RESEARCH ARTICLE
Peiminine regulates bone-fat balance by canonical Wnt/β-catenin pathway in an ovariectomized rat model
Hanwen Gu,
Jian Wei,
Hanwen Gu
Department of Joint Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
Jian Wei
Department of Joint Orthopedics, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou, China
Correspondence
Jian Wei, Department of Joint Orthopedics, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou 545006, China.
Email: [email protected]
Search for more papers by this authorHanwen Gu,
Jian Wei,
Hanwen Gu
Department of Joint Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
Jian Wei
Department of Joint Orthopedics, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou, China
Correspondence
Jian Wei, Department of Joint Orthopedics, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou 545006, China.
Email: [email protected]
Search for more papers by this authorAbstract
Peiminine is a major biologically active component of Fritillaria thunbergii Miq that exhibits good anticancer, antiinflammatory, and anti-osteoclast effects. However, its effects on osteoporosis (OP) remain unknown. This study aimed to explore whether Peiminine was able to regulate osteogenesis and adipogenesis in ovariectomized (OVX) rat. The effects on the differentiation of bone marrow stem cells (BMSCs), function of Wnt/β-catenin pathway, ALP activity, calcium nodule deposition, as well as adipocyte formation in vitro by Peiminine at different concentrations, were detected. The curative effects of Peiminine on the ovariectomy-induced osteoporosis model by micro-CT and bone histomorphology assays were analyzed. The promotion of osteogenic differentiation and inhibition of adipogenic differentiation by Peiminine (5–40 μg/mL) was detected and the optimum concentration was 20 μg/mL. Mechanistically, Peiminine regulated the fate of BMSCs in vitro, and activated Wnt/β-catenin signaling pathway by restraining phosphorylation of β-catenin and promoting the nuclear translocation of β-catenin. Moreover, Peiminine prevented ovariectomy-induced osteoporosis by alleviating trabecular bone loss and inhibiting adipose formation. Our data suggested that Peiminine could attenuate ovariectomy-induced osteoporosis by alleviating trabecular bone loss and inhibiting adipose formation. These encouraging discoveries could lay the foundation for Peiminine to be a promising preventive treatment strategy for skeletal diseases, such as osteoporosis.
CONFLICT OF INTEREST STATEMENT
The authors declare that there is no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ptr7780-sup-0001-FigureS1.tifimage/tif, 296.4 KB | Figure S1. The effect on proliferation of BMSCs after treatment of Peiminine (Pm). MTT assay were performed after 24, 48, and 72 h treatment of Peiminine to explore the effect on proliferation of BMSCs. The values are the means ± S.E.M., n = 5. **p < 0.01 versus control. |
| ptr7780-sup-0002-FigureS2.tifimage/tif, 19.7 MB | Figure S2. Safety evaluation of Peiminine (Pm) treatment in each rats group. (A) Representative pathological HE staining of the kidney (×400) at 8 weeks post-surgery in each treatment group. (B) Representative pathological HE staining of the liver (×200) at 8 weeks post-surgery in each treatment group. (C) Serum alanine aminotransferase (ALT) at 8 weeks post-surgery in each treatment group. (D) Serum aspartate aminotransferase (AST) at 8 weeks post-surgery in each treatment group. (E) Serum urea nitrogen (UN) at 8 weeks post-surgery in each treatment group. (F) Serum creatinine (Cr) at 8 weeks post-surgery in each treatment group. One-way ANOVA followed by Tukey's post hoc test was performed for multiple group comparisons. n = 10 per group. