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Hyperglycemia impairs osteoblast cell migration and chemotaxis due to a decrease in mitochondrial biogenesis

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Abstract

Diabetes is associated with an increase in skeletal fragility and risk of fracture. However, the underlying mechanism for the same is not well understood. Specifically, the results from osteoblast cell culture studies are ambiguous due to contradicting reports. The use of supraphysiological concentrations in these studies, unachievable in vivo, might be the reason for the same. Therefore, here, we studied the effect of physiologically relevant levels of high glucose during diabetes (11.1 mM) on MC3T3-E1 osteoblast cell functions. The results showed that high glucose exposure to osteoblast cells increases their differentiation and mineralization without any effect on the proliferation. However, high glucose decreases their migratory potential and chemotaxis with a decrease in the associated cell signaling. Notably, this decrease in cell migration in high glucose conditions was accompanied by aberrant localization of Dynamin 2 in osteoblast cells. Besides, high glucose also caused a shift in mitochondrial dynamics towards the appearance of more fused and lesser fragmented mitochondria, with a concomitant decrease in the expression of DRP1, suggesting decreased mitochondrial biogenesis. In conclusion, here we are reporting for the first time that hyperglycemia causes a reduction in osteoblast cell migration and chemotaxis. This decrease might lead to an inefficient movement of osteoblasts to the erosion site resulting in uneven mineralization and skeletal fragility found in type 2 diabetes patients, in spite of having normal bone mineral density (BMD).

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References

  1. Cozen L (1972) Does diabetes delay fracture healing? Clin Orthop Relat Res 82:134–140

    Article  CAS  Google Scholar 

  2. Jiao H, Xiao E, Graves DT (2015) Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep 13:327–335. https://doi.org/10.1007/s11914-015-0286-8

    Article  PubMed  PubMed Central  Google Scholar 

  3. Oei L, Zillikens MC, Dehghan A, Buitendijk GH, Castano-Betancourt MC, Estrada K, Stolk L, Oei EH, van Meurs JB, Janssen JA, Hofman A, van Leeuwen JP, Witteman JC, Pols HA, Uitterlinden AG, Klaver CC, Franco OH, Rivadeneira F (2013) High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam Study. Diabetes Care 36:1619–1628. https://doi.org/10.2337/dc12-1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. American Diabetes A (2006) Standards of medical care in diabetes—2006. Diabetes Care 29(Suppl 1):S4–42

    Google Scholar 

  5. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M, Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378:31–40. https://doi.org/10.1016/S0140-6736(11)60679-X

    Article  CAS  PubMed  Google Scholar 

  6. Stoner GD (2017) Hyperosmolar hyperglycemic state. Am Fam Phys 96:729–736

    Google Scholar 

  7. Bartolome A, Lopez-Herradon A, Portal-Nunez S, Garcia-Aguilar A, Esbrit P, Benito M, Guillen C (2013) Autophagy impairment aggravates the inhibitory effects of high glucose on osteoblast viability and function. Biochem J 455:329–337. https://doi.org/10.1042/BJ20130562

    Article  CAS  PubMed  Google Scholar 

  8. Botolin S, McCabe LR (2006) Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem 99:411–424. https://doi.org/10.1002/jcb.20842

    Article  CAS  PubMed  Google Scholar 

  9. Cunha JS, Ferreira VM, Maquigussa E, Naves MA, Boim MA (2014) Effects of high glucose and high insulin concentrations on osteoblast function in vitro. Cell Tissue Res 358:249–256. https://doi.org/10.1007/s00441-014-1913-x

    Article  CAS  PubMed  Google Scholar 

  10. Liu Z, Jiang H, Dong K, Liu S, Zhou W, Zhang J, Meng L, Rausch-Fan X, Xu X (2015) Different concentrations of glucose regulate proliferation and osteogenic differentiation of osteoblasts via the PI3 kinase/Akt pathway. Implant Dent 24:83–91. https://doi.org/10.1097/ID.0000000000000196

