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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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
Hygum K, Starup-Linde J, Langdahl BL (2019) Diabetes and bone. Osteoporos Sarcopenia 5:29–37
Rask-Madsen C, King GL (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17:20–33
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
Jiao H, Xiao E, Graves DT (2015) Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep 13:327–335
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
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
Botolin S, McCabe LR (2006) Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem 99:411–424
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
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
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
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
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
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
Raisz LG, Rodan GA (2003) Pathogenesis of osteoporosis. Endocrinol Metab Clin North Am 32:15–24
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
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
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
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
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
Wu YY, Xiao E, Graves DT (2015) Diabetes mellitus related bone metabolism and periodontal disease. Int J Oral Sci 7:63–72
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
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
Hankenson KD, Dishowitz M, Gray C, Schenker M (2011) Angiogenesis in bone regeneration. Injury 42:556–561
Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376–380
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
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
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
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
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
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
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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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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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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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.
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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