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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2024

Open Access 01-12-2024 | Osteoporosis | Research

Alamandine attenuates ovariectomy-induced osteoporosis by promoting osteogenic differentiation via AMPK/eNOS axis

Authors: Wanxin Luo, Chen Yao, Jie Sun, Bo Zhang, Hao Chen, Jin Miao, Yafeng Zhang

Published in: BMC Musculoskeletal Disorders | Issue 1/2024

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Abstract

Background

Alamandine is a newly characterized peptide of renin angiotensin system. Our study aims to investigate the osteo-preservative effects of alamandine, explore underlying mechanism and bring a potential preventive strategy for postmenopausal osteoporosis in the future.

Methods

An ovariectomy (OVX)-induced rat osteoporosis model was established for in vivo experiments. Micro-computed tomography and three-point bending test were used to evaluate bone strength. Histological femur slices were processed for immunohistochemistry (IHC). Bone turnover markers and nitric oxide (NO) concentrations in serum were determined with enzyme-linked immunosorbent assay (ELISA). The mouse embryo osteoblast precursor (MC3T3-E1) cells were used for in vitro experiments. The cell viability was analysed with a Cell Counting Kit‑8. We performed Alizarin Red S staining and alkaline phosphatase (ALP) activity assay to observe the differentiation status of osteoblasts. Western blotting was adopted to detect the expression of osteogenesis related proteins and AMP-activated protein kinase/endothelial nitric oxide synthase (AMPK/eNOS) in osteoblasts. DAF-FM diacetate was used for semi-quantitation of intracellular NO.

Results

In OVX rats, alamandine alleviated osteoporosis and maintained bone strength. The IHC showed alamandine increased osteocalcin and collagen type I α1 (COL1A1) expression. The ELISA revealed alamandine decreased bone turnover markers and restored NO level in serum. In MC3T3-E1 cells, alamandine promoted osteogenic differentiation. Western blotting demonstrated that alamandine upregulated the expression of osteopontin, Runt-related transcription factor 2 and COL1A1. The intracellular NO was also raised by alamandine. Additionally, the activation of AMPK/eNOS axis mediated the effects of alamandine on MC3T3-E1 cells and bone tissue. PD123319 and dorsomorphin could repress the regulating effect of alamandine on bone metabolism.

