Antiosteoporosis and bone protective effect of alpinumisoflavone in steroid-induced osteoporosis rats via alteration of apoptosis, inflammatory and RANK/RANKL/OPG signaling pathway

Abstract

Objective: To estimate the bone protective effect of alpinumisoflavone, a natural prenylated isoflavonoid, against glucocorticoid-induced osteoporosis in rats. Methods: Male Wistar rats received intramuscular administration of dexamethasone (4 mg/mL) at a dose level of 7 mg/kg for 5 weeks, and then alpinumisoflavone (5, 10, and 15 mg/kg) and alendronate (2 mg/kg) from 2 weeks. The body weight and organ weight (femoral, vagina, and uterus) were estimated. MicroCT analysis, bone turnover markers, bone parameters, oxidative stress parameters, and inflammatory cytokines were estimated. mRNA expressions of related genes were also estimated. Results: Alpinumisoflavone remarkably boosted body weight and organ weight (ureters and vagina), improved microCT analysis parameters, and boosted levels of bone markers. Besides, alpinumisoflavone considerably (P<0.001) restored the level of bone turnover markers and oxidative stress parameters, remarkably suppressed the level of cytokines such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and increased transforming growth factor-β and insulin-like growth factor. It also significantly restored the osteoprotegerin (OPG, RANKL, and OPG/RANKL ratio) levels and the mRNA expression of Caspase (3, 6, 7, 9), BMPs, OPN, ALP, RUNX2, and OCN. Conclusions: The current result suggests the bone protective effect of alpinumisoflavone against glucocorticoid-induced osteoporosis in rats.

Keywords

Osteoporosis / Alpinumisoflavone / Bone parameters / Inflammation / Oxidative stress

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

The authors received no extramural funding for the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

JL performed the experimental study. JLQ and GWZ interpreted the experimental data. XBJ designed the experimental study. All the authors equally contributed to proof reading.

References

[1] Ensrud KE, Crandall CJ. Osteoporosis. Ann Intern Med 2024; 177(1): ITC1-ITC16.

[2] Wang H, Yang L, Chao J. Antiosteoporosis and bone protective effect of dieckol against glucocorticoid-induced osteoporosis in rats. Front Endocrinol (Lausanne) 2022; 13: 932488.

[3] Chakrabarti K, Joseph McCune W. Glucocorticoid-induced osteoporosis in premenopausal women: Management for the rheumatologist. Curr Opin Rheumatol 2023; 35(3): 161-169.

[4] Laurent MR, Goemaere S, Verroken C, Bergmann P, Body JJ, Bruyère O. Prevention and treatment of glucocorticoid-induced osteoporosis in adults: Consensus recommendations from the belgian bone club. Front Endocrinol 2022; 13: 908727.

[5] Liang H, Zhao J, Tian T. Pharmacological interventions for glucocorticoid-induced osteoporosis: An umbrella review. Horm Metab Res 2023; 55(8): 511-519.

[6] Zhang L, Li X, Ying T, Wang T, Fu F. The use of herbal medicines for the prevention of glucocorticoid-induced osteoporosis. Front Endocrinol 2021; 12: 744647.

[7] Adami G, Saag KG. Glucocorticoid-induced osteoporosis update. Curr Opin Rheumatol 2019; 31: 388-393.

[8] Lane NE. Glucocorticoid-induced osteoporosis: New insights into the pathophysiology and treatments. Curr Osteoporos Rep 2019; 17(1): 1-7.

[9] Castrén E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis 2017; 97: 119-126.

[10] Alattar R, Abdel Alim AA, Abdelmetal S, Abdel Aziz S. Corticosteroid-induced osteoporosis and osteonecrosis: The role of oxidative stress. Zagazig Vet J 2020; 48(1): 1-11.

[11] Kamaruzzaman M, Thanu A, Yusof M, Soelaiman I, Ramli E. Kelulut honey ameliorates glucocorticoid induced osteoporosis via its antioxidant activity in rats. Asian Pac J Trop Biomed 2019; 9(12): 493-500.

[12] Xia C, Dong X, Li H, Cao M, Sun D, He S. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J (Engl) 2022; 135(5): 584-590.

[13] Sun X, Gan L, Li N, Sun S, Li N. Tabersonine ameliorates osteoblast apoptosis in rats with dexamethasone-induced osteoporosis by regulating the Nrf2/ROS/Bax signalling pathway. AMB Express 2020; 10: 165.

[14] Ma Q. Role of Nrf2 in oxidative stress and toxicity. Ann Rev Pharmacol Toxicol 2013; 53: 401-426.

[15] Shi XM, Chutkan N, Hamrick MarkW, Isales CM. Mechanism of glucocorticoid-induced osteoporosis: An update. In: Qian XX (ed.) Glucocorticoids - New recognition of our familiar friend. IntechOpen; 2012, p. 7-16.

[16] Komori T. Glucocorticoid signaling and bone biology. Horm Metab Res 2016; 48(11): 755-763.

[17] Hachemi Y, Rapp AE, Picke AK, Weidinger G, Ignatius A, Tuckermann J. Molecular mechanisms of glucocorticoids on skeleton and bone regeneration after fracture. J Mol Endocrinol 2018; 61: R75-R90.

[18] Reeves PG, Nielsen FH, Fahey GC. AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 1993; 123(11): 1939-1951.

[19] Tolba MF, El-Serafi AT, Omar HA. Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals. Toxicol Appl Pharmacol 2017; 324: 26-35.

