Skip to main content

Advertisement

SpringerLink
Log in

The Clinical Relevance of the Bone Vascular System: Age-Related Implications

  • Review Paper
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

]The microcirculation of bone and marrow is vital for bone development, maintenance, and repair. In addition to the well-known function of transporting oxygen, nutrients, systemic hormones, precursor cells, waste, etc., the bone vascular network plays a role in the mechanical induction of bone formation. In addition, arteries and marrow sinusoids are critical components of hematopoietic stem cell niches. This review discusses the various roles of the bone and marrow microcirculation in regard to (1) bone development, remodeling, and fracture repair; (2) the regulation of bone intramedullary pressure and interstitial fluid flow; and (3) the mobilization of mature blood cells into the peripheral circulation. Age-associated dysfunction of the microcirculation is discussed in relation to how it may disturb bone and marrow homeostasis, fracture repair, and organismal vitality. Finally, the review invites the reader to consider the efficacy of treatments designed to alleviate bone and marrow pathologies in the face of a compromised vascular network.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kang L, Reyes RA, Muller-Delp JM. Aging impairs flow-induced dilation in coronary arterioles: role of NO and H(2)O(2). Am J Physiol Heart Circ Physiol. 2009;297:H1087–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Park Y, Prisby RD, Behnke BJ, Dominguez JM 2nd, Lesniewski LA, Donato AJ, et al. Effects of aging, TNF-α, and exercise training on angiotensin II-induced vasoconstriction of rat skeletal muscle arterioles. J Appl Physiol. 2012;113(7):1091–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lesniewski L, Durrant JR, Connell ML, Henson GD, Black AD, Donato AJ, et al. Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol Heart Circ Physiol. 2011;301(3):H1025–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Prisby RD, Ramsey MW, Behnke BJ, Dominguez JM, Donato AJ, Allen MR, et al. Aging reduces skeletal blood flow, endothelium-dependent vasodilation and nitric oxide bioavailability in rats. J Bone Miner Res. 2007;22:1280–8.

    Article  CAS  PubMed  Google Scholar 

  5. Prisby RD, Muller-Delp J, Delp MD, Nurkiewicz TR. Age, gender and hormonal status modulate the vascular toxicity of the diesel exhaust extract phenanthraquinone. J Toxicol Environ Health A. 2008;71:464–70.

    Article  CAS  PubMed  Google Scholar 

  6. Dominguez JM, Prisby RD, Muller-Delp JM, Allen MR, Delp MD. Increased nitric oxide-mediated vasodilation of bone resistance arteries is associated with increased trabecular bone volume after endurance training in rats. Bone. 2010;46:813–9. https://doi.org/10.1016/j.bone.2009.10.029.

    Article  CAS  PubMed  Google Scholar 

  7. Prisby RD, Dominguez JM 2nd, Muller-Delp J, Allen MR, Delp MD. Aging and estrogen status: a possible endothelium-dependent vascular coupling mechanism in bone remodeling. PLoS One. 2012;7:e48564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lee S, Bice A, Hood B, Ruiz J, Kim J, Prisby RD. Intermittent PTH 1-34 administration improves the marrow microenvironment and endothelium-dependent vasodilation in bone arteries of aged rats. J Appl Physiol. 2018;124(6):1426–37. https://doi.org/10.1152/japplphysiol.00847.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Prisby R. Bone marrow blood vessel ossification and “microvascular dead space” in rat and human long bone. Bone. 2014;64:195–203. https://doi.org/10.1016/j.bone.2014.03.041.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Burkhardt R, Kettner G, Bohm W, Schmidmeier M, Schlag R, Frisch B, et al. Changes in trabecular bone, hematopoiesis and bone-marrow vessels in aplastic-anemia, primary osteoporosis, and old-age: a comparative histomorphometric study. Bone. 1987;8(3):157–64.

    Article  CAS  PubMed  Google Scholar 

  11. Bocchi L, Orso CA, Passarello F, Lio R, Petrelli L, Tanganelli P, et al. Atherosclerosis of the microcirculation in the femoral head: based on a study by optical and electron microscopy of femoral heads removed at operation. Ital J Orthop Traumatol. 1985;11(3):365–70.

