and anticoagulant compounds [ 16 , 17 , 18 , 19 ]. As such, they can be defined as new pharmaceutical candidates [ 20 ].…”