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Femoral Skeletal Perfusion is Reduced in Male Mice with Type 1 Diabetes

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Abstract

The bone vasculature and blood flow are critical for bone modeling, remodeling, and regeneration. Vascular complications are one of the major health concerns of people with type 1 diabetes (T1D). Moreover, people with T1D have lower bone mineral density and increased bone fragility. The goal of this study was to understand whether bone perfusion was altered in a mouse model of T1D and how this related to changes in bone mass. T1D was induced via the administration of streptozotocin in 12-week-old C57BL/6NHsd male mice. The assessment of bone perfusion utilized the injection of fluorescent microspheres with assessment of levels in the bone. Femoral blood flow and VEGF-A expression in the cortical bone shafts were lower in the T1D mice, compared to healthy controls, in this pattern followed that of changes in bone mass. These data demonstrate a possible association between reduced skeletal perfusion and reduced bone mass in the setting of T1D.

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References

  1. Esposito S, Mariotti Zani E, Torelli L, Scavone S, Petraroli M, Patianna V, Predieri B, Iughetti L, Principi N (2021) Childhood vaccinations and type 1 diabetes. Front Immunol 12:667889

    Article  CAS  Google Scholar 

  2. Hygum K, Starup-Linde J, Langdahl BL (2019) Diabetes and bone. Osteoporos Sarcopenia 5:29–37

    Article  Google Scholar 

  3. Rask-Madsen C, King GL (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17:20–33

    Article  CAS  Google Scholar 

  4. Ferrari SL, Abrahamsen B, Napoli N, Akesson K, Chandran M, Eastell R, El-Hajj Fuleihan G, Josse R, Kendler DL, Kraenzlin M, Suzuki A, Pierroz DD, Schwartz AV, Leslie WD, BaDWGo IOF (2018) Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos Int 29:2585–2596

    Article  CAS  Google Scholar 

  5. Jiao H, Xiao E, Graves DT (2015) Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep 13:327–335

    Article  Google Scholar 

  6. Wan C, Gilbert SR, Wang Y, Cao XM, Shen X, Ramaswamy G, Jacobsen KA, Alaql ZS, Gerstenfeld LC, Einhorn TA, Eberhardt AW, Deng L, Guldberg RE, Clemens TL (2008) Role of hypoxia inducible factor-1 alpha pathway in bone regeneration. J Musculoskelet Neuronal Interact 8:323–324

    CAS  PubMed  Google Scholar 

  7. Ishizuka T, Hinata T, Watanabe Y (2011) Superoxide induced by a high-glucose concentration attenuates production of angiogenic growth factors in hypoxic mouse mesenchymal stem cells. J Endocrinol 208:147–159

    Article  CAS  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

    Article  CAS  Google Scholar 

  9. Peng J, Hui K, Hao C, Peng Z, Gao QX, Jin Q, Lei G, Min J, Qi Z, Bo C, Dong QN, Bing ZH, Jia XY, Fu DL (2016) Low bone turnover and reduced angiogenesis in streptozotocin-induced osteoporotic mice. Connect Tissue Res 57:277–289

    Article  CAS  Google Scholar 

  10. Wang Y, Wan C, Deng L, Liu X, Cao X, Gilbert SR, Bouxsein ML, Faugere MC, Guldberg RE, Gerstenfeld LC, Haase VH, Johnson RS, Schipani E, Clemens TL (2007) The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 117:1616–1626

    Article  CAS  Google Scholar 

  11. Goring A, Sharma A, Javaheri B, Smith RC, Kanczler JM, Boyde A, Hesse E, Mahajan S, Olsen BR, Pitsillides AA, Schneider P, Oreffo RO, Clarkin CE (2019) Regulation of the bone vascular network is sexually dimorphic. J Bone Miner Res 34:2117–2132

    Article  Google Scholar 

  12. Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, Olsen BR (2012) Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest 122:3101–3113

    Article  CAS  Google Scholar 

  13. Stabley JN, Prisby RD, Behnke BJ, Delp MD (2015) Type 2 diabetes alters bone and marrow blood flow and vascular control mechanisms in the ZDF rat. J Endocrinol 225:47–58

    Article  CAS  Google Scholar 

  14. Prisby RD, Ramsey MW, Behnke BJ, Dominguez JM, Donato AJ, Allen MR, Delp MD (2007) Aging reduces skeletal blood flow, endothelium-dependent vasodilation, and NO bioavailability in rats. J Bone Miner Res 22:1280–1288

    Article  CAS  Google Scholar 

  15. Raisz LG, Rodan GA (2003) Pathogenesis of osteoporosis. Endocrinol Metab Clin North Am 32:15–24

    Article  Google Scholar 

  16. Maycas M, McAndrews KA, Sato AY, Pellegrini GG, Brown DM, Allen MR, Plotkin LI, Gortazar AR, Esbrit P, Bellido T (2017) PTHrP-derived peptides restore bone mass and strength in diabetic mice: additive effect of mechanical loading. J Bone Miner Res 32:486–497

    Article  CAS  Google Scholar 

  17. Aref MW, Swallow EA, Chen NX, Moe SM, Allen MR (2018) Skeletal vascular perfusion is altered in chronic kidney disease. Bone Rep 8:215–220

    Article  Google Scholar 

  18. Kohler R, Tastad CA, Stacy AJ, Swallow EA, Metzger CE, Allen MR, Wallace JM (2021) The effect of single versus group μCT on the detection of trabecular and cortical disease phenotypes in mouse bones. JBMR Plus 5:e10473

    Article  CAS  Google Scholar 

  19. Metzger CE, Swallow EA, Stacy AJ, Allen MR (2021) Adenine-induced chronic kidney disease induces a similar skeletal phenotype in male and female C57BL/6 mice with more severe deficits in cortical bone properties of male mice. PLoS ONE 16:e0250438