[20] Xavier A, Toumi H, Lespessailles E. Animal model for glucocorticoid induced osteoporosis: A systematic review from 2011 to 2021. Int J Mol Sci 2022; 23(1): 377.

[21] Cho SK, Sung YK. Update on glucocorticoid induced osteoporosis. Endocrinol Metab 2021; 36: 536-543.

[22] Compston J. Glucocorticoid-induced osteoporosis: An update. Endocrine 2018; 61: 7-16.

[23] Feng M, Zhang R, Gong F, Yang P, Fan L, Ni J. Protective effects of necrostatin-1 on glucocorticoid-induced osteoporosis in rats. J Steroid Biochem Mol Biol 2014; 144(PB): 455-462.

[24] Coin A, Sergi G, Benincà P, Lupoli L, Cinti G, Ferrara L. Bone mineral density and body composition in underweight and normal elderly subjects. Osteoporos Int 2000; 11(12): 1043-1050.

[25] Mo H, Zhang N, Li H, Li F, Pu R. Beneficial effects of Cuscuta chinensis extract on glucocorticoid-induced osteoporosis through modulation of RANKL/OPG signals. Brazilian J Med Biol Res 2019; 52(12): e8754.

[26] Zhang ZF, Min JK, Wang D, Zhong JM. Pinoresinol diglucoside exhibits protective effect on dexamethasone-induced osteoporosis in rats. Trop J Pharm Res 2016; 15(11): 2451-2457.

[27] Gu G, Hentunen TA, Nars M, Härkönen PL, Väänänen HK. Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis 2005; 10(3): 583-595.

[28] Utaminingtyas NI, Ma’arif B, Megawati DS, Atmaja RRD. Activity of 70% ethanol extract of Chrysophyllum cainito in increasing vertebrae trabecular bone density in female mice. Maj Obat Tradis 2018; 23(3): 119.

[29] Kim Y, Brodt MD, Tang SY, Silva MJ. MicroCT for scanning and analysis of mouse bones. In: Walker JM (ed.) Methods in molecular biology. Springer; 2021, p. 169-198.

[30] Qiu Y, Tang C, Serrano-Sosa M, Hu J, Zhu J, Tang G. Bone microarchitectural parameters can detect oxytocin induced changes prior to bone density on mitigating bone deterioration in rabbit osteoporosis model using micro-CT. BMC Musculoskelet Disord 2019; 20(1): 560.

[31] Taylor AD, Saag KG. Anabolics in the management of glucocorticoid-induced osteoporosis: An evidence-based review of long-term safety, efficacy and place in therapy. Core Evid 2019; 14: 41-50.

[32] Hozayen WG, El-Desouky MA, Soliman HA, Ahmed RR, Khaliefa AK. Antiosteoporotic effect of Petroselinum crispum, Ocimum basilicum and Cichorium intybus L. in glucocorticoid-induced osteoporosis in rats. BMC Complement Altern Med 2016; 16(1): 165.

[33] Zhao J, Li Y, Zhang H, Shi D, Li Q, Meng Y. Preventative effects of metformin on glucocorticoid-induced osteoporosis in rats. J Bone Miner Metab 2019; 37(5): 805-814.

[34] Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev 1996; 17: 333-368.

[35] Yang L, Zhang B, Liu J, Dong Y, Li Y, Li N, et al. Protective effect of acteoside on ovariectomy-induced bone loss in mice. Int J Mol Sci 2019; 20(12): 2974.

[36] Cho CW, Park YS, Yan XT, Kim HJ, Kim YH, Kim KT. Quantitation of phenolic compounds related to antioxidant and antiosteoporosis activities in ripe and unripe maesil (Prunus mume). J Food Qual 2020; 2020: 1-13.

[37] Hirao T, Kim BG, Habuchi H, Kawaguchi K, Nakahari T, Marunaka Y. Transforming growth factor-β1 and bone morphogenetic protein-2 inhibit differentiation into mature ependymal multiciliated cells. Biol Pharm Bull 2023; 46(1): 111-122.

[38] Si X, Liu X, Li J, Wu X. Transforming growth factor-β1 promotes homing of bone marrow mesenchymal stem cells in renal ischemia-reperfusion injury. Int J Clin Exp Pathol 2015; 8(10): 12368-12378.

[39] Zhao Y, Wang HL, Li TT, Yang F, Tzeng CM. Baicalin ameliorates dexamethasone-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway. Drug Des Devel Ther 2020; 14: 195-206.

[40] Ni X, Wu B, Li S, Zhu W, Xu Z, Zhang G. Equol exerts a protective effect on postmenopausal osteoporosis by upregulating OPG/RANKL pathway. Phytomedicine 2023; 108: 154509.

[41] Florencio-Silva R, Sasso GRDS, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of bone tissue: Structure, function, and factors that influence bone cells. BioMed Res Int 2015; 2015: 421746.

[42] Grabowski P. Physiology of bone. Endocr Dev 2015; 28(6): 33-55.

[43] Kim J, Lee H, Kang KS, Chun KH, Hwang GS. Protective effect of Korean Red Ginseng against glucocorticoid-induced osteoporosis in vitro and in vivo. J Ginseng Res 2015; 39(1): 46-53.

[44] Deng ZH, Li YS, Gao X, Lei GH, Huard J. Bone morphogenetic proteins for articular cartilage regeneration. Osteoarthr Cartil 2018; 26: 1153-1161.

[45] Tang H, Zhang X, Xue G, Xu F, Wang Q, Yang P. The biology of bone morphogenetic protein signaling pathway in cerebrovascular system. Chin Neurosurg J 2021; 7(1): 36.