Research progress of phytoestrogen in prevention and treatment of periodontitis

Periodontitis is one of the most common chronic infectious diseases in the oral cavity Alveolar bone resorption is an important clinical feature Studies have shown that the disorder of estrogen metabolism is closely related to the occurrence of periodontitis The prevalence of periodontitis increased with age When women reach perimenopause (40-50 years old), the level of estrogen in the body drops significantly Estrogen can act on osteoclasts through cell receptor pathway, inhibit osteoclast differentiation and cause the decrease of tumor necrosis factor - α, receptor activator for nuclear factor - κ B ligand, RANKL / osteoprotegerin (OPG) and other cytokines, so as to alleviate alveolar bone absorption In addition, estrogen can slow down the progression of periodontitis by regulating the production of chemokines by periodontal ligament cells Therefore, the progressive decrease of estrogen level can lead to the decrease of alveolar bone quality and the increase of periodontitis susceptibility Estrogen replacement therapy can improve periodontal inflammation and alveolar bone absorption in perimenopausal women, and has the potential to prevent and treat periodontitis However, estrogen replacement therapy can also induce gene mutation and cell carcinogenesis, and increase the risk of breast cancer, endometrial cancer and other diseases Therefore, to avoid adverse reactions has become an urgent problem to be solved in the process of estrogen replacement therapy, and the search for more safe drugs to replace estrogen has been concerned by the medical community In recent years, more and more researches have turned to phytoestrogens, which are expected to provide new ideas for the prevention and treatment of periodontitis and other diseases 1 Phytoestrogens 1.1 phytoestrogens are a kind of non steroidal compounds that exist naturally in plants They are similar to steroids in chemical structure and can produce estrogen like effects It can prevent and treat metabolic diseases, cardiovascular diseases, malignant tumors, menopausal symptoms, osteoporosis, atherosclerosis and nervous system degeneration 1.2 according to the chemical structure, phytoestrogens are mainly divided into isoflavones, coumarins, lignans, etc Isoflavones are almost only found in legumes, and soybean is the most abundant source Soybean isoflavones can be divided into many sub categories, such as genistein, daidzein, glycitein, puerarin and so on Lignans are found mainly in all grains, fruits and vegetables Coumarins are the most abundant in the buds of clover and alfalfa In addition to the above three types, phytoestrogens include flavonoids, stilbenes, quinones, sterols and mycoestrogens 2 Phytoestrogens and periodontitis phytoestrogens are natural and high-quality estrogen analogues, which can regulate the secretion and metabolism of endogenous estrogens by binding with estrogen receptor (ER) In recent years, studies have shown that phytoestrogens have a series of estrogen like properties, such as promoting osteogenesis, delaying bone absorption and inhibiting immune inflammatory response These estrogen like effects may play an important role in the regulation of alveolar bone metabolism, the immune inflammatory response of periodontal tissues and the alleviation of periodontal tissue damage, thus providing the possibility for exogenous phytoestrogens to prevent and treat periodontitis 2.1 phytoestrogen and alveolar bone metabolism alveolar bone is an important part of periodontal tissue, alveolar bone absorption is the main pathological change of periodontitis, so promoting alveolar bone repair and reconstruction is the key to periodontitis treatment The level of estrogen in postmenopausal women is decreasing, and bone resorption is higher than that in men of the same age Osteoporosis and even fracture are easy to occur The decrease of bone quality is not only in the long bone, but also in the jaw Animal experiments showed that estrogen deficiency significantly increased alveolar bone absorption induced by ligation, decreased alveolar crest height (ACh) and aggravated the course of periodontitis in rats after ovariectomy Exogenous estrogen can not only enhance the differentiation of mesenchymal stem cells, promote the proliferation and differentiation of osteoblasts, but also inhibit the differentiation of osteoclasts and induce osteoclast apoptosis Phytoestrogens have similar effects as natural estrogen substitutes 2.1.1 phytoestrogens and osteoblasts such as Setchell have been found that genistein and daidzein, the main components of soybean isoflavone, can combine with Er on the surface of osteoblasts to promote osteoblasts proliferation, differentiation and osteogenesis through a series of signal transduction mechanisms Genistein can induce Er α gene expression through mitogen activated protein kinase (MAPK) / nuclear factor kappa B (NF - κ b) / activator protein 1 (AP-1) signal pathway, thus stimulating bone morphogenetic protein (BMP Expression of protein, BMP-6, collagen I (Col I), osteocalcin (OCN) and other related genes and mineralization of osteoblasts The differentiation and maturation of osteoblasts are regulated by a complex network of proteins, including BMP-6, col Ⅰ and OCN BMP-6 and col Ⅰ are involved in the differentiation and mineralization of extracellular matrix of osteoblasts Col Ⅰ is helpful for the adhesion and differentiation of osteoblasts Therefore, genistein can affect bone metabolism by regulating the expression of bone formation related genes and proteins Daidzein promotes the