    CAS  PubMed  Google Scholar 

  12. Ramseier E. Untersuchungen uber arteriosklerotische veranderungen der knochenarterien. Virchows Archiv. A, Pathology. 1962;336(1):77–86.

    Article  Google Scholar 

  13. Takasaki M, Tsurumi N, Harada M, Rokugo N, Ebihara Y, Wakasugi K. Changes of bone marrow arteries with aging. Jpn J Geriat. 1999;36:638–43.

    Article  CAS  Google Scholar 

  14. Griffith JF, Yeung DK, Tsang PH, Choi KC, Kwok TC, Ahuja AT, et al. Compromised bone marrow perfusion in osteoporosis. J Bone Miner Res. 2008;23:1068–75.

    Article  PubMed  Google Scholar 

  15. Griffith JF, Yeung DKW, Antonia GE, Lee FKH, Hong AWL, Wong SYS, et al. Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy. Radiology. 2005;236:945–51.

    Article  PubMed  Google Scholar 

  16. Bloomfield S, Hogan HA, Delp MD. Decreases in bone blood flow and bone material properties in aging Fischer-344 rats. Clin Orthop Related Res. 2002;396:248–57.

    Article  Google Scholar 

  17. Choi I, Chung CY, Cho TJ, Yoo WJ. Angiogenesis and mineralization during distraction osteogenesis. J Korean Med Sci. 2002;17:435–47.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Amir L, Becking AG, Jovanovic A, Perdijk FB, Everts V, Bronckers AL. Formation of new bone during vertical distraction osteogenesis of the human mandible is related to the presence of blood vessels. Clin Oral Implants Res. 2006;17:410–6.

    Article  PubMed  Google Scholar 

  19. Rowe N, Mehrara BJ, Luchs JS, Dudziak ME, Steinbrech DS, Illei PB, et al. Angiogenesis during mandibular distraction osteogenesis. Ann Plast Surg. 1999;42(5):470–5.

    Article  CAS  PubMed  Google Scholar 

  20. Kanczler JM, Oreffo RO. Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater. 2008;15:100–14.

    Article  CAS  PubMed  Google Scholar 

  21. Hansen E. Mircovascularization, osteogenesis, and myelopoiesis in normal and pathological conditions. In: Schoutens A, Arlet J, Gardeniers JWM, Hughes SPF, editors. Bone circulation and vascularization in normal and pathological conditions, Nato Science Series: A. New York: Plenum Press; 1993. p. 29–41.

    Chapter  Google Scholar 

  22. Thompson T, Owens PD, Wilson DJ. Intramembranous osteogenesis and angiogenesis in the chick embryo. J Anat. 1989;166:55–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Li G, Simpson AH, Kenwright J, Triffitt JT. Effect of lengthening rate on angiogenesis during distraction osteogenesis. J Orthop Res. 1999;17(3):362–7.

    Article  CAS  PubMed  Google Scholar 

  24. Reilly T, Seldes R, Luchetti W, Brighton CT. Similarities in the phenotypic expression of pericytes and bone cells. Clin Orthop Relat Res. 1998;346:95–103.

    Article  Google Scholar 

  25. Kuznetsov S, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey PG. Circulating skeletal stem cells. J Cell Biol. 2001;153:1133–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lewinson D, Maor G, Rozen N, Rabinovich I, Stahl S, Rachmiel A. Expression of vascular antigens by bone cells during bone regeneration in a membranous bone distraction system. Histochem Cell Biol. 2001;116(5):381–8.

    Article  CAS  PubMed  Google Scholar 

  27. Bronckers A, Sasaguri K, Cavender AC, D'Souza RN, Engelse MA. Expression of Runx2/Cbfa1/Pebp2alphaA during angiogenesis in postnatal rodent and fetal human orofacial tissues. J Bone Miner Res. 2005;20:428–37.

    Article  CAS  PubMed  Google Scholar 

  28. Choi I, Ahn JH, Chung CY, Cho TJ. Vascular proliferation and blood supply during distraction osteogenesis: a scanning electron microscopic observation. J Orthop Res. 2000;18:698–705.

    Article  CAS  PubMed  Google Scholar 

  29. Aronson J, Harrison BH, Stewart CL, Harp JH Jr. The histology of distraction osteogenesis using different external fixators. Clin Orthop Relat Res. 1989;241:106–16.

