Genistein Improves Bone Healing via Triggering Estrogen Receptor Alpha-Mediated Expressions of Osteogenesis-Associated Genes and Consequent Maturation of Osteoblasts

Wu, Gong; Tai, Ying Hsuan; Cherng, Yih-Giun; Chang, Chuen Chau; Liu, Shing‐Hwa; Chen, Ruei Ming

doi:10.1021/acs.jafc.0c02830

Cited by 26 publications

(23 citation statements)

References 57 publications

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“…However, recent studies on long bones have shown that chondrocytes can be directly transformed into bone cells (Jing et al, 2015). A large number of studies have shown that the combined effect of estrogen and ER can promote the transformation of a variety of cells, including chondrocytes, to bone formation (Gao et al, 2015;Jing et al, 2015;Shi et al, 2017;Wu et al, 2020). In the present study, we found that high concentrations of 17β- The Wnt/β-catenin pathway is a key pathway involved in chondrocyte maturation and cartilage development in longitudinal bone growth (Kinsley et al, 2015;Yuan et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that exhaustion of the growth plate chondrocyte proliferation capacity or premature osteogenic transformation and estrogen‐promoted growth plate aging will lead to epiphyseal fusion (Shim, 2015; Weise et al, 2001). A large number of studies have shown that the combination of high‐dose estrogen and ER promotes the transformation of a variety of cells, including chondrocytes, to bone formation (Gao et al, 2015; Jing et al, 2015; Shi et al, 2017; Wu et al, 2020). Low‐dose estrogen is important for pubertal growth spurts in early puberty, and the high‐dose estrogen in growth plate cartilage is essential for the fusion of the epiphyzes in late puberty (Börjesson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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ERα/β/DMP1 axis promotes trans‐differentiation of chondrocytes to bone cells through GSK‐3β/β‐catenin pathway

Xue

Fan

et al. 2022

Journal of Anatomy

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Estrogen‐induced premature closing of the growth plate in the long bones is a major cause of short stature after premature puberty. Recent studies have found that chondrocytes can directly trans‐differentiate into osteoblasts in the process of endochondral bone formation, which indicates that cartilage formation and osteogenesis may be a continuous biological process. However, whether estrogen promotes the direct trans‐differentiation of chondrocytes into osteoblasts remains largely unknown. Chondrocytes were treated with different concentrations of 17β‐estradiol, and Alizarin Red staining and alkaline phosphatase activity assay were used to detected osteogenesis. Specific short hairpin RNA and tamoxifen were used to block the estrogen receptor (ER) pathway and osteogenic marker genes and downstream gene expression were detected using real‐time quantitative polymerase chain reaction, western blot, and immunohistochemistry staining. The findings showed that 17β‐estradiol promoted the chondrocyte osteogenesis in vitro, even at high concentrations. In addition, blocking of the ERα/β pathway inhibited the trans‐differentiation of chondrocytes into osteogenic cells. Furthermore, we found that dentin matrix protein 1 (DMP1), which is a direct downstream molecular of ER, was involved in 17β‐estradiol/ER pathway‐regulated osteogenesis. As well, glycogen synthase kinase‐3 beta (GSK‐3β)/β‐catenin signal pathway also participates in ERα/β/DMP1‐regulated chondrocyte osteogenesis. The GSK‐3β/β‐catenin signal pathway was involved in ERα/β/DMP1‐regulated chondrocyte osteogenesis. These findings suggest that ER/DMP1/GSK‐3β/β‐catenin plays a vital role in estrogen regulation of chondrocyte osteogenesis and provide a therapeutic target for short stature caused by epiphyseal fusion.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ERα/β/DMP1 axis promotes trans‐differentiation of chondrocytes to bone cells through GSK‐3β/β‐catenin pathway

Xue

Fan

et al. 2022

Journal of Anatomy

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“…Increasing osteocalcin expression and promotes osteoblastogenesis through the NOS pathways. Genistein accelerates osteoblast maturation by stimulating ERα‐mediated bone osteogenesis gene expression (Wu et al., 2020). Genistein and silicon have synergistic effects on preventing bone loss in rats (Chen, Zheng, et al., 2019).…”