Conclusion

Alamandine attenuates ovariectomy-induced osteoporosis by promoting osteogenic differentiation via AMPK/eNOS axis.
Appendix
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Literature
1.
Reid IR. A broader strategy for osteoporosis interventions. Nat Rev Endocrinol. 2020;16(6):333–9.PubMedCrossRef
2.
Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 2006;38(2 Suppl 1):4–9.CrossRef
3.
4.
Reid IR. Short-term and long-term effects of osteoporosis therapies. Nat Rev Endocrinol. 2015;11(7):418–28.PubMedCrossRef
5.
Barrett-Connor E, Grady D, Stefanick ML. The rise and fall of menopausal hormone therapy. Annu Rev Public Health. 2005;26:115–40.PubMedCrossRef
6.
Nelson ER, Wardell SE, McDonnell DP. The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone. 2013;53(1):42–50.PubMedCrossRef
7.
Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev. 1977;57(2):313–70.PubMedCrossRef
8.
9.
Grace JA, Herath CB, Mak KY, Burrell LM, Angus PW. Update on new aspects of the renin-angiotensin system in Liver Disease: clinical implications and new therapeutic options. Clin Sci (Lond). 2012;123(4):225–39.PubMedCrossRef
10.
Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R. Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J. 2008;22(7):2465–75.PubMedCrossRef
11.
Shimizu H, Nakagami H, Osako MK, Nakagami F, Kunugiza Y, Tomita T, Yoshikawa H, Rakugi H, Ogihara T, Morishita R. Prevention of osteoporosis by angiotensin-converting enzyme inhibitor in spontaneous hypertensive rats. Hypertens Res. 2009;32(9):786–90.PubMedCrossRef
12.
Donmez BO, Ozdemir S, Sarikanat M, Yaras N, Koc P, Demir N, Karayalcin B, Oguz N. Effect of angiotensin II type 1 receptor blocker on osteoporotic rat femurs. Pharmacol Rep. 2012;64(4):878–88.PubMedCrossRef
13.
Rejnmark L, Vestergaard P, Mosekilde L. Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study. J Hypertens. 2006;24(3):581–9.PubMedCrossRef
14.
Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, Jankowski J, Jankowski V, Sousa F, Alzamora A, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11.PubMedCrossRef
15.
Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader M. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol. 2019;316(5):H958–70.PubMedPubMedCentralCrossRef
16.
Schleifenbaum J. Alamandine and its receptor MrgD pair up to join the protective arm of the renin-angiotensin system. Front Med (Lausanne). 2019;6:107.PubMedCrossRef
17.
Carey RM. Newly discovered components and actions of the renin-angiotensin system. Hypertension. 2013;62(5):818–22.PubMedCrossRef
18.
Jesus ICG, Mesquita TRR, Monteiro ALL, Parreira AB, Santos AK, Coelho ELX, Silva MM, Souza LAC, Campagnole-Santos MJ, Santos RS, et al. Alamandine enhances cardiomyocyte contractility in hypertensive rats through a nitric oxide-dependent activation of CaMKII. Am J Physiol Cell Physiol. 2020;318(4):C740–50.PubMedPubMedCentralCrossRef
19.
20.
Tao ZS, Zhou WS, Xu HG, Yang M. Parathyroid hormone (1–34) can reverse the negative effect of valproic acid on the osseointegration of titanium rods in ovariectomized rats. J Orthop Translat. 2021;27:67–76.PubMedCrossRef
21.
Zhou X, Sun S, Chen Y, Liu C, Li D, Cheng Q, He M, Li Y, Xu K, Ta D. Pulsed frequency modulated ultrasound promotes therapeutic effects of osteoporosis induced by ovarian failure in mice. Ultrasonics. 2023;132:106973.PubMedCrossRef
22.
Wang L, Pan Y, Liu M, Sun J, Yun L, Tu P, Wu C, Yu Z, Han Z, Li M, et al. Wen-Shen-Tong-Luo-Zhi-Tong Decoction regulates bone-fat balance in osteoporosis by adipocyte-derived exosomes. Pharm Biol. 2023;61(1):568–80.PubMedPubMedCentralCrossRef
23.
Yano T, Yamada M, Inoue D. Effect of Sequential Treatment with bisphosphonates after Teriparatide in Ovariectomized rats: a direct comparison between Risedronate and Alendronate. Calcif Tissue Int. 2017;101(1):102–10.PubMedPubMedCentralCrossRef
24.
Jesus ICG, Scalzo S, Alves F, Marques K, Rocha-Resende C, Bader M, Santos RAS, Guatimosim S. Alamandine acts via MrgD to induce AMPK/NO activation against ANG II hypertrophy in cardiomyocytes. Am J Physiol Cell Physiol. 2018;314(6):C702–11.PubMedCrossRef
25.
de Carvalho Santuchi M, Dutra MF, Vago JP, Lima KM, Galvao I, de Souza-Neto FP, Morais ESM, Oliveira AC, de Oliveira FCB, Goncalves R, et al. Angiotensin-(1–7) and Alamandine promote anti-inflammatory response in Macrophages in Vitro and in vivo. Mediators Inflamm. 2019;2019:2401081.PubMedPubMedCentralCrossRef
26.
Mizutani J, Tokuda H, Matsushima-Nishiwaki R, Kato K, Kondo A, Natsume H, Kozawa O, Otsuka T. Involvement of AMP-activated protein kinase in TGF-beta-stimulated VEGF synthesis in osteoblasts. Int J Mol Med. 2012;29(4):550–6.PubMedPubMedCentralCrossRef
27.
Qin X, Wu Y, Liu S, Yang L, Yuan H, Cai S, Flesch J, Li Z, Tang Y, Li X, et al. Surface modification of Polycaprolactone Scaffold with Improved Biocompatibility and controlled growth factor release for enhanced stem cell differentiation. Front Bioeng Biotechnol. 2021;9:802311.PubMedCrossRef
28.
Yu C, Chen L, Zhou W, Hu L, Xie X, Lin Z, Panayi AC, Zhan X, Tao R, Mi B, et al. Injectable Bacteria-sensitive hydrogel promotes repair of infected fractures via sustained release of miRNA Antagonist. ACS Appl Mater Interfaces. 2022;14(30):34427–42.PubMedPubMedCentralCrossRef
