Application of lactoferrin for the prevention and restoration of bone tissue in Wistar rats under conditions of hindlimb unloading
- Autores: Gordienko K.V.1, Lukicheva N.A.1, Akhmetzyanova A.I.2, Kolupaev A.K.3, Sachenkov O.A.2, Baltina T.V.2, Sadchikova E.R.3, Vassilieva G.Y.1
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Afiliações:
- Institute for Biomedical Problems of the Russian Academy of Sciences
- Kazan (Volga region) Federal University
- Institute of Gene Biology Russian Academy of Sciences
- Edição: Volume 110, Nº 8 (2024)
- Páginas: 1253-1263
- Seção: EXPERIMENTAL ARTICLES
- URL: https://gynecology.orscience.ru/0869-8139/article/view/651624
- DOI: https://doi.org/10.31857/S0869813924080035
- EDN: https://elibrary.ru/BCOGVV
- ID: 651624
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Resumo
The influence of gravitational unloading (antiorthostatic suspension) and subsequent recovery on the mineral density and mechanical properties of the femoral and tibial bones of Wistar rats was studied with oral administration of a biotechnological analog of human lactoferrin (200 mg/kg) derived from the milk of producer goats. Bone mineral density was determined by dual-energy X-ray absorptiometry, and strength and stiffness were assessed through three-point bending tests.
It was shown that gravitational unloading for 21 days led to a decrease in the mineral density of the tibial and femoral bones. The administration of lactoferrin did not significantly affect the mineral density or projected area of the studied bones. No statistically significant differences in mechanical stiffness were found between the experimental groups, but after readaptation, the ultimate strength was significantly higher in the groups that received lactoferrin. Thus, the obtained results may indicate the potential of lactoferrin preparations as prophylactic agents for maintaining bone strength. At the same time, maintaining bone mineral density under deficit-stimulating conditions requires consideration of alternative dosages and delivery methods of the drug.
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Sobre autores
K. Gordienko
Institute for Biomedical Problems of the Russian Academy of Sciences
Autor responsável pela correspondência
Email: k.vl.gordienko@gmail.com
Rússia, Moscow
N. Lukicheva
Institute for Biomedical Problems of the Russian Academy of Sciences
Email: k.vl.gordienko@gmail.com
Rússia, Moscow
A. Akhmetzyanova
Kazan (Volga region) Federal University
Email: k.vl.gordienko@gmail.com
Rússia, Kazan
A. Kolupaev
Institute of Gene Biology Russian Academy of Sciences
Email: k.vl.gordienko@gmail.com
Rússia, Moscow
O. Sachenkov
Kazan (Volga region) Federal University
Email: k.vl.gordienko@gmail.com
Rússia, Kazan
T. Baltina
Kazan (Volga region) Federal University
Email: k.vl.gordienko@gmail.com
Rússia, Kazan
E. Sadchikova
Institute of Gene Biology Russian Academy of Sciences
Email: k.vl.gordienko@gmail.com
Rússia, Moscow
G. Vassilieva
Institute for Biomedical Problems of the Russian Academy of Sciences
Email: k.vl.gordienko@gmail.com
Rússia, Moscow
Bibliografia
- Jiang S-D, Dai L-Y, Jiang L-S (2006) Osteoporosis after spinal cord injury. Osteoporos Int 17: 180–192. https://doi.org/10.1007/s00198–005–2028–8
- Aliprantis AO, Stolina M, Kostenuik PJ, Poliachik SL, Warner SE, Bain SD, Gross TS (2012) Transient muscle paralysis degrades bone via rapid osteoclastogenesis. FASEB J 26: 1110–1118. https://doi.org/10.1096/fj.11–196642
- Baran R, Wehland M, Schulz H, Heer M, Infanger M, Grimm D (2022) Microgravity-related changes in bone density and treatment options: a systematic review. IJMS23: 8650. https://doi.org/10.3390/ijms23158650
- Genah S, Monici M, Morbidelli L (2021) The Effect of Space Travel on Bone Metabolism: Considerations on Today’s Major Challenges and Advances in Pharmacology. IJMS22: 4585. https://doi.org/10.3390/ijms22094585
- LeBlanc A, Schneider V, Shackelford L, West S, Oganov V, Bakulin A, Voronin L (2000) Bone mineral and lean tissue loss after long duration space flight. J Musculoskelet Neuron Interact 1: 157–160.