    Article  PubMed  Google Scholar 

  11. Ma P, Gu B, Xiong W, Tan B, Geng W, Li J, Liu H (2014) Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS ONE 9:e112243. https://doi.org/10.1371/journal.pone.0112243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shao X, Cao X, Song G, Zhao Y, Shi B (2014) Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. J Diabetes Res 2014:453940. https://doi.org/10.1155/2014/453940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Terada M, Inaba M, Yano Y, Hasuma T, Nishizawa Y, Morii H, Otani S (1998) Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells. Bone 22:17–23. https://doi.org/10.1016/s8756-3282(97)00220-2

    Article  CAS  PubMed  Google Scholar 

  14. Wu YY, Yu T, Zhang XH, Liu YS, Li F, Wang YY, Wang YY, Gong P (2012) 1,25(OH)2D3 inhibits the deleterious effects induced by high glucose on osteoblasts through undercarboxylated osteocalcin and insulin signaling. J Steroid Biochem Mol Biol 132:112–119. https://doi.org/10.1016/j.jsbmb.2012.05.002

    Article  CAS  PubMed  Google Scholar 

  15. Zayzafoon M, Stell C, Irwin R, McCabe LR (2000) Extracellular glucose influences osteoblast differentiation and c-Jun expression. J Cell Biochem 79:301–310

    Article  CAS  Google Scholar 

  16. Lopez-Herradon A, Portal-Nunez S, Garcia-Martin A, Lozano D, Perez-Martinez FC, Cena V, Esbrit P (2013) Inhibition of the canonical Wnt pathway by high glucose can be reversed by parathyroid hormone-related protein in osteoblastic cells. J Cell Biochem 114:1908–1916. https://doi.org/10.1002/jcb.24535

    Article  CAS  PubMed  Google Scholar 

  17. Patel VB (2017) Biomarkers in bone disease. Springer, Berlin Heidelberg, New York

    Book  Google Scholar 

  18. Garcia-Hernandez A, Arzate H, Gil-Chavarria I, Rojo R, Moreno-Fierros L (2012) High glucose concentrations alter the biomineralization process in human osteoblastic cells. Bone 50:276–288. https://doi.org/10.1016/j.bone.2011.10.032

    Article  CAS  PubMed  Google Scholar 

  19. Balint E, Szabo P, Marshall CF, Sprague SM (2001) Glucose-induced inhibition of in vitro bone mineralization. Bone 28:21–28. https://doi.org/10.1016/s8756-3282(00)00426-9

    Article  CAS  PubMed  Google Scholar 

  20. Zhen D, Chen Y, Tang X (2010) Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complicat 24:334–344. https://doi.org/10.1016/j.jdiacomp.2009.05.002

    Article  PubMed  Google Scholar 

  21. Thiel A, Reumann MK, Boskey A, Wischmann J, von Eisenhart-Rothe R, Mayer-Kuckuk P (2018) Osteoblast migration in vertebrate bone. Biol Rev Camb Philos Soc 93:350–363. https://doi.org/10.1111/brv.12345

    Article  PubMed  Google Scholar 

  22. Ali SJ, Ellur G, Patel K, Sharan K (2019) Chlorpyrifos exposure induces parkinsonian symptoms and associated bone loss in adult swiss Albino mice. Neurotox Res 36:700–711. https://doi.org/10.1007/s12640-019-00092-0

    Article  CAS  PubMed  Google Scholar 

  23. Sharan K, Lewis K, Furukawa T, Yadav VK (2017) Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res. https://doi.org/10.1111/jpi.12423

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ali SJ, Ellur G, Khan MT, Sharan K (2019) Bone loss in MPTP mouse model of Parkinson's disease is triggered by decreased osteoblastogenesis and increased osteoclastogenesis. Toxicol Appl Pharmacol 363:154–163. https://doi.org/10.1016/j.taap.2018.12.003

    Article  CAS  PubMed  Google Scholar 

  25. Sharan K, Mishra JS, Swarnkar G, Siddiqui JA, Khan K, Kumari R, Rawat P, Maurya R, Sanyal S, Chattopadhyay N (2011) A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: the role of aryl hydrocarbon receptor as a mediator of osteogenic action. J Bone Miner Res 26:2096–2111. https://doi.org/10.1002/jbmr.434