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Abdelrazek, H. M. A., Mahmoud, M. M. A., Tag, H. M., Greish, S. M., Eltamany, D. A., & Soliman, M. T. A. (2019). Soy Isoflavones ameliorate metabolic and immunological alterations of Ovariectomy in female Wistar rats: Antioxidant and estrogen sparing potential. Oxidative Medicine and Cellular Longevity, 2019, 5713606. https://doi.org/10.1155/2019/5713606
- Ambrosi, T. H., Scialdone, A., Graja, A., Gohlke, S., Jank, A. M., Bocian, C., & Schulz, T. J. (2017). Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell, 20(6), 771–784 e776. https://doi.org/10.1016/j.stem.2017.02.009
- Barazzoni, R., Gortan Cappellari, G., Ragni, M., & Nisoli, E. (2018). Insulin resistance in obesity: An overview of fundamental alterations. Eating and Weight Disorders, 23(2), 149–157. https://doi.org/10.1007/s40519-018-0481-6
- Black, D. M., Geiger, E. J., Eastell, R., Vittinghoff, E., Li, B. H., Ryan, D. S., & Adams, A. L. (2020). Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. The New England Journal of Medicine, 383(8), 743–753. https://doi.org/10.1056/NEJMoa1916525
- Chen, M., Han, H., Zhou, S., Wen, Y., & Chen, L. (2021). Morusin induces osteogenic differentiation of bone marrow mesenchymal stem cells by canonical Wnt/beta-catenin pathway and prevents bone loss in an ovariectomized rat model. Stem Cell Research & Therapy, 12(1), 173. https://doi.org/10.1186/s13287-021-02239-3
- Chodari, L., Dilsiz Aytemir, M., Vahedi, P., Alipour, M., Vahed, S. Z., Khatibi, S. M. H., & Eftekhari, A. (2021). Targeting mitochondrial biogenesis with polyphenol compounds. Oxidative Medicine and Cellular Longevity, 2021, 4946711. https://doi.org/10.1155/2021/4946711
- Chu, M., Sun, Z., Fan, Z., Yu, D., Mao, Y., & Guo, Y. (2021). Bi-directional regulation functions of lanthanum-substituted layered double hydroxide nanohybrid scaffolds via activating osteogenesis and inhibiting osteoclastogenesis for osteoporotic bone regeneration. Theranostics, 11(14), 6717–6734. https://doi.org/10.7150/thno.56607
- Compston, J. E., McClung, M. R., & Leslie, W. D. (2019). Osteoporosis. The Lancet, 393(10169), 364–376. https://doi.org/10.1016/s0140-6736(18)32112-3
- Fan, Y., Hanai, J. I., Le, P. T., Bi, R., Maridas, D., DeMambro, V., & Lanske, B. (2017). Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metabolism, 25(3), 661–672. https://doi.org/10.1016/j.cmet.2017.01.001
- Frey, J. L., Kim, S. P., Li, Z., Wolfgang, M. J., & Riddle, R. C. (2018). Beta-catenin directs long-chain fatty acid catabolism in the osteoblasts of male mice. Endocrinology, 159(1), 272–284. https://doi.org/10.1210/en.2017-00850
- Gong, Q., Li, Y., Ma, H., Guo, W., Kan, X., Xu, D., & Fu, S. (2018). Peiminine protects against lipopolysaccharide-induced mastitis by inhibiting the AKT/NF-kappaB, ERK1/2 and p38 signaling pathways. International Journal of Molecular Sciences, 19(9), 2637. https://doi.org/10.3390/ijms19092637
- Guo, Q., Chen, Y., Guo, L., Jiang, T., & Lin, Z. (2016). miR-23a/b regulates the balance between osteoblast and adipocyte differentiation in bone marrow mesenchymal stem cells. Bone Research, 4, 16022. https://doi.org/10.1038/boneres.2016.22
- Han, L., Wang, B., Wang, R., Gong, S., Chen, G., & Xu, W. (2019). The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor. Stem Cell Research & Therapy, 10(1), 377. https://doi.org/10.1186/s13287-019-1498-0