- Оганов ВС, Бакулин АВ, Новиков ВЕ, Мурашко ЛМ, Кабицкая ОЕ, Моргун ВВ, Воронин ЛИ, Шнайдер В, Шейклфорд Л, Лебланк А (2005) Реакции костной системы человека в космическом полете: Феноменология. Авиакосм экол мед 39: 3–9. [Oganov VS, Bakulin AV, Novikov VE, Murashko LM, Kabitskaya OE, Morgun VV, Voronin LI, Schneider V, Shackelford L, LeBlanc A (2005) Reactions of the human skeletal system in space flight: phenomenology. Aviakosm Ekol Med 39: 3–9. (In Russ)].
- Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM (2009) Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res 5: 843–850. https://doi.org/10.1002/jbmr.5650050807
- Kaplansky AS, Durnova GN, Burkovskaya TE, Vorotnikova EV (1991) The effect of microgravity on bone fracture healing in rats flown on Cosmos-2044. Physiologist 34: S196–S199.
- Капланский АС, Дурнова ГН, Сахарова ЗФ, Ильина-Какуева ЕИ (1987) Гистоморфометрический анализ костей крыс, находившихся на борту биоспутника «Космос-1667». Косм биол авиакосм мед 21: 25–31. [Kaplanskiy AS, Durnova GN, Sakharova ZF, Ilʹina-Kakueva EI (1987) Histomorphometric analysis of the bones of rats on board the Kosmos 1667 biosatellite. Kosm Biol Aviakosm Med 21: 25–31. (In Russ)].
- Hariom SK, Ravi A, Mohan GR, Pochiraju HD, Chattopadhyay S, Nelson EJR (2021) Animal physiology across the gravity continuum. Acta Astronautica 178: 522–535. https://doi.org/10.1016/j.actaastro.2020.09.044
- Дурнова ГН, Капланский АС, Логинов ВИ (2006) Динамика восстановления структуры большеберцовых костей крыс после остеопении, вызванной вывешиванием. Авиакосм экол мед 40: 29–31. [Durnova GN, Kaplanskiy AS, Loginov VI (2006) [Dynamics of restoration of the structure of the tibia bones of rats after osteopenia caused by hindlimb suspension]. Aviakosm Ekol Med 40: 29–31. (In Russ)].
- Дурнова ГН, Капланский АС (2003) Сравнительное гистоморфометрическое исследование большеберцовых костей у самцов и самок крыс при вывешивании за хвост в антиортостатическом положении. Авиакосм экол мед 37: 29–32. [Durnova GN, Kaplanskiy AS (2003) Comparative histomorphometric study of the tibia in male and female rats when suspended by the tail in an antiorthostatic position. Aviakosm Ekol Med 37: 29–32. (In Russ)].
- Metzger CE, Anand Narayanan S, Phan PH, Bloomfield SA (2020) Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment. NPJ Microgravity 6: 28. https://doi.org/10.1038/s41526–020–00118–4
- Grano M, Mori G, Minielli V, Barou O, Colucci S, Giannelli G, Alexandre C, Zallone AZ, Vico L (2002) Rat hindlimb unloading by tail suspension reduces osteoblast differentiation, induces IL-6 secretion, and increases bone resorption in ex vivo cultures. Calcified Tissue Int 70: 176–185. https://doi.org/10.1007/s00223–001–2034–6
- Lang TF, Leblanc AD, Evans HJ, Lu Y (2006) Adaptation of the proximal femur to skeletal reloading after long-duration spaceflight. J Bone Mineral Res 21: 1224–1230. https://doi.org/10.1359/jbmr.060509
- Goldman IL, Georgieva SG, Gurskiy YaG, Krasnov AN, Deykin AV, Popov AN, Ermolkevich TG, Budzevich AI, Chernousov AD, Sadchikova ER (2012) Production of human lactoferrin in animal milk. Biochem Cell Biol 90: 513–519. https://doi.org/10.1139/o11–088
- Chernousov AD, Nikonova MF, Sharova NI, Mitin АN, Litvina ММ, Sadchikov PE, Goldman IL, Yarilin АА, Sadchikova ЕR (2013) Neolactoferrin as a stimulator of innate and adaptive immunity. Acta Naturae 5: 71–76. https://doi.org/10.32607/20758251–2013–5–4–71–76
- Naot D, Palmano K, Cornish J (2012) Lactoferrin – A Potential Anabolic Intervention in Osteoporosis. In: Dionyssiotis Y (ed) Osteoporosis. In Tech.
