Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells

Abstract

Osteoporosis with bone loss is widely recognized as a major health problem. Bone homeostasis is maintained by balancing bone formation and bone resorption. The imbalance caused by increased bone resorption over bone formation can lead to various bone-related diseases such as osteoporosis and rheumatoid arthritis. Osteoclasts are the principal cells responsible for bone resorption and the main targets of anti-resorptive therapies. However, excessive inhibition of osteoclast differentiation may lead to inhibition of osteoblast differentiation. Therefore, it is important to screen for new compounds capable of inhibiting bone resorption and enhancing bone formation. Toddalia asiatica (L.) Lam. has been utilized traditionally for medicinal purposes such as the treatment of rheumatism. Currently, the extract is considered to be a good source of pharmacological agents for the treatment of bone-related diseases, but the active compounds have yet to be identified. We investigated whether toddaculin, derived from Toddalia asiatica (L.) Lam., affects both processes by inhibiting bone resorption and enhancing bone formation. Towards this end, we used pre-osteoclastic RAW 264 cells and pre-osteoblastic MC3T3-E1 cells. We found that toddaculin not only inhibited the differentiation of osteoclasts via activation of the NF-κB, ERK 1/2, and p38 MAPK signaling pathways, but it also induced differentiation and mineralization of osteoblasts by regulating differentiation factors. Thus, toddaculin might be beneficial for the prevention and treatment of osteoporosis.

Separation of New Coumarin Glycosides from Toddalia asiatica Using Offline Two-Dimensional High-Performance Liquid Chromatography

“…The roots and barks of T. asiatica have been used in Miao minority medicine, mainly in Guizhou, Yunnan, and Guangxi provinces in China, for the treatment of fall injuries, rheumatic arthralgia, stomachache, chronic lumbago, and diarrhea [3,4]. Previous phytochemical and pharmacological investigations of different parts of this plant revealed that coumarins are the main secondary metabolites [5], some of which exhibited cytotoxic, antimalarial [6], antiviral [7], anti-inflammatory [8], antibacterial [9], anti-platelet aggregation [10], anti-plasmodial, larvicidal [11], phosphodiesterase-4 inhibitory [12], and osteoclastogenesis activities [13]. Even though coumarins are rather studied, less attention has been paid to their glycosides.…”

Evaluation of Aculeatin and Toddaculin Isolated from <i>Toddalia asiatica</i> as Anti-inflammatory Agents in LPS-Stimulated RAW264 Macrophages

“…13) Conversely, TOD inhibited the differentiation of osteoclasts and induced osteoblastogenesis, 14) whereas ACU did not affect osteoclastogenesis nor osteoblastogenesis under the same conditions. Epoxidation of a prenyl group seems to play an important role in the various biological activities.…”

“…This phenomenon was also observed in our previous study using receptor activator of NF-κB ligand-stimulated RAW264 cells. 14) However, the contribution of JNK activation to the anti-inflammatory effect of TOD was unclear and further study was required.…”

“…13) Furthermore, toddaculin (TOD) inhibits osteoclastogenesis in RAW264 cells and enhances osteoblastogenesis in MC3T3-E1 cells. 14) On the other hand, another research group showed that ACU and TOD exhibit inducible NO synthase (iNOS) protein expression-inhibitory activity in LPS-stimulated mouse macrophage cells. 15) However, detailed mechanisms underlying these results were unclear.…”

Safety and analgesic properties of ethanolic extracts of <i>Toddalia asiatica</i> (L) Lam. (<i>rutaceae</i>) used for central and peripheral pain management among the east african ethnic communities

“…Toddaculin isolated from of Toddalia asiatica (L.) has been found to inhibit the differentiation of osteoclasts via activation of the NF-κB, ERK 1/2, and p38 MAPK signaling pathways. Additionally, it induces differentiation and mineralization of osteoblasts by regulating differentiation factors ( 7 ). Ethyl acetate extract of T. asiatica leaves (TALEe) exert significant antidiabetic and antioxidant effects in STZ-induced diabetic rats ( 8 ).…”