    Google Scholar 

  30. Aldegheri R, Volino C, Ambito Z, Tessari G, Trivella G. Use of ultrasound to monitor limb lengthening by callotasis. J Pediatr Orthop. 1993;2(1):22–7.

    Article  Google Scholar 

  31. Aronson L. The biology of distraction osteogenesis. Operative principles of Ilizarow. In: Fracture treatment, nonunion, osteomyelitis, lengthening, deformity correction. Baltimore: Williams and Wilkins; 1991.

    Google Scholar 

  32. Aronson J. Experimental assessment of bone regenerate quality during distraction osteogenesis. In: Brighton C, Friedlander GE, Lane JM, editors. Bone formation and repair. Illinois: The Amercian Academy of Orthopedic Surgeons; 1994. p. 441–63.

    Google Scholar 

  33. Aronson J. Temporal and spatial increases in blood flow during distraction osteogenesis. Clin Orthop Relat Res. 1994;301:124–31.

    Google Scholar 

  34. Yasui N, Sato M, Ochi T, Kimura T, Kawahata H, Kitamura Y, et al. Three modes of ossification during distraction osteogenesis in the rat. J Bone Joint Surg Br. 1997;79(5):824–30.

    Article  CAS  PubMed  Google Scholar 

  35. Marks SC, Hermey DC. The structure and development of bone. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. San Diego: Academic Press; 1996.

    Google Scholar 

  36. Ortega N, Wang K, Ferrara N, Werb Z, Vu TH. Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation. Dis Model Mech. 2010;3(3-4):224–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gerber H-P, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Medicine. 1999;5:623–8.

    CAS  Google Scholar 

  38. Ben Shoham A, Rot C, Stern T, Krief S, Akiva A, Dadosh T, et al. Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology. Development. 2016;143(21):3933–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010;19:329–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ramasamy S, Kusumbe AP, Wang L, Adams RH. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. 2014;507:376–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kusumbe A, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507:323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Doll B. Developmental biology of the skeletal system. In: Hollinger J, Einhorn TA, Doll BA, Sfeir C, editors. Bone tissue engineering. Boca Raton, FL: CRC Press; 2005. p. 3–26.

    Google Scholar 

  43. Frost H. The skeletal intermediary organization. Metab Bone Dis Relat Res. 1983;4(5):281–90.

    Article  CAS  PubMed  Google Scholar 

  44. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res. 2001;16:1575–82.

    Article  CAS  PubMed  Google Scholar 

  45. Parfitt A. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55(3):273–86.

    Article  CAS  PubMed  Google Scholar 

  46. Parfitt AM. Mini-review: osteoclast precursors as leukocytes: importance of the area code. Bone. 1998;23:491–4.

    Article  CAS  PubMed  Google Scholar 

  47. Melsen F, Mosekilde L, Eriksen EF. Spatial distribution of sinusoids in relation to remodeling sites: evidence for specialized sinusoidal structures associated with formative sites. J Bone Miner Res. 1995;10:S209.

    Google Scholar 

  48. Ferguson C, Alpern E, Miclau T, Helms JA. Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev. 1999;87(1-2):57–66.

    Article  CAS  PubMed  Google Scholar 

  49. Paradis G, Kelly PJ. Blood flow and mineral deposition in canine tibial fractures. J Bone Joint Surg Am. 1975;57(2):220–6.

    Article  CAS  PubMed  Google Scholar 

  50. McCarthy ID, Hughes SPF. Extraction of 99mTC-methylene diphosphonate as a function of bone blood flow. In: Artlet J, Ficat RP, Hungerford DS, editors. Bone circulation. Baltimore: Williams and Wilkins; 1984. p. 167–70.

    Google Scholar 

  51. Santolini E, Goumenos SD, Giannoudi M, Sanguineti F, Stella M, Giannoudis PV. Femoral and tibial blood supply: a trigger for non-union? Injury. 2014;45:1665–73.