    Article  CAS  PubMed  Google Scholar 

  26. Lewis KE, Sharan K, Takumi T, Yadav VK (2017) Skeletal site-specific changes in bone mass in a genetic mouse model for human 15q11-13 duplication seen in autism. Sci Rep 7:9902. https://doi.org/10.1038/s41598-017-09921-8

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lamers ML, Almeida ME, Vicente-Manzanares M, Horwitz AF, Santos MF (2011) High glucose-mediated oxidative stress impairs cell migration. PLoS ONE 6:e22865. https://doi.org/10.1371/journal.pone.0022865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen HC (2005) Boyden chamber assay. Methods Mol Biol 294:15–22. https://doi.org/10.1385/1-59259-860-9:015

    Article  PubMed  Google Scholar 

  29. Khan MP, Mishra JS, Sharan K, Yadav M, Singh AK, Srivastava A, Kumar S, Bhaduaria S, Maurya R, Sanyal S, Chattopadhyay N (2013) A novel flavonoid C-glucoside from Ulmus wallichiana preserves bone mineral density, microarchitecture and biomechanical properties in the presence of glucocorticoid by promoting osteoblast survival: a comparative study with human parathyroid hormone. Phytomedicine 20:1256–1266. https://doi.org/10.1016/j.phymed.2013.07.007

    Article  CAS  PubMed  Google Scholar 

  30. Bachagol D, Joseph GS, Ellur G, Patel K, Aruna P, Mittal M, China SP, Singh RP, Sharan K (2018) Stimulation of liver IGF-1 expression promotes peak bone mass achievement in growing rats: a study with pomegranate seed oil. J Nutr Biochem 52:18–26. https://doi.org/10.1016/j.jnutbio.2017.09.023

    Article  CAS  PubMed  Google Scholar 

  31. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA (1997) Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol 137:481–492. https://doi.org/10.1083/jcb.137.2.481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stahle M, Veit C, Bachfischer U, Schierling K, Skripczynski B, Hall A, Gierschik P, Giehl K (2003) Mechanisms in LPA-induced tumor cell migration: critical role of phosphorylated ERK. J Cell Sci 116:3835–3846. https://doi.org/10.1242/jcs.00679

    Article  CAS  PubMed  Google Scholar 

  33. Tanimura S, Takeda K (2017) ERK signalling as a regulator of cell motility. J Biochem 162:145–154. https://doi.org/10.1093/jb/mvx048

    Article  CAS  PubMed  Google Scholar 

  34. Xue G, Hemmings BA (2013) PKB/Akt-dependent regulation of cell motility. J Natl Cancer Inst 105:393–404. https://doi.org/10.1093/jnci/djs648

    Article  CAS  PubMed  Google Scholar 

  35. Kruchten AE, McNiven MA (2006) Dynamin as a mover and pincher during cell migration and invasion. J Cell Sci 119:1683–1690. https://doi.org/10.1242/jcs.02963

    Article  CAS  PubMed  Google Scholar 

  36. Razidlo GL, Wang Y, Chen J, Krueger EW, Billadeau DD, McNiven MA (2013) Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Rac1 GEF Vav1. Dev Cell 24:573–585. https://doi.org/10.1016/j.devcel.2013.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singh M, Jadhav HR, Bhatt T (2017) Dynamin functions and ligands: classical mechanisms behind. Mol Pharmacol 91:123–134. https://doi.org/10.1124/mol.116.105064

    Article  CAS  PubMed  Google Scholar 

  38. Eleniste PP, Huang S, Wayakanon K, Largura HW, Bruzzaniti A (2014) Osteoblast differentiation and migration are regulated by dynamin GTPase activity. Int J Biochem Cell Biol 46:9–18. https://doi.org/10.1016/j.biocel.2013.10.008

    Article  CAS  PubMed  Google Scholar 

  39. Abdelgawad ME, Soe K, Andersen TL, Merrild DM, Christiansen P, Kjaersgaard-Andersen P, Delaisse JM (2014) Does collagen trigger the recruitment of osteoblasts into vacated bone resorption lacunae during bone remodeling? Bone 67:181–188. https://doi.org/10.1016/j.bone.2014.07.012