- Hang, K., Ye, C., Xu, J., Chen, E., Wang, C., Zhang, W., & Pan, Z. (2019). Apelin enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells partly through Wnt/beta-catenin signaling pathway. Stem Cell Research & Therapy, 10(1), 189. https://doi.org/10.1186/s13287-019-1286-x
- Hoque, J., Shih, Y. V., Zeng, Y., Newman, H., Sangaj, N., Arjunji, N., & Varghese, S. (2021). Bone targeting nanocarrier-assisted delivery of adenosine to combat osteoporotic bone loss. Biomaterials, 273, 120819. https://doi.org/10.1016/j.biomaterials.2021.120819
- Huang, J., Yin, H., Rao, S. S., Xie, P. L., Cao, X., Rao, T., & Xie, H. (2018). Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice. Theranostics, 8(9), 2435–2446. https://doi.org/10.7150/thno.22144
- Islam, M. N., Das, S. R., Emin, M. T., Wei, M., Sun, L., Westphalen, K., & Bhattacharya, J. (2012). Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature Medicine, 18(5), 759–765. https://doi.org/10.1038/nm.2736
- Kim, B. Y., Rutka, J. T., & Chan, W. C. (2010). Nanomedicine. The New England Journal of Medicine, 363(25), 2434–2443. https://doi.org/10.1056/NEJMra0912273
- Kirk, B., Zanker, J., & Duque, G. (2020). Osteosarcopenia: Epidemiology, diagnosis, and treatment-facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, 11(3), 609–618. https://doi.org/10.1002/jcsm.12567
- Li, B., He, X., Dong, Z., Xuan, K., Sun, W., Gao, L., & Jin, Y. (2020). Ionomycin ameliorates hypophosphatasia via rescuing alkaline phosphatase deficiency-mediated L-type Ca(2+) channel internalization in mesenchymal stem cells. Bone Research, 8, 19. https://doi.org/10.1038/s41413-020-0090-7
- Li, C. J., Cheng, P., Liang, M. K., Chen, Y. S., Lu, Q., Wang, J. Y., & Luo, X. H. (2015). MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. The Journal of Clinical Investigation, 125(4), 1509–1522. https://doi.org/10.1172/JCI77716
- Li, H., Wang, C., He, T., Zhao, T., Chen, Y. Y., Shen, Y. L., & Wang, L. L. (2019). Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics, 9(7), 2017–2035. https://doi.org/10.7150/thno.29400
- Li, V. S., Ng, S. S., Boersema, P. J., Low, T. Y., Karthaus, W. R., Gerlach, J. P., & Clevers, H. (2012). Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell, 149(6), 1245–1256. https://doi.org/10.1016/j.cell.2012.05.002
- Li, Y., Wang, L., Zhang, M., Huang, K., Yao, Z., Rao, P., & Xiao, J. (2020). Advanced glycation end products inhibit the osteogenic differentiation potential of adipose-derived stem cells by modulating Wnt/beta-catenin signalling pathway via DNA methylation. Cell Proliferation, 53(6), e12834. https://doi.org/10.1111/cpr.12834
- Li, Y. J., Wu, J. Y., Liu, J., Xu, W., Qiu, X., Huang, S., & Xiang, D. X. (2021). Artificial exosomes for translational nanomedicine. Journal of Nanobiotechnology, 19(1), 242. https://doi.org/10.1186/s12951-021-00986-2
- Liu, F., Yuan, Y., Bai, L., Yuan, L., Li, L., Liu, J., & Zhang, J. (2021). LRRc17 controls BMSC senescence via mitophagy and inhibits the therapeutic effect of BMSCs on ovariectomy-induced bone loss. Redox Biology, 43, 101963. https://doi.org/10.1016/j.redox.2021.101963
- Liu, Y., Wang, C., Wang, G., Sun, Y., Deng, Z., Chen, L., & Xu, J. (2019). Loureirin B suppresses RANKL-induced osteoclastogenesis and ovariectomized osteoporosis via attenuating NFATc1 and ROS activities. Theranostics, 9(16), 4648–4662. https://doi.org/10.7150/thno.35414
