Exploring the Therapeutic Potential of Isoorientin in the Treatment of Osteoporosis: a Study Using Network Pharmacology and Experimental Validation

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2024 Feb 20

PMID 38378457

Authors

Bo Zhang

Zechao Qu

Hua Hui

Baorong He

Dong Wang

Yong Zhang

Yiwei Zhao

Jingjun Zhang

Liang Yan

Affiliations

Soon will be listed here.

Abstract

Background: Isoorientin (ISO) is a glycosylated flavonoid with antitumor, anti-inflammatory, and antioxidant properties. However, its effects on bone metabolism remain largely unknown.

Methods: In this study, we aimed to investigate the effects of ISO on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation in vitro and bone loss in post-ovariectomy (OVX) rats, as well as to elucidate the underlying mechanism. First, network pharmacology analysis indicated that MAPK1 and AKT1 may be potential therapeutic targets of ISO and that ISO has potential regulatory effects on the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways, as well as oxidative stress. ISO was added to RAW264.7 cells stimulated by RANKL, and its effects on osteoclast differentiation were evaluated using tartrate-resistant acid phosphatase (TRAP) staining, TRAP activity measurement, and F-actin ring analysis. Reactive oxygen species (ROS) production in osteoclasts was detected using a ROS assay kit. The effects of ISO on RANKL-triggered molecular cascade response were further investigated by Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence staining. In addition, the therapeutic effects of ISO were evaluated in vivo.

Results: ISO inhibited osteoclastogenesis in a time- and concentration-dependent manner. Mechanistically, ISO downregulated the expression of the main transcription factor for osteoclast differentiation by inhibiting MAPK and PI3K/AKT1 signaling pathways. Moreover, ISO exhibited protective effects in OVX-induced bone loss rats. This was consistent with the results derived from network pharmacology.

Conclusion: Our findings suggest a potential therapeutic utility of ISO in the management of osteoclast-associated bone diseases, including osteoporosis.

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References

Qu Z, Zhang B, Kong L, Gong Y, Feng M, Gao X . Receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis signaling pathway and related therapeutic natural compounds. Front Pharmacol. 2022; 13:1043975. PMC: 9683337. DOI: 10.3389/fphar.2022.1043975. View

Takayanagi H . Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007; 7(4):292-304. DOI: 10.1038/nri2062. View

Qu Z, An H, Feng M, Huang W, Wang D, Zhang Z . Urolithin B suppresses osteoclastogenesis via inhibiting RANKL-induced signalling pathways and attenuating ROS activities. J Cell Mol Med. 2022; 26(16):4428-4439. PMC: 9357644. DOI: 10.1111/jcmm.17467. View

Hopkins A . Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008; 4(11):682-90. DOI: 10.1038/nchembio.118. View

Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T . Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS One. 2007; 2(10):e1058. PMC: 2020440. DOI: 10.1371/journal.pone.0001058. View

Li S, Liu H, Lin Z, Li Z, Chen Y, Chen B . Isoorientin attenuates doxorubicin-induced cardiac injury via the activation of MAPK, Akt, and Caspase-dependent signaling pathways. Phytomedicine. 2022; 101:154105. DOI: 10.1016/j.phymed.2022.154105. View

Liu Y, Wang C, Wang G, Sun Y, Deng Z, Chen L . Loureirin B suppresses RANKL-induced osteoclastogenesis and ovariectomized osteoporosis via attenuating NFATc1 and ROS activities. Theranostics. 2019; 9(16):4648-4662. PMC: 6643439. DOI: 10.7150/thno.35414. View

Wang X, Wang Z, Zheng J, Li S . TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med. 2021; 19(1):1-11. DOI: 10.1016/S1875-5364(21)60001-8. View

Yuan L, Wu Y, Ren X, Liu Q, Wang J, Liu X . Isoorientin attenuates lipopolysaccharide-induced pro-inflammatory responses through down-regulation of ROS-related MAPK/NF-κB signaling pathway in BV-2 microglia. Mol Cell Biochem. 2013; 386(1-2):153-65. DOI: 10.1007/s11010-013-1854-9. View

10.

Vandoorne K, Magland J, Plaks V, Sharir A, Zelzer E, Wehrli F . Bone vascularization and trabecular bone formation are mediated by PKB alpha/Akt1 in a gene-dosage-dependent manner: in vivo and ex vivo MRI. Magn Reson Med. 2010; 64(1):54-64. PMC: 3558735. DOI: 10.1002/mrm.22395. View

11.

Fremin C, Saba-El-Leil M, Levesque K, Ang S, Meloche S . Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development. Cell Rep. 2015; 12(6):913-21. DOI: 10.1016/j.celrep.2015.07.011. View

12.

Yao H, Chen Y, Shi P, Hu J, Li S, Huang L . Screening and quantitative analysis of antioxidants in the fruits of Livistona chinensis R. Br using HPLC-DAD-ESI/MS coupled with pre-column DPPH assay. Food Chem. 2012; 135(4):2802-7. DOI: 10.1016/j.foodchem.2012.07.076. View

13.

Kitaura H, Marahleh A, Ohori F, Noguchi T, Shen W, Qi J . Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption. Int J Mol Sci. 2020; 21(14). PMC: 7404053. DOI: 10.3390/ijms21145169. View

14.

Ziqubu K, Dludla P, Joubert E, Muller C, Louw J, Tiano L . Isoorientin: A dietary flavone with the potential to ameliorate diverse metabolic complications. Pharmacol Res. 2020; 158:104867. DOI: 10.1016/j.phrs.2020.104867. View

15.

Zhu C, Shen S, Zhang S, Huang M, Zhang L, Chen X . Autophagy in Bone Remodeling: A Regulator of Oxidative Stress. Front Endocrinol (Lausanne). 2022; 13:898634. PMC: 9279723. DOI: 10.3389/fendo.2022.898634. View

16.

Tang Y, Mo Y, Xin D, Xiong Z, Zeng L, Luo G . Regulation of osteoblast autophagy based on PI3K/AKT/mTOR signaling pathway study on the effect of β-ecdysterone on fracture healing. J Orthop Surg Res. 2021; 16(1):719. PMC: 8684673. DOI: 10.1186/s13018-021-02862-z. View

17.

Agidigbi T, Kim C . Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases. Int J Mol Sci. 2019; 20(14). PMC: 6678498. DOI: 10.3390/ijms20143576. View

18.

Han J, Yang K, An J, Jiang N, Fu S, Tang X . The Role of NRF2 in Bone Metabolism - Friend or Foe?. Front Endocrinol (Lausanne). 2022; 13:813057. PMC: 8906930. DOI: 10.3389/fendo.2022.813057. View

19.

Yang K, Cao F, Xue Y, Tao L, Zhu Y . Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis. Front Physiol. 2022; 13:840293. PMC: 8927967. DOI: 10.3389/fphys.2022.840293. View

20.

Motta M, Pannone L, Pantaleoni F, Bocchinfuso G, Radio F, Cecchetti S . Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum. Am J Hum Genet. 2020; 107(3):499-513. PMC: 7477014. DOI: 10.1016/j.ajhg.2020.06.018. View