    Article  PubMed  Google Scholar 

  52. Tzioupis C, Giannoudis PV. Prevalence of long-bone non-unions. Injury. 2007;38:S3–9.

    Article  PubMed  Google Scholar 

  53. Brookes M, Revell WJ. Blood supply of bone: scientific aspects. London: Springer-Verlag; 1998.

    Book  Google Scholar 

  54. McCarthy I. The physiology of bone blood flow: a review. J Bone Joint Surg Am. 2006;88:4–9.

    PubMed  Google Scholar 

  55. Zamboni L, Pease DC. The vascular bed of red bone marrow. J Ultrastruct Res. 1961;5:65–85.

    Article  CAS  PubMed  Google Scholar 

  56. Cowin S, Cardoso L. Blood and interstitial flow in the hierarchical pore space architecture of bone tissue. J Biomech. 2015;48(5):842–54.

    Article  PubMed  Google Scholar 

  57. Montgomery R, Sutker BD, Bronk JT, Smith SR, Kelly PJ. Interstitial fluid flow in cortical bone. Microvasc Res. 1988;35:295–307.

    Article  CAS  PubMed  Google Scholar 

  58. Lam H, Brink P, Qin YX. Skeletal nutrient vascular adaptation induced by external oscillatory intramedullary fluid pressure intervention. J Orthop Surg Res. 2010;5. https://doi.org/10.1186/1749-1799X-1185-1118.

  59. Grüneboom A, Hawwari I, Weidner D, Culemann S, Müller S, Henneberg S, et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab. 2019. https://doi.org/10.1038/s42255-018-0016-5.

  60. Delp MD, Evans MV, Duan C. Effects of aging on cardiac output, regional blood flow, and body composition in Fischer-344 rats. J Appl Physiol. 1998;85(5):1813–22.

    Article  CAS  PubMed  Google Scholar 

  61. Prisby R. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. J Endocrinol. 2017;235:R77–R100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kwon R, Meays DR, Tang WJ, Frangos JA. Microfluidic enhancement of intramedullary pressure increases interstitial fluid flow and inhibits bone loss in hindlimb suspended mice. J Bone Mineral Res. 2010;25:1798–807.

    Article  Google Scholar 

  63. Thomas I, Gregg PJ, Walder DN. Intra-osseous phlebography and intramedullary pressure in the rabbit femur. J Bone and Joint Surg. 1982;64:239–42.

    Article  CAS  Google Scholar 

  64. Piekarski K, Munro M. Transport mechanism operating between blood supply and osteocytes in long bones. Nature. 1977;269:80–2.

    Article  CAS  PubMed  Google Scholar 

  65. Wolff J. The law of bone remodeling. Berlin: Springer; 1986.

    Book  Google Scholar 

  66. Qin Y, Kaplan T, Saldanha A, Rubin C. Fluid pressure gradients, arising from oscillations in intramedullary pressure, is correlated with the formation of bone and inhibition of intracortical porosity. J Biomech. 2003;36(10):1427–37.

    Article  PubMed  Google Scholar 

  67. Revell WJ, Brookes M. Haemodynamic changes in the rat femur and tibia following femoral vein ligation. J Anat. 1994;184:625–33.

    PubMed  PubMed Central  Google Scholar 

  68. Kelly P, Bronk JT. Venous pressure and bone formation. Microvasc Res. 1990;39:364–75.

    Article  CAS  PubMed  Google Scholar 

  69. Hu M, Cheng J, Bethel N, Serra-Hsu F, Ferreri S, Lin L, et al. Interrelation between external oscillatory muscle coupling amplitude and in vivo intramedullary pressure related bone adaptation. Bone. 2014;66:178–81.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Johnson DL, McAllister TN, Frangos JA. Fluid flow stimulates rapid and continuous release of nitric oxide in osteoblasts. Am J Phys. 1996;271:E205–8.

    CAS  Google Scholar 

  71. McAllister TN, Du T, Frangos JA. Fluid shear stress stimulates prostaglandin and nitric oxide release in bone marrow-derived preosteoclast-like cells. Biochem Biophys Res Commun. 2000;270:643–8.

    Article  CAS  PubMed  Google Scholar 

  72. McAllister TN, Frangos JA. Steady and transient fluid shear stress stimulate NO release in osteoblast through distinct biochemical pathways. J Bone Miner Res. 1999;14:930–6.

    Article  CAS  PubMed  Google Scholar 

  73. Zaman G, Pitsillides AA, Rawlinson SC, Suswillo RF, Mosley JR, Cheng MZ, et al. Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J Bone Miner Res. 1999;14(7):1123–31.