- Liu, Y. Q., Zhan, L. B., Liu, T., Cheng, M. C., Liu, X. Y., & Xiao, H. B. (2014). Inhibitory effect of Ecliptae herba extract and its component wedelolactone on pre-osteoclastic proliferation and differentiation. Journal of Ethnopharmacology, 157, 206–211. https://doi.org/10.1016/j.jep.2014.09.033
- Liu, Z. Z., Hong, C. G., Hu, W. B., Chen, M. L., Duan, R., Li, H. M., & Xie, H. (2020). Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3. Autophagy, 1-17, 2766–2782. https://doi.org/10.1080/15548627.2020.1839286
- Liu, Z. Z., Hong, C. G., Hu, W. B., Chen, M. L., Duan, R., Li, H. M., & Xie, H. (2021). Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3. Autophagy, 17(10), 2766–2782. https://doi.org/10.1080/15548627.2020.1839286
- Luo, Z., Zheng, B., Jiang, B., Xue, X., Xue, E., & Zhou, Y. (2019). Peiminine inhibits the IL-1beta induced inflammatory response in mouse articular chondrocytes and ameliorates murine osteoarthritis. Food & Function, 10(4), 2198–2208. https://doi.org/10.1039/c9fo00307j
- Maria, S., Samsonraj, R. M., Munmun, F., Glas, J., Silvestros, M., Kotlarczyk, M. P., & Witt-Enderby, P. A. (2018). Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: Implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. Journal of Pineal Research, 64(3), e12465. https://doi.org/10.1111/jpi.12465
- Miao, C. G., Yang, Y. Y., He, X., Li, X. F., Huang, C., Huang, Y., & Li, J. (2013). Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cellular Signalling, 25(10), 2069–2078. https://doi.org/10.1016/j.cellsig.2013.04.002
- Model, J. F. A., Lima, M. V., Ohlweiler, R., Lopes Vogt, E., Rocha, D. S., Souza, S. K., & Vinagre, A. S. (2021). Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats. Molecular and Cellular Endocrinology, 524, 111158. https://doi.org/10.1016/j.mce.2021.111158
- Oichi, T., Otsuru, S., Usami, Y., Enomoto-Iwamoto, M., & Iwamoto, M. (2020). Wnt signaling in chondroprogenitors during long bone development and growth. Bone, 137, 115368. https://doi.org/10.1016/j.bone.2020.115368
- Reed, J. T., Pareek, T., Sriramula, S., & Pabbidi, M. R. (2020). Aging influences cerebrovascular myogenic reactivity and BK channel function in a sex-specific manner. Cardiovascular Research, 116(7), 1372–1385. https://doi.org/10.1093/cvr/cvz314
- Ruan, X., Yang, L., Cui, W. X., Zhang, M. X., Li, Z. H., Liu, B., & Wang, Q. (2016). Optimization of supercritical fluid extraction of Total alkaloids, Peimisine, Peimine and Peiminine from the bulb of Fritillaria thunbergii Miq, and evaluation of antioxidant activities of the extracts. Materials (Basel), 9(7), 524. https://doi.org/10.3390/ma9070524
- Rubinfeld, B., Albert, I., Porfiri, E., Fiol, C., Munemitsu, S., & Polakis, P. (1996). Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science, 272(5264), 1023–1026. https://doi.org/10.1126/science.272.5264.1023
- Sadie-Van Gijsen, H., Crowther, N. J., Hough, F. S., & Ferris, W. F. (2013). The interrelationship between bone and fat: From cellular see-saw to endocrine reciprocity. Cellular and Molecular Life Sciences, 70(13), 2331–2349. https://doi.org/10.1007/s00018-012-1211-2
- Shim, K. S., Gu, D. R., Hwang, Y. H., Yang, H., Ryuk, J. A., & Ha, H. (2021). Water extract of Fritillariae thunbergii Bulbus inhibits RANKL-mediated Osteoclastogenesis and Ovariectomy-induced trabecular bone loss. Molecules, 27(1), 169. https://doi.org/10.3390/molecules27010169
- Song, L., Liu, M., Ono, N., Bringhurst, F. R., Kronenberg, H. M., & Guo, J. (2012). Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. Journal of Bone and Mineral Research, 27(11), 2344–2358. https://doi.org/10.1002/jbmr.1694