- Sachenkov O, Kharislamova L, Shamsutdinova N, Kirillova E, Konoplev Y (2015) Evaluation of the bone tissue mechanical parameters after induced alimentary Cu-deficiency followed by supplementary injection of Cu nanoparticles in rats. IOP Conf Ser: Mater Sci Eng 98: 012015. https://doi.org/10.1088/1757–899X/98/1/012015
- Bastos AR, Da Silva LP, Maia FR, Pina S, Rodrigues T, Sousa F, Oliveira JM, Cornish J, Correlo VM, Reis RL (2019) Lactoferrin-hydroxyapatite containing spongy-like hydrogels for bone tissue engineering. Materials 12: 2074. https://doi.org/10.3390/ma12132074
- Trybek G, Jedliński M, Jaroń A, Preuss O, Mazur M, Grzywacz A (2020) Impact of lactoferrin on bone regenerative processes and its possible implementation in oral surgery – a systematic review of novel studies with metanalysis and metaregression. BMC Oral Health 20: 232. https://doi.org/10.1186/s12903–020–01211–6
- Blais A, Malet A, Mikogami T, Martin-Rouas C, Tomé D (2009) Oral bovine lactoferrin improves bone status of ovariectomized mice. Am J Physiol Endocrinol Metabolism 296: E1281–E1288. https://doi.org/10.1152/ajpendo.90938.2008
- Grey A, Banovic T, Zhu Q, Watson M, Callon K, Palmano K, Ross J, Naot D, Reid IR, Cornish J (2004) The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells. Mol Endocrinol 18: 2268–2278. https://doi.org/10.1210/me.2003–0456
- Cornish J (2004) Lactoferrin promotes bone growth. Biometals 17: 331–335. https://doi.org/10.1023/B: BIOM.0000027713.18694.91
- Jia B, Xie L, Zheng Q, Yang P, Zhang W, Ding C, Qian A, Shang P (2014) A hypomagnetic field aggravates bone loss induced by hindlimb unloading in rat femurs. PLoS One 9: e105604. https://doi.org/10.1371/journal.pone.0105604
- He J, Feng X, Wang J, Shi W, Li H, Danilchenko S, Kalinkevich A, Zhovner M (2018) Icariin prevents bone loss by inhibiting bone resorption and stabilizing bone biological apatite in a hindlimb suspension rodent model. Acta Pharmacol Sin 39: 1760–1767. https://doi.org/10.1038/s41401–018–0040–8
- Smith JK (2020) Osteoclasts and microgravity. Life 10: 207. https://doi.org/10.3390/life10090207
- Lloyd SA, Morony SE, Ferguson VL, Simske SJ, Stodieck LS, Warmington KS, Livingston EW, Lacey DL, Kostenuik PJ, Bateman TA (2015) Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice. Bone 81: 562–572. https://doi.org/10.1016/j.bone.2015.08.021
- Hou J, Xue Y, Lin Q (2012) Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway. Acta Pharmacol Sin 33: 1277–1284. https://doi.org/10.1038/aps.2012.83
- Guo HY, Jiang L, Ibrahim SA, Zhang L, Zhang H, Zhang M, Ren FZ (2009) Orally administered lactoferrin preserves bone mass and microarchitecture in ovariectomized rats. J Nutrition 139: 958–964. https://doi.org/10.3945/jn.108.100586
- Gao R, Watson M, Callon KE, Tuari D, Dray M, Naot D, Amirapu S, Munro JT, Cornish J, Musson DS (2018) Local application of lactoferrin promotes bone regeneration in a rat critical-sized calvarial defect model as demonstrated by micro-CT and histological analysis: local lactoferrin promotes bone regeneration. J Tissue Eng Regen Med 12: e620–e626. https://doi.org/10.1002/term.2348
- Ильин ЕА, Новиков ВЕ (1980) Стенд для моделирования физиологических эффектов невесомости в лабораторных экспериментах с крысами. Косм биол авиакосм мед 14: 79–80. [Il’in EA, Novikov VE (1980) Workbench for modelling the physiological effects of weightlessness in laboratory experiments with rats. Kosm Biol Aviakosm Med 14: 79–80. (In Russ)].