    Article  CAS  PubMed  Google Scholar 

  74. Hikiji H, Shin WS, Oida S, Takato T, Koizumi T, Toyo-Oka T. Direct action of nitric oxide on osteoblastic differentiation. FEBS Lett. 1997;410:238–42.

    Article  CAS  PubMed  Google Scholar 

  75. Riancho JA, Salas E, Zarrabeitia MT, Olmos JM, Amado JA, Fernandez-Luna JL, et al. Expression and functional role of nitric oxide synthase in osteoblast-like cells. J Bone Miner Res. 1995;10:439–46.

    Article  CAS  PubMed  Google Scholar 

  76. Kasten TP, Collin-Osdoby P, Patel N, Osdoby P, Krukowski M, Misko TP, et al. Potentiation of osteoclast bone-resorption activity by inhibition of nitric oxide synthase. Proc Natl Acad Sci U S A. 1994;91:3569–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Akamine T, Jee WS, Ke HZ, Li XJ, Lin BY. Prostaglandin E2 prevents bone loss and adds extra bone to immobilized distal femoral metaphysis in female rats. Bone. 1991;13:11–22.

    Article  Google Scholar 

  78. Alam A, Gallagher A, Shankar V, Ghate MA, Datta HK, Huang CL, et al. Endothelin inhibits osteoclastic bone resorption by a direct effect on cell motility: implications for the vascular control of bone resorption. Endocrinology. 1992;130:3617–24.

    Article  CAS  PubMed  Google Scholar 

  79. Fiorelli G, Orlando C, Benvenuti S, Franceschelli F, Bianchi S, Pioli P, et al. Characterization, regulation, and function of specific cell membrane receptors for insulin-like growth factor I on bone endothelial cells. J Bone Miner Res. 1994;9:329–37.

    Article  CAS  PubMed  Google Scholar 

  80. Shinozuka K, Hashimoto M, Masumura S, Bjur RA, Westfall DP, Hattori K. In vitro studies of release of adenine nucleotides and adenosine from rat vascular endothelium in response to alpha 1-adrenoceptor stimulation. Br J Pharmacol. 1994;113:1203–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang Y, Fujita N, Oh-hara T, Morinaga Y, Nakagawa T, Yamada M, et al. Production of interleukin-11 in bone-derived endothelial cells and its role in the formation of osteolytic bone metastasis. Oncogene. 1998;16(6):693–703.

    Article  CAS  PubMed  Google Scholar 

  82. Kage K, Fujita N, Oh-hara T, Ogata E, Fujita T, Tsuruo T. Basic fibroblast growth factor induces cyclooxygenase-2 expression in endothelial cells derived from bone. Biochem Biophys Res Commun. 1999;254:259–63.

    Article  CAS  PubMed  Google Scholar 

  83. Ishida A, Fujita N, Kitazawa R, Tsuruo T. Transforming growth factor-beta induces expression of receptor activator of NF-kappa B ligand in vascular endothelial cells derived from bone. J Biol Chem. 2002;277:26217–24.

    Article  CAS  PubMed  Google Scholar 

  84. Brandi ML, Collin-Osdoby P. Vascular biology and the skeleton. J Bone Miner Res. 2006;21(2):183–92.

    Article  CAS  PubMed  Google Scholar 

  85. Gonzalez C, Rosas-Hernandez H, Jurado-Manzano B, Ramirez-Lee MA, Salazar-Garcia S, Martinez-Cuevas PP, et al. The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings. Acta Pharmacol Sin. 2015;36:572–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wen Q, Lee KO, Sim SZ, Xu XG, Sim MK. Des-aspartate-angiotensin I causes specific release of PGE2 and PGI2 in HUVEC via the angiotensin AT1 receptor and biased agonism. Eur J Pharmacol. 2015;768:173–81.

    Article  CAS  PubMed  Google Scholar 

  87. Gutterman D, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K, et al. The human microcirculation: regulation of flow and beyond. Circ Res. 2016;118(1):157–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol. 2008;8:290–301.