proliferation and differentiation of osteoblasts by activating the BMP-2/Smads signaling pathway, enhancing the viability of osteoblasts, OCN synthesis and BMP-2 levels, as well as the expression of some osteoblast differentiation marker genes, such as ALP, Smad1, Runx2, Osx and Col Ⅰ Daidzein can also enhance the expression of key osteogenic genes (Runx2, c-fos, SPARC, Dlx5, SPP1, COL1A1, IGF1, SOST and DMP1) in human bone marrow derived mesenchymal stem cells Setchell et al Showed that equol produced by intestinal bacteria metabolizing daidzein had better estrogen activity Estriol can promote the proliferation and differentiation of rat osteoblasts by activating Er, and up regulate the expression of related genes Osthole and Psoralen in coumarins can significantly enhance the differentiation of rat calvarial osteoblasts by activating BMP and other signaling pathways Lignans can induce the proliferation and differentiation of osteoblasts in vitro and reduce the expression of RANKL Quercetin in flavonoids can also stimulate the differentiation of osteoblasts, while baicalin can promote the differentiation and mineralization of osteoblasts by activating Wnt / β - catenin signaling pathway In addition, puerarin can induce the proliferation of human bone marrow mesenchymal stem cells and osteoblasts differentiation, so as to induce bone growth, but its effect on breast epithelium and uterus is far less than that of estrogen The above results show that different kinds of phytoestrogens can regulate osteoblasts through different signaling pathways, such as BMP signaling pathway, Wnt / β - catenin signaling pathway, so as to play a role in promoting osteoblasts proliferation, differentiation and mineralization It is suggested that the osteogenic mechanism of phytoestrogens is complex and may involve multiple signal regulatory networks, which will lay a foundation for further study In addition, a small number of phytoestrogens can not only affect osteoblasts, but also affect the expression of related genes in BMSCs, so as to promote their osteogenic differentiation It is suggested that phytoestrogens have the potential to regulate alveolar bone metabolism and promote osteogenesis 2.1.2 phytoestrogen and osteoclast periodontitis is a kind of pathological bone disease, which is characterized by pathological bone absorption, in which osteoclast plays a key role and inhibits osteoclast proliferation and differentiation, which is considered to be the key to prevent and treat periodontitis bone absorption Phytoestrogens can not only play a role in osteoblasts, but also inhibit bone resorption by inhibiting the growth, differentiation or apoptosis of osteoclasts Park et al Showed that soybean extract can stimulate osteoblasts to secrete OPG and reduce the level of RANKL, thus inhibiting the differentiation of osteoclasts induced by RANKL Genistein, daidzein and coumarin in soybean isoflavone can directly inhibit TNF - α induced osteoclast formation and bone resorption In the co culture system of mouse bone marrow cells and primary osteoblasts in vitro, one metabolite of daidzein, estriol, inhibited osteoclast formation in a dose-dependent manner, while the other metabolite, o-demethylolenin (ODMA), slightly inhibited osteoclast formation, and the effect was not dose-dependent Daidzein can inhibit osteoclast formation and induce osteoclast apoptosis in vitro, and the effect is similar to genistein Formononetin inhibits osteoclast differentiation by inhibiting RANKL induced NF - κ B, c-fos, a key transcription factor in osteoclast formation, and NFATc 1 Puerarin can significantly inhibit the differentiation of RAW264.7 cells into osteoclasts induced by lipopolysaccharide, and down regulate the expression of tumor necrosis factor receptor associated protein by inhibiting the secretion of TNF - α, IL-1 β and prostaglandin (PG) E2 Expression of osteoclast related genes of protein, trap, cathepsin (CTS) K and matrix metalloproteinases (MMP) - 9 Schizandrin a in lignans can inhibit the activation of RANKL induced MAPK signaling pathway, including Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) 1 / 2 phosphorylation, thus inhibiting the formation and function of osteoclasts Arctigenin, another lignan, inhibits osteoclast differentiation and function by inhibiting the formation of NFATc1 Triptolide in terpenoids inhibits osteoclast formation and bone resorption by inhibiting RANKL induced NF - κ B activity in bone marrow-derived macrophages (bmms) In addition, resveratrol in stilbenes and quercetin in flavonoids can down regulate the differentiation of osteoclast precursor cells into osteoclasts, which indicates that phytoestrogen has the effect of inhibiting osteoclast formation and differentiation These results suggest that most phytoestrogens inhibit osteoclast differentiation by reducing the level of RANKL Of course, TNF - α and other osteoclast activating factors are also important By inhibiting the formation and function of osteoclasts and down regulating the osteoclast differentiation of osteoclast precursor cells, phytoestrogens are expected to become an auxiliary treatment of periodontitis 2.2 phytoestrogen and periodontal immune inflammatory response periodontitis is a chronic inflammatory disease caused by the dynamic imbalance between bacterial invasion and host defense In the process of periodontitis occurrence and development, the body resists bacterial invasion through immune inflammatory reaction, and excessive immune inflammatory reaction is an important reason for periodontal tissue damage Lipopolysaccharide is the weight of cell wall of gram negative bacteria