    Article  CAS  Google Scholar 

  20. Sato AY, Cregor M, McAndrews K, Li T, Condon KW, Plotkin LI, Bellido T (2019) Glucocorticoid-induced bone fragility is prevented in female mice by blocking Pyk2/anoikis signaling. Endocrinology 160:1659–1673

    Article  Google Scholar 

  21. Wu YY, Xiao E, Graves DT (2015) Diabetes mellitus related bone metabolism and periodontal disease. Int J Oral Sci 7:63–72

    Article  CAS  Google Scholar 

  22. Chen J, Hendriks M, Chatzis A, Ramasamy SK, Kusumbe AP (2020) Bone vasculature and bone marrow vascular niches in health and disease. J Bone Miner Res 35:2103–2120

    Article  CAS  Google Scholar 

  23. Prisby RD, Swift JM, Bloomfield SA, Hogan HA, Delp MD (2008) Altered bone mass, geometry and mechanical properties during the development and progression of type 2 diabetes in the Zucker diabetic fatty rat. J Endocrinol 199:379–388

    Article  CAS  Google Scholar 

  24. Hankenson KD, Dishowitz M, Gray C, Schenker M (2011) Angiogenesis in bone regeneration. Injury 42:556–561

    Article  Google Scholar 

  25. Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376–380

    Article  CAS  Google Scholar 

  26. Sivaraj KK, Dharmalingam B, Mohanakrishnan V, Jeong HW, Kato K, Schröder S, Adams S, Koh GY, Adams RH (2020) YAP1 and TAZ negatively control bone angiogenesis by limiting hypoxia-inducible factor signaling in endothelial cells. Elife 9

  27. Hu XF, Xiang G, Wang TJ, Ma YB, Zhang Y, Yan YB, Zhao X, Wu ZX, Feng YF, Lei W (2021) Impairment of type H vessels by NOX2-mediated endothelial oxidative stress: critical mechanisms and therapeutic targets for bone fragility in streptozotocin-induced type 1 diabetic mice. Theranostics 11:3796–3812

    Article  CAS  Google Scholar 

  28. Hanne NJ, Easter ED, Cole JH (2019) Minimally invasive laser Doppler flowmetry is suitable for serial bone perfusion measurements in mice. Bone Rep 11:100231

    Article  Google Scholar 

  29. Grüneboom A, Hawwari I, Weidner D, Culemann S, Müller S, Henneberg S, Brenzel A, Merz S, Bornemann L, Zec K, Wuelling M, Kling L, Hasenberg M, Voortmann S, Lang S, Baum W, Ohs A, Kraff O, Quick HH, Jäger M, Landgraeber S, Dudda M, Danuser R, Stein JV, Rohde M, Gelse K, Garbe AI, Adamczyk A, Westendorf AM, Hoffmann D, Christiansen S, Engel DR, Vortkamp A, Krönke G, Herrmann M, Kamradt T, Schett G, Hasenberg A, Gunzer M (2019) A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab 1:236–250

    Article  Google Scholar 

  30. Kalaitzoglou E, Popescu I, Bunn RC, Fowlkes JL, Thrailkill KM (2016) Effects of type 1 diabetes on osteoblasts, osteocytes, and osteoclasts. Curr Osteoporos Rep 14:310–319

    Article  Google Scholar 

  31. Chen D, Tian W, Li Y, Tang W, Zhang C (2012) Osteoblast-specific transcription factor Osterix (Osx) and HIF-1α cooperatively regulate gene expression of vascular endothelial growth factor (VEGF). Biochem Biophys Res Commun 424:176–181

    Article  CAS  Google Scholar 

  32. Ucer Ozgurel S, McAndrews K, Halladay D, Cregor M, Bellido T (2019) Female mice exhibit a reduced diabetic response to streptozotocin compared to male mice and do not lose bone. In: ASBMR

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Acknowledgements

GTT was performed by the Center for Diabetes and Metabolic Diseases Core Facility. This research was supported by the National Institutes of Health NIH-NIAMS (5T32AR065971-06 to SUO).

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Author notes

  1. Serra Ucer Ozgurel

    Present address: Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA

Authors and Affiliations

  1. Department of Anatomy, Cell Biology, and Physiology, School of Medicine, Indiana University, Indianapolis, IN, USA

    Serra Ucer Ozgurel, Elizabeth A. Swallow, Corinne E. Metzger & Matthew R. Allen

  2. Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA

    Matthew R. Allen

  3. Department of Medicine - Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA

    Matthew R. Allen

  4. Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA

    Matthew R. Allen

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  1. Serra Ucer Ozgurel
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  2. Elizabeth A. Swallow
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  3. Corinne E. Metzger
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  4. Matthew R. Allen
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Contributions

SUO and MRA designed the primary study. SUO, EAS, and CEM performed all animal procedures; SUO analyzed the data. SUO drafted the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Serra Ucer Ozgurel.

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Conflict of interest

Serra Ucer Ozgurel, Elizabeth A. Swallow, Corinne E. Metzger, Matthew R. Allen have nothing to disclose. Dr. Allen is in the Editorial Board of Calcified Tissue International and Musculoskeletal Research Journal.

Human and Animal Rights and Informed Consent

All procedures involving animals were in compliance with the Institutional Animal Care and Use Committee at Indiana University School of Medicine (Protocol number: 20038).

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Ucer Ozgurel, S., Swallow, E.A., Metzger, C.E. et al. Femoral Skeletal Perfusion is Reduced in Male Mice with Type 1 Diabetes. Calcif Tissue Int 111, 323–330 (2022). https://doi.org/10.1007/s00223-022-00992-y

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  • DOI: https://doi.org/10.1007/s00223-022-00992-y

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