Section: Therapeutic Effects Of Genisteinmentioning

confidence: 99%

Cellular and molecular mechanisms of genistein in prevention and treatment of diseases: An overview

Nazari-Khanamiri

Ghasemnejad‐Berenji

2021

J Food Biochem

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Genistein is the simplest secondary metabolite in soybeans and belongs to a group of compounds called isoflavones. It is a phytoestrogen and it makes up more than 60% of soy isoflavones. Studies have shown the anti‐inflammatory, anti‐apoptotic, and anti‐angiogenic effects of genistein in addition to its modulatory effects on steroidal hormone receptors. In this review, we discuss the pharmacologic and therapeutic effects of genistein on various diseases. Practical applications In this review, we have discussed the therapeutic effects of genistein as the main constituent of soybeans on health conditions. Its antioxidant, anti‐inflammatory, anti‐apoptotic and, anti‐angiogenic effects need more attention. The pharmacological properties of genistein make this natural isoflavone a potential treatment for various diseases such as postmenopausal symptoms, cancer, bone, brain, and heart diseases. Special emphasis should be given to it, resulting in using it in clinical as a safe, potent, and bioactive molecule.

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“…As estrogen analogs, phytoestrogen family members have been proved the potential of promoting osteoporotic fracture healing. For example, psoralen and equol were proved to promote OVX animal fracture healing in the pre-clinical studies [ 17 , 18 , 19 ]. Genistein was also found to improve bone fracture healing by activating ERα signaling pathways and osteoblast maturation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…For example, psoralen and equol were proved to promote OVX animal fracture healing in the pre-clinical studies [ 17 , 18 , 19 ]. Genistein was also found to improve bone fracture healing by activating ERα signaling pathways and osteoblast maturation [ 17 ]. Here we hypothesize that sesamin, a phytoestrogen, could promote osteoporotic fracture healing by activating the ERα signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Sesamin Promotes Osteoporotic Fracture Healing by Activating Chondrogenesis and Angiogenesis Pathways

Yang

Wang

et al. 2022

Nutrients

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Osteoporotic fracture has been regarded as one of the most common bone disorders in the aging society. The natural herb-derived small molecules were revealed as potential treatment approaches for osteoporotic fracture healing. Sesamin is a member of lignan family, which possesses estrogenic activity and plays a significant role in modulating bone homeostasis. Our previous study reported the promoting effect of sesamin on postmenopausal osteoporosis treatment. However, the role of sesamin in osteoporotic fracture healing has not been well studied yet. In this study, we further investigated the putative treatment effect of sesamin on osteoporotic fracture healing. Our study indicated that sesamin could activate bone morphogenetic protein 2 (BMP2) signaling pathway and further promotes in vitro chondrogenesis and angiogenesis activities. This promoting effect was abolished by the treatment of ERα inhibitor. In the osteoporotic bone fracture model, we demonstrated that sesamin markedly improves the callus formation and increases the cartilaginous area at the early-stage, as well as narrowing the fracture gap, and expands callus volume at the late-stage fracture healing site of the OVX mice femur. Furthermore, the angiogenesis at the osteoporotic fracture site was also significantly improved by sesamin treatment. In conclusion, our research illustrated the therapeutic potential and underlying regulation mechanisms of sesamin on osteoporotic fracture healing. Our studies shed light on developing herb-derived bioactive compounds as novel drugs for the treatment of osteoporotic fracture healing, especially for postmenopausal women with low estrogen level.

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Genistein Improves Bone Healing via Triggering Estrogen Receptor Alpha-Mediated Expressions of Osteogenesis-Associated Genes and Consequent Maturation of Osteoblasts

Cited by 26 publications

References 57 publications

ERα/β/DMP1 axis promotes trans‐differentiation of chondrocytes to bone cells through GSK‐3β/β‐catenin pathway

ERα/β/DMP1 axis promotes trans‐differentiation of chondrocytes to bone cells through GSK‐3β/β‐catenin pathway

Cellular and molecular mechanisms of genistein in prevention and treatment of diseases: An overview

Sesamin Promotes Osteoporotic Fracture Healing by Activating Chondrogenesis and Angiogenesis Pathways

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