Osthole enhances the bone mass of senile osteoporosis and stimulates the expression of osteoprotegerin by activating β-catenin signaling

Jin, Zhenxiong; Liao, Xinyuan; Da, Wei-Wei; Zhao, Yongjian; Li, Xiaofeng; Tang, Dezhi

doi:10.1186/s13287-021-02228-6

Cited by 17 publications

(8 citation statements)

References 43 publications

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“…Similar results were reported by Li et al; that is, osthole inhibited osteoclast formation and partially reversed bone loss induced by 5/6 nephrectomy in mice through the upregulation of osteoprotegerin (OPG)/RANKL [103]. It was also found that osthole could stimulate the expression of OPG via the activation of β-catenin signaling pathway and enhance the bone mass of senile osteoporosis [104]. Zhang et al discovered that osthole-mediated osteogenesis was related to the activation of the cAMP/CREB signaling pathway and downstream transcription factor osterix expression [105].…”

Section: Osteogenic Activitysupporting

confidence: 85%

Osthole: an overview of its sources, biological activities, and modification development

Sun

Zhang

2021

Med Chem Res

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Osthole, also known as osthol, is a coumarin derivative found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. It can be obtained via extraction and separation from plants or total synthesis. Plenty of experiments have suggested that osthole exhibited multiple biological activities covering antitumor, anti-inflammatory, neuroprotective, osteogenic, cardiovascular protective, antimicrobial, and antiparasitic activities. In addition, there has been some research done on the optimization and modification of osthole. This article summarizes the comprehensive information regarding the sources and modification progress of osthole. It also introduces the up-to-date biological activities of osthole, which could be of great value for its use in future research.

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Section: Osteogenic Activitysupporting

confidence: 85%

Osthole: an overview of its sources, biological activities, and modification development

Sun

Zhang

2021

Med Chem Res

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“…Functionally, BMP2 has a close relationship with binding to N‐propeptide, ( 39 ) and OPG may inhibit osteoclastogenesis. ( 41,42 ) Collectively, our findings suggest that c.187T>A plays a dominant role in OI genesis, and c.175C>T may interact with this dominant site to affect bone formation.…”

Section: Discussionmentioning

confidence: 65%

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

Cao

Ren

et al. 2020

Journal of Bone and Mineral Research

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Osteogenesis imperfecta (OI) is a hereditary skeletal disorder that is mainly caused by variants in COL1A1/2. So far, no specific treatment has been developed to correct its underlying etiology. We aimed to gain a better understanding of the pathological mechanisms of OI and develop gene therapies to correct OI-causing variants. A de novel cis-double-variant c.[175C>T; 187T>A] in COL1A1 was identified from a 5-year-old OI patient by whole-exome sequencing (WES). Three peptide nucleic acids (PNAs) were designed and then transfected patient-derived fibroblasts. PNA2 affected the translational strand and induced an optimal interfering effect at 0.25μM concentration, proved by Sanger sequencing, qPCR, Western blot, and immunostaining. Additionally, induced pluripotent stem cells (iPSCs) were cultured from patient-derived fibroblasts. Clones of iPSCs with c.187T>A variant and those with both variants largely restored their osteogenic capacities after CRISPR/Cas9 gene editing, which corrected the variants. Importantly, correcting c.187T>A variant alone in CRISPR-edited iPSCs was sufficient to alleviate OI phenotypes, as indicated by increased levels of COL1A1, COL1A2, ALP mRNAs, and COL1A1 protein. Our findings suggest that c.187T>A is the dominant variant of cis-double-variant in COL1A1 that led to OI, and PNA interference and CRISPR/Cas9 gene editing may be new therapeutic tools for OI treatment.

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“…Moreover, previous studies have shown that osthole attenuates osteoclast formation by stimulating the activation of β‐catenin‐Osteoprotegerin (OPG) signalling and could be a potential drug for senile osteoporosis. 30 Furthermore, other signalling pathways have been reported to promote fracture healing in osteoporotic bone, such as epidermal growth factor receptor, 31 growth differentiation factor 11‐fat mass, and obesity‐associated protein axis. 32 Besides, oxidative stress and inflammation 33 might promote fracture healing, which requires in‐depth exploration.…”

Section: Discussionmentioning

confidence: 99%

Role of skeletal muscle satellite cells in the repair of osteoporotic fractures mediated by β‐catenin

Jin

Zhao

et al. 2022

J cachexia sarcopenia muscle

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Background Osteoporosis is a metabolic disease, and osteoporotic fracture (OPF) is one of its most serious complications. It is often ignored that the influence of the muscles surrounding the fracture on the healing of OPF. We aimed to clarify the role of skeletal muscle satellite cells (SMSCs) in promoting OPF healing by β-catenin, to improve our understanding of SMSCs, and let us explore its potential as a therapeutic target. Methods Skeletal muscles were obtained from control non-OPF or OPF patients for primary SMSCs culture (n = 3, 33% females, mean age 60 ± 15.52). Expression of SMSCs was measured. In vivo, 3-month-old female C57BL/6 mice underwent OVX surgery. Three months later, the left tibia fracture model was again performed. The control and the treatment group (n = 24, per group, female). The treatment group was treated with an agonist (osthole). Detection of SMSCs in muscles and fracture healing at 7, 14, and 28 three time points (n = 8, 8, 8, female). To further clarify the scientific hypothesis, we innovatively used Pax7-Cre ERT2/+ ;β-catenin fx/fx transgenic mice (n = 12, per group, male). Knock out β-catenin in SMSC to observe the proliferation and osteogenic differentiation of SMSCs, and OPF healing. In vitro primary cells of SMSCs from 3-month-old litter-negative β-catenin fx/fx transgenic mice. After adenovirus-CRE transfection, the myogenic and osteogenic differentiation of SMSC was observed. Results We find that human SMSCs reduced proliferation and osteogenic differentiation in patients with OPF (À38.63%, P < 0.05). And through animal experiments, it was found that activation of β-catenin promoted the proliferation and osteogenic differentiation of SMSC at the fracture site, thereby accelerating the healing of the fracture site (189.47%, P < 0.05). To prove this point of view, in the in vivo Pax7-Cre ERT2/+ ;β-catenin fx/fx transgenic mouse experiment, we innovatively found that knocking out β-catenin in SMSC will cause a decrease in bone mass and bone microstructure, and accompanied by delayed fracture healing (À35.04%, P < 0.001). At the same time, through in vitro SMSC culture experiments, it was found that their myogenic (À66.89%, P < 0.01) and osteogenic differentiation (À16.5%, P < 0.05) ability decreased. Conclusions These results provide the first practical evidence for a direct contribution of SMSCs to promote the healing of OPF with important clinical implications as it may help in the treatment of delayed healing and non-union of OPFs, and mobilization of autologous stem cell therapy in orthopaedic applications.

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Osthole enhances the bone mass of senile osteoporosis and stimulates the expression of osteoprotegerin by activating β-catenin signaling

Cited by 17 publications

References 43 publications

Osthole: an overview of its sources, biological activities, and modification development

Osthole: an overview of its sources, biological activities, and modification development

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

Role of skeletal muscle satellite cells in the repair of osteoporotic fractures mediated by β‐catenin

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