Elucidation of the action of geranylgeraniol which reciprocally regulates bone resorption and bone formation and its application to osteoporosi

Abstract

Professor Mineko Tomomura is a researcher based in the Meikai University School of Dentistry in Japan, where she is working on a research project entitled 'Elucidation of the action of geranylgeraniol which reciprocally regulates bone resorption and bone formation and its application to osteoporosis'. She explains some of the issues surrounding current treatment methods: 'Bisphosphonate and RANKL antibody, which suppress the bone resorption activity of osteoclast, are mainly used in the treatment of osteoporosis. Patients taking these treatments are prone to osteonecrosis during teeth extraction (bisphosphonate-related osteonecrosis of the jaw: BRONJ, anti-resorptive agents-related osteonecrosis of the jaw: ARONJ),' she states. 'PTH promotes bone resorption by persistent stimulation, however, it was recognised that intermittent stimulation promotes bone formation, and it was approved as the first osteoporosis treatment drug with bone formation. Unfortunately, in the treatment of PTH and bisphosphonate combination, bone formation by PTH is not effective. Therefore, it is important to search for substances that simultaneously act to suppress bone resorption and promote bone formation.' Osteoclast responsible for bone resorption and osteoblast responsible for bone formation are at the core of bone homeostasis. Various factors control the differentiation and function of osteoclast and osteoblast and exploring these mechanisms are key to shedding light on the biomodulation of vertebrates. Tomomura and the team are interested in one compound in particular; the researchers' work is exploring the potential of geranylgeraniol (GGOH), a diterpene alcohol that plays a role in several important biological processes, to be used in the treatment of osteoporosis. The idea is that GGOH prevents the inhibition of osteoclast formation and bone reabsorption. Tomomura believes GGOH could be key to developing a successful treatment. She provides an insight into this work: 'Bone diseases in which bone resorption is predominant and the high risk of fracture are associated not only postmenopausal osteoporosis, but also chronic inflammation such as rheumatoid arthritis, ageing, lifestyle diseases (diabetes, dyslipidemia) and sarcopenia. Thus, osteoporosis has come to be considered from the viewpoint of a metabolic disease of the whole body, not the problem of only bone tissue. I would like to examine the effectiveness of GGOH on these diseases,' she states. The project is funded by a KAKEN Grant-in-Aid for Scientific Research. It began in April 2016 and will run until March 2019. The researchers found in their investigations that GGOH works by suppressing TRAP activity and multi-nucleated cell formation rate, which is a marker of osteoclast differentiation by RANKL, in bone marrow-derived osteoclast precursor cells in a concentration-dependent manner. Tomomura highlights further of the team's findings: 'GGOH increased ALP activity, which is a differentiation marker of osteoblasts by vitamin C and glycerophosphate, and the amount of protein of type 1 collagen in calvarial osteoblastic cells. Furthermore, administration of GGOH to mice suppressed the LPS-induced absorption of the mouse calvaria,' she highlights. The team largely makes use of cultured cells in its research, but looking ahead, plans to study the effectiveness of GGOH using more osteoporosis model mice.