Mechanistic Analysis of Eriodictyol on Bone loss
저자
발행사항
서울 : 숙명여자대학교 대학원, 2012
학위논문사항
학위논문(석사)-- 숙명여자대학교 대학원 : 제약학과 생명약학전공 2012. 2
발행연도
2012
작성언어
영어
주제어
발행국(도시)
서울
형태사항
viii, 79 p. ; 26 cm
일반주기명
지도교수: 임미정
소장기관
Thanks to growing up with science, our human life span is longer than it has been in times past, and we are going to move from an “Aging society” into an “Aged society”. That means, it appears there will be an increase in many diseases related to this situation. Among them, bone disease is increasing, especially osteoporosis. Osteoporosis comes from many causes, for example, from an imbalance of cells, hormones and vitamin D3. For a number of reasons, lower bone mineral density is deeply connected to osteo-immunology.
In this study, I focused on the bone remodeling process that is controlled by two types of cells, the osteoblast and osteoclast. The osteoblast is responsible for the synthesis of bone, and the osteoclast is responsible for bone resorption. In the bone remodeling process there is a balance between the number of ostoclast and osteoblast cells. If the rate of osteoclast is higher than osteoblast, bone mineral density (BMD) will be decreased, leading to osteoporosis. We call this process “Osteoclastogenesis”.
In osteoclastogenesis, the most important factor is RANKL which is a ligand of RANK. In this paper, I used bone marrow macrophage cells (BMMs) from the bone marrow of mice with macrophage colony stimulate factor (M-CSF). Then BMMs were treated with RANKL that differentiated them to pre-osteoclast or mature osteoclast.
Eriodictyol, which is a natural flavonoid compound, was the focused a mechanistic analysis of eriodictyol on bone loss via osteoclastogenesis. Eriodictyol(5,7,3`4`-tetrahydroxyflavanone) is extracted from rosehip or citrus fruits like lemon peel. It is also known as a bioflavonoid or vitamin P. According to other papers, bioflavonoids help to increase the work of vitamin C, which includes the synthesis of collagen, anti-inflammatory, anti-bacterial and anti-oxidant functions. From one of them, I suspected that eriodictyol is able to influence anti-oxidant functions, and so I tried to study its effects on osteoporosis.
Eriodictyol is an aglycon of eriocitrin that is consumed and absorbed by enzymes or acidic hydrolysis in the liver. Based on the study, I conducted tests to check its effects on osteoclast formation. The result was that eriodictyol inhibited osteoclast formation about 50% higer than eriodicitrin of the same concentration.
Eriodictyol (IC50=10M) dose-dependently inhibited RANKL-induced osteoclast formation and affected each stage on treatment day, especially the late stage more than early. Through RT-PCR assay, it attenuated osteoclast differentiation on the osteoclast marker gene like CTR and Cathepsin K. Eriodictyol also perfectly blocked RANKL-induced bone resorption on dentin. To check the expression strength of signals on western blotting, I detected some pathways related to osteoclastogenesis. Thus, eriodictyol suppressed RANKL-induced NFATc1, COX-2, p38 and ERK expression. Besides, eriodictyol rescued NFATc1 activation about 70% on the overexpression test.
Eriodictyol inhibited LPS-induced osteoclast formation just as RANKL- induced it. It was based on these results that I conducted an in vivo test. First of all, ICR mice were directly injected LPS on calvaria for acute inflammation. Then they were injected with eriodictyol (12.5mg/kg) with corn-oil by i.p for some days. After several days, the calvaria were extracted for TRAP stain, which is checked to determine the range of inflammation. As a result, I suspected that eriodictyol might block bone loss from LPS-induced inflammation. The other in vivo test is OVX, the goal of which is the recovery of BMD or BMC on ovariectomied mice when treated with eriodictyol. After ovariectomy, one group was orally treated by eriodictyol (12.5mg/kg), the others were treated with just a neutral solution. I then checked for any changed BMC level between the two groups. On investigation the eriodictyol treated mouse group showed a recovery of leg BMC level. Therefore these results suggest that eriodictyol regulates bone loss.
Recently it was discovered that eriodictyol is a TRPV1 receptor antagonist, which is connected with neuro-pain, like capsazepine. So I examined what is different between eriodictyol and other TRPV1 receptor antagonists. Other TRPV1 receptor antagonists worked similarly to eriodictyol in some experiments. Only eriodictyol, however, affected the RANKL-induced mature osteoclast form, which was changed from mature to pre-osteoclast. After stopping treatment with eriodictyol, the pre-osteoclast grew up mature again. Because eriodictyol does not induce apoptosis, it has a temporally limited effect on mature osteoclast.
For these reasons, I concluded that eriodictyol blocks RANKL- or LPS-induced osteoclastogenesis, and it also interrupts bone loss. I suggest that eriodictyol will be used as a therapeutic drug for osteoporosis in the future.
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