- Sun, X., Xie, Z., Hu, B., Zhang, B., Ma, Y., Pan, X., & Chen, Z. (2020). The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-kappab signaling. Redox Biology, 28, 101309. https://doi.org/10.1016/j.redox.2019.101309
- Takada, I., Kouzmenko, A. P., & Kato, S. (2009). Molecular switching of osteoblastogenesis versus adipogenesis: Implications for targeted therapies. Expert Opinion on Therapeutic Targets, 13(5), 593–603. https://doi.org/10.1517/14728220902915310
- Tencerova, M., & Kassem, M. (2016). The bone marrow-derived stromal cells: Commitment and regulation of Adipogenesis. Front Endocrinol (Lausanne), 7, 127. https://doi.org/10.3389/fendo.2016.00127
- Wang, Q., Chen, D., Jin, H., Ye, Z., Wang, C., Chen, K., & Xu, J. (2020). Hymenialdisine: A marine natural product that acts on both osteoblasts and osteoclasts and prevents estrogen-dependent bone loss in mice. Journal of Bone and Mineral Research, 35(8), 1582–1596. https://doi.org/10.1002/jbmr.4025
- Weivoda, M. M., Chew, C. K., Monroe, D. G., Farr, J. N., Atkinson, E. J., Geske, J. R., & Khosla, S. (2020). Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nature Communications, 11(1), 87. https://doi.org/10.1038/s41467-019-14003-6
- Weske, S., Vaidya, M., Reese, A., von Wnuck Lipinski, K., Keul, P., Bayer, J. K., & Levkau, B. (2018). Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss. Nature Medicine, 24(5), 667–678. https://doi.org/10.1038/s41591-018-0005-y
- Wu, H., Wang, Y., Li, W., Chen, H., Du, L., Liu, D., & Chen, Q. (2019). Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome. Autophagy, 15(11), 1882–1898. https://doi.org/10.1080/15548627.2019.1596482
- Yan, J., Herzog, J. W., Tsang, K., Brennan, C. A., Bower, M. A., Garrett, W. S., & Charles, J. F. (2016). Gut microbiota induce IGF-1 and promote bone formation and growth. Proceedings of the National Academy of Sciences of the United States of America, 113(47), E7554–E7563. https://doi.org/10.1073/pnas.1607235113
- Yao, Q., Yu, C., Zhang, X., Zhang, K., Guo, J., & Song, L. (2017). Wnt/β-catenin signaling in osteoblasts regulates global energy metabolism. Bone, 97, 175–183. https://doi.org/10.1016/j.bone.2017.01.028
- You, W., Fan, L., Duan, D., Tian, L., Dang, X., Wang, C., & Wang, K. (2014). Foxc2 over-expression in bone marrow mesenchymal stem cells stimulates osteogenic differentiation and inhibits adipogenic differentiation. Molecular and Cellular Biochemistry, 386(1–2), 125–134. https://doi.org/10.1007/s11010-013-1851-z
- Yu, B., Huo, L., Liu, Y., Deng, P., Szymanski, J., Li, J., & Wang, C. Y. (2018). PGC-1alpha controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell, 23(2), 193–209 e195. https://doi.org/10.1016/j.stem.2018.06.009
- Zhang, Y., Chen, C. Y., Liu, Y. W., Rao, S. S., Tan, Y. J., Qian, Y. X., & Xie, H. (2021). Neuronal induction of bone-fat imbalance through osteocyte neuropeptide Y. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 8(24), e2100808. https://doi.org/10.1002/advs.202100808
- Zhang, Z., Jia, B., Yang, H., Han, Y., Wu, Q., Dai, K., & Zheng, Y. (2021). Zn0.8Li0.1Sr-a biodegradable metal with high mechanical strength comparable to pure Ti for the treatment of osteoporotic bone fractures: In vitro and in vivo studies. Biomaterials, 275, 120905. https://doi.org/10.1016/j.biomaterials.2021.120905
- Zhu, M., Xu, W., Jiang, J., Wang, Y., Guo, Y., Yang, R., & Wang, S. (2021). Peiminine suppresses RANKL-induced Osteoclastogenesis by inhibiting the NFATc1, ERK, and NF-kappaB signaling pathways. Front Endocrinol (Lausanne), 12, 736863. https://doi.org/10.3389/fendo.2021.736863
Citing Literature