    Article  CAS  PubMed  Google Scholar 

  40. Kawabata T, Otsuka T, Fujita K, Sakai G, Kim W, Matsushima-Nishiwaki R, Kuroyanagi G, Kozawa O, Tokuda H (2018) HSP70 inhibitors reduce the osteoblast migration by epidermal growth factor. Curr Mol Med 18:486–495. https://doi.org/10.2174/1566524019666181213112847

    Article  CAS  PubMed  Google Scholar 

  41. Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF (2015) Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res 35:600–604. https://doi.org/10.3109/10799893.2015.1030412

    Article  CAS  PubMed  Google Scholar 

  42. Aoki K, Kondo Y, Naoki H, Hiratsuka T, Itoh RE, Matsuda M (2017) Propagating wave of ERK activation orients collective cell migration. Dev Cell 43(305–317):e5. https://doi.org/10.1016/j.devcel.2017.10.016

    Article  CAS  Google Scholar 

  43. Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J Cell Sci 117:4619–4628. https://doi.org/10.1242/jcs.01481

    Article  CAS  PubMed  Google Scholar 

  44. Fiuza M, Rostosky CM, Parkinson GT, Bygrave AM, Halemani N, Baptista M, Milosevic I, Hanley JG (2017) PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 alpha-appendage and dynamin. J Cell Biol 216:3323–3338. https://doi.org/10.1083/jcb.201701034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McMahon HT, Boucrot E (2011) Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol 12:517–533. https://doi.org/10.1038/nrm3151

    Article  CAS  PubMed  Google Scholar 

  46. Gonzalez-Jamett AM, Baez-Matus X, Olivares MJ, Hinostroza F, Guerra-Fernandez MJ, Vasquez-Navarrete J, Bui MT, Guicheney P, Romero NB, Bevilacqua JA, Bitoun M, Caviedes P, Cardenas AM (2017) Dynamin-2 mutations linked to centronuclear myopathy impair actin-dependent trafficking in muscle cells. Sci Rep 7:4580. https://doi.org/10.1038/s41598-017-04418-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yamada H, Takeda T, Michiue H, Abe T, Takei K (2016) Actin bundling by dynamin 2 and cortactin is implicated in cell migration by stabilizing filopodia in human non-small cell lung carcinoma cells. Int J Oncol 49:877–886. https://doi.org/10.3892/ijo.2016.3592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Maritzen T, Schachtner H, Legler DF (2015) On the move: endocytic trafficking in cell migration. Cell Mol Life Sci 72:2119–2134. https://doi.org/10.1007/s00018-015-1855-9

    Article  CAS  PubMed  Google Scholar 

  49. Lee JE, Westrate LM, Wu H, Page C, Voeltz GK (2016) Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540:139–143. https://doi.org/10.1038/nature20555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y (2013) Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32:4814–4824. https://doi.org/10.1038/onc.2012.494

    Article  CAS  PubMed  Google Scholar 

  51. Ferreira-da-Silva A, Valacca C, Rios E, Populo H, Soares P, Sobrinho-Simoes M, Scorrano L, Maximo V, Campello S (2015) Mitochondrial dynamics protein Drp1 is overexpressed in oncocytic thyroid tumors and regulates cancer cell migration. PLoS ONE 10:e0122308. https://doi.org/10.1371/journal.pone.0122308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Che TF, Lin CW, Wu YY, Chen YJ, Han CL, Chang YL, Wu CT, Hsiao TH, Hong TM, Yang PC (2015) Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC. Oncotarget 6:37349–37366. https://doi.org/10.18632/oncotarget.5736

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by Science and Engineering Research Board (SERB), Government of India (K.S.), and the Department of Biotechnology, Government of India (K.S.). Funding from the CSIR-Central Food Technological Research Institute, Mysore, India, is acknowledged. Research fellowship grants from the DBT (H.P.), and Council of Scientific and Industrial Research (M.T.K.), Government of India, are also acknowledged.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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  1. Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, 570020, India

    Heena Pahwa, Md. Touseef Khan & Kunal Sharan

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Kunal Sharan

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  1. Heena Pahwa
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Pahwa, H., Khan, M.T. & Sharan, K. Hyperglycemia impairs osteoblast cell migration and chemotaxis due to a decrease in mitochondrial biogenesis. Mol Cell Biochem 469, 109–118 (2020). https://doi.org/10.1007/s11010-020-03732-8

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