29.
Agriesti F, Landini F, Tamma M, Pacelli C, Mazzoccoli C, Calice G, Ruggieri V, Capitanio G, Mori G, Piccoli C, et al. Bioenergetic profile and redox tone modulate in vitro osteogenesis of human dental pulp stem cells: new perspectives for bone regeneration and repair. Stem Cell Res Ther. 2023;14(1):215.PubMedPubMedCentralCrossRef
30.
Asaba Y, Ito M, Fumoto T, Watanabe K, Fukuhara R, Takeshita S, Nimura Y, Ishida J, Fukamizu A, Ikeda K. Activation of renin-angiotensin system induces osteoporosis independently of Hypertension. J Bone Miner Res. 2009;24(2):241–50.PubMedCrossRef
31.
Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, Inagami T, Ezura Y, Noda M. Angiotensin II type 2 receptor blockade increases bone mass. J Biol Chem. 2009;284(8):4857–64.PubMedCrossRef
32.
33.
Seeman E, Delmas PD. Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354(21):2250–61.PubMedCrossRef
34.
Ding W, Miao Z, Feng X, Luo A, Tan W, Li P, Wang F. Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts. Peptides. 2022;154:170816.PubMedCrossRef
35.
Saura M, Tarin C, Zaragoza C. Recent insights into the implication of nitric oxide in osteoblast differentiation and proliferation during bone development. ScientificWorldJournal. 2010;10:624–32.PubMedPubMedCentralCrossRef
36.
Jamal SA, Hamilton CJ. Nitric oxide donors for the treatment of osteoporosis. Curr Osteoporos Rep. 2012;10(1):86–92.PubMedCrossRef
37.
Wimalawansa SJ. Nitroglycerin therapy is as efficacious as standard estrogen replacement therapy (Premarin) in prevention of oophorectomy-induced bone loss: a human pilot clinical study. J Bone Miner Res. 2000;15(11):2240–4.PubMedCrossRef
38.
Horowitz MC. Cytokines and estrogen in bone: anti-osteoporotic effects. Science. 1993;260(5108):626–7.PubMedCrossRef
39.
Pratelli L, Cenni E, Granchi D, Tarabusi C, Ciapetti G, Pizzoferrato A. [Cytokines of bone turnover in postmenopause and old age]. Minerva Med. 1999;90(4):101–9.PubMed
40.
41.
Shah M, Kola B, Bataveljic A, Arnett TR, Viollet B, Saxon L, Korbonits M, Chenu C. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass. Bone. 2010;47(2):309–19.PubMedPubMedCentralCrossRef
42.
Kim EK, Lim S, Park JM, Seo JK, Kim JH, Kim KT, Ryu SH, Suh PG. Human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by AMP-activated protein kinase. J Cell Physiol. 2012;227(4):1680–7.PubMedCrossRef
43.
Quinn JM, Tam S, Sims NA, Saleh H, McGregor NE, Poulton IJ, Scott JW, Gillespie MT, Kemp BE, van Denderen BJ. Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function. FASEB J. 2010;24(1):275–85.PubMedPubMedCentralCrossRef
44.
Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T. Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. Biochem Biophys Res Commun. 2008;375(3):414–9.PubMedCrossRef
45.
Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, et al. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone. 2011;48(4):885–93.PubMedCrossRef
46.
Uchiyama T, Okajima F, Mogi C, Tobo A, Tomono S, Sato K. Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue. PLoS ONE. 2017;12(6):e0178769.PubMedPubMedCentralCrossRef
47.
Zizzo MG, Caldara G, Bellanca A, Nuzzo D, Di Carlo M, Serio R. PD123319, angiotensin II type II receptor antagonist, inhibits oxidative stress and inflammation in 2, 4-dinitrobenzene sulfonic acid-induced Colitis in rat and ameliorates colonic contractility. Inflammopharmacology. 2020;28(1):187–99.PubMedCrossRef
48.
Saito S, Furuno A, Sakurai J, Park HR, Shin-ya K, Tomida A. Compound C prevents the unfolded protein response during glucose deprivation through a mechanism Independent of AMPK and BMP signaling. PLoS ONE. 2012;7(9):e45845.PubMedPubMedCentralCrossRef
49.
Jiang F, Qi X, Wu X, Lin S, Shi J, Zhang W, Jiang X. Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment. Bioact Mater. 2023;25:307–18.PubMedPubMedCentral
50.
Geng Q, Gao H, Yang R, Guo K, Miao D. Pyrroloquinoline Quinone prevents Estrogen Deficiency-Induced osteoporosis by inhibiting oxidative stress and Osteocyte Senescence. Int J Biol Sci. 2019;15(1):58–68.PubMedPubMedCentralCrossRef
51.
Krishnan B, Smith TL, Dubey P, Zapadka ME, Torti FM, Willingham MC, Tallant EA, Gallagher PE. Angiotensin-(1–7) attenuates metastatic Prostate cancer and reduces osteoclastogenesis. Prostate. 2013;73(1):71–82.PubMedCrossRef
52.
Queiroz-Junior CM, Santos A, Galvao I, Souto GR, Mesquita RA, Sa MA, Ferreira AJ. The angiotensin converting enzyme 2/angiotensin-(1–7)/Mas receptor axis as a key player in alveolar bone remodeling. Bone. 2019;128:115041.PubMedCrossRef
53.
Sha NN, Zhang JL, Poon CC, Li WX, Li Y, Wang YF, Shi W, Lin FH, Lin WP, Wang YJ, et al. Differential responses of bone to angiotensin II and angiotensin(1–7): beneficial effects of ANG(1–7) on bone with exposure to high glucose. Am J Physiol Endocrinol Metab. 2021;320(1):E55–E70.PubMedCrossRef
Metadata
Title
Alamandine attenuates ovariectomy-induced osteoporosis by promoting osteogenic differentiation via AMPK/eNOS axis
Authors
Wanxin Luo
Chen Yao
Jie Sun
Bo Zhang
Hao Chen
Jin Miao
Yafeng Zhang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2024
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-023-07159-2

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