Terpenoid From Tuber Of Dioscorea Bulbifera And Modified Analogues With Suppressing Activity Against Osteoclast Differentiation

Abstract

Osteoporosis is often found in elderly. There are many causes of osteoporosis such as life style, aging, gender. Osteoporosis is found in females rather than males, as a result of decreasing the level of estrogen in post-menopausal female. Osteoporosis is characterized by decreasing bone mass and bone tissue. Normally, bone remodeling is maintained by balance between bone formation and bone resorption. Therefore, the main cause of osteoporosis is an imbalance between osteoblasts and osteoclasts. As a result, the condition makes bone fragile and increased risk of fracture. Therefore, osteoclasts are the target of osteoporosis treatment. Nowadays, treatments of osteoporosis have several side effects. In this study, the chemical constituents of plants were investigated to potential develop for osteoporosis drug. One terpenoid isolated from tuber of Dioscorea bulbifera and 11 modified analogues of natural terpenoid were used in this study. All compounds were screened for the anti-osteoclastogenic activity murine bone-marrow-derived macrophage precursors. All tester compounds did not cytoxicity and anti-inflammatory activity in RAW 264.7. From anti-osteoclastogenic activity screening, we found that ASTP069, a modified analogue, significantly suppressed the differentiation of the tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells induced by receptor activator of nuclear factor-kB ligand (RANKL) with an IC50 of ASTP069 10.07±0.05 µM. At the transcription level, we found that ASTP069 clearly decreased the expression of nfatc1, ctsk and irf8 leading to inhibit osteoclastogenesis and osteoclast function. The effect of ASTP069 on signaling pathway was investigated. The results showed that ASTP069 decreased activation of NF-kB pathway but did not affect the activation of MAPK pathway by suppressing NF-kB p65 nuclear translocation. The results indicated that ASTP069 inhibited osteoclastogenesis by downregulation of nuclear factor of activated T cells (NFATc1) and the other osteoclast-related genes via NF-kB pathway. Therefore, the modified terpenoid from D. bulbifera has therapeutic potential for development as anti-osteoporosis drug.