- Morey-Holton ER, Globus RK (2002) Hindlimb unloading rodent model: technical aspects. J Appl Physiol 92: 1367–1377. https://doi.org/10.1152/japplphysiol.00969.2001
- Akhmetzyanova AI, Sharafutdinova KR, Sabirova DE, Baltin ME, Gerasimov OV, Baltina TV, Sachenkov OA (2022) Assessing the effect of spinal cord injury severity on the mechanical properties of the hind limb bones of experimental rats. Russ J Biomechan 26: 38–46. https://doi.org/10.15593/RZhBiomeh/2022.4.04
- Sadchikov PE, Goldman IL, Razin SV, Chernousov AD, Alekseeva LI, Sadchikova ER (2016) The molecular mechanism of lactoferrin influence on bone formation. Osteopor Bone Dis 19: 12–22. https://doi.org/10.14341/osteo2016312–22
- Evans JD (1996) Straightforward statistics for the behavioral sciences. Brooks/Cole Pub. Co, Pacific Grove.
- Cunningham HC, West DWD, Baehr LM, Tarke FD, Baar K, Bodine SC, Christiansen BA (2018) Age-dependent bone loss and recovery during hindlimb unloading and subsequent reloading in rats. BMC Musculoskelet Disord 19: 223. https://doi.org/10.1186/s12891–018–2156-x
- Krause AR, Speacht TA, Steiner JL, Lang CH, Donahue HJ (2020) Mechanical loading recovers bone but not muscle lost during unloading. NPJ Microgravity 6: 36. https://doi.org/10.1038/s41526–020–00126–4
- Lloyd SA, Bandstra ER, Willey JS, Riffle SE, Tirado-Lee L, Nelson GA, Pecaut MJ, Bateman TA (2012) Effect of proton irradiation followed by hindlimb unloading on bone in mature mice: A model of long-duration spaceflight. Bone 51: 756–764. https://doi.org/10.1016/j.bone.2012.07.001
- Osterhoff G, Morgan EF, Shefelbine SJ, Karim L, McNamara LM, Augat P (2016) Bone mechanical properties and changes with osteoporosis. Injury 47: S11–S20. https://doi.org/10.1016/S0020–1383(16)47003–8
- Globus RK, Morey-Holton E (2016) Hindlimb unloading: rodent analog for microgravity. J Appl Physiol 120: 1196–1206. https://doi.org/10.1152/japplphysiol.00997.2015
- Wang B, Timilsena YP, Blanch E, Adhikari B (2019) Lactoferrin: structure, function, denaturation and digestion. Critical reviews in food science and nutrition 59: 580–596. https://doi.org/10.1080/10408398.2017.1381583
- Amidon GL, DeBrincat GA, Najib N (1991) Effects of Gravity on Gastric Emptying, Intestinal Transit, and Drug Absorption. J Clin Pharm 31: 968–973. https://doi.org/10.1002/j.1552–4604.1991.tb03658.x
- Афонин БВ, Гончарова НП, Карамышев ЮА (2007) Функциональное состояние желудка человека в эксперименте с 4-месячной антиортостатической гипокинезией. Авиакосм экол мед 41: 37–43. [Afonin BV, Goncharova NP, Karamyshev YuA (2007) Functional state of the human stomach in an experiment with 4-month antiorthostatic hypokinesia. Aviakosm Ekol Med 41: 37–43. (In Russ)].
- Shimano MM, Volpon JB (2009) Biomechanics and structural adaptations of the rat femur after hindlimb suspension and treadmill running. Braz J Med Biol Res 42: 330–338. https://doi.org/10.1590/S0100–879X2009000400004
- Ильин ЕА (1984) Исследование на биоспутниках «Космос». Косм биол авиакосм мед 18: 57–66. [Il’in EA (1984) Research on the Kosmos biosatellites. Kosm Biol Aviakosm Med 18: 57–66. (In Russ)].
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