    Article  CAS  PubMed  Google Scholar 

  89. Goldsby RA, Kindt TJ, Osborne BA. Immunology. 4th ed. New York: W.H. Freeman and Company; 2000.

    Google Scholar 

  90. Zhu L, Emerson SG. A new bone to pick: osteoblasts and the haematopoietic stem-cell niche. BioEssays. 2004;26:595–9.

    Article  PubMed  Google Scholar 

  91. Fliedner T, Graessle D, Paulsen C, Reimers K. Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure. Cancer Biother Radiopharm. 2002;17(4):405–26.

    Article  CAS  PubMed  Google Scholar 

  92. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4:7–25.

    CAS  PubMed  Google Scholar 

  93. Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006;116:1195–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.

    Article  CAS  PubMed  Google Scholar 

  95. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood. 2001;97:2293–9.

    Article  CAS  PubMed  Google Scholar 

  96. Gong JK. Endosteal marrow: a rich source of hematopoietic stem cells. Science. 1978;199(4336):1443–5.

    Article  CAS  PubMed  Google Scholar 

  97. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109(5):625–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Arai F, Suda T. Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Ann N Y Acad Sci. 2007;1106:41–53.

    Article  CAS  PubMed  Google Scholar 

  99. Calvi L, Link DC. The hematopoietic stem cell niche in homeostasis and disease. Blood. 2015;126(22):2443–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schiff L, Poncz M, Bergman A, Frenette PS. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014;20:1315–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H, Inra CN, et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature. 2015;526:126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dennis JE, Charbord P. Origin and differentiation of human and murine stroma. Stem Cells. 2002;20(3):205–14.

    Article  CAS  PubMed  Google Scholar 

  103. Moore A, Blake GM, Taylor KA, Rana AE, Wong M, Chen P, et al. Assessment of regional changes in skeletal metabolism following 3 and 18 months of teriparatide treatment. J Bone Miner Res. 2010;25:960–7.

    CAS  PubMed  Google Scholar 

  104. Taichman R. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005;105(7):2631–9.

    Article  CAS  PubMed  Google Scholar 

  105. Gurkan U, Akkus O. The mechanical environment of bone marrow: a review. Ann Biomed Eng. 2008;36:1978–91.

    Article  PubMed  Google Scholar 

  106. Brookes M, Lloyd EG. Marrow vascularization and oestrogen-induced endosteal bone formation in mice. J Anat. 1961;95:220–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bianco P, Riminucci M, Kuznetsov S, Robey PG. Multipotential cells in the bone marrow stroma: regulation in the context of organ physiology. Crit Rev Eukaryot Gene Expr. 1999;9(2):159–73.

    Article  CAS  PubMed  Google Scholar 

  108. Kiel M, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–21.

    Article  CAS  PubMed  Google Scholar 

  109. Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ramasamy S, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, et al. Blood flow controls bone vascular function and osteogenesis. Nat Commun. 2016;7. https://doi.org/10.1038/ncomms13601.

  111. Wickramasinghe S. Observations on the ultrastructure of sinusoids and reticular cells in human bone marrow. Clin Lab Haematol. 1991;13:263–78.

    Article  CAS  PubMed  Google Scholar 

  112. Hudson G, Yoffey JM. The passage of lymphocytes through the sinusoidal endothelium of guinea-pig bone marrow. Proc R Soc Lond B Biol Sci. 1966;165:486–96.

    Article  CAS  PubMed  Google Scholar 

  113. Weiss L. The structure of bone marrow. Functional interrelationships of vascular and hematopoietic compartments in experimental hemolytic anemia: an electron microscopic study. J Morphol. 1965;117:467–537.

    Article  CAS  PubMed  Google Scholar 

  114. De Bruyn P, Michelson S, Thomas TB. The migration of blood cells of the bone marrow through the sinusoidal wall. J Morphol. 1971;133(4):417–37.

    Article  PubMed  Google Scholar 

  115. Campbell F. Ultrastructural studies of transmural migration of blood cells in the bone marrow of rats, mice and guinea pigs. Am J Anat. 1972;135(4):521–35.

    Article  CAS  PubMed  Google Scholar 

  116. Tavassoli M, Crosby WH. Fate of the nucleus of the marrow erythroblast. Science. 1973;179(4076):912–3.

    Article  CAS  PubMed  Google Scholar 

  117. Giordano G, Lichtman MA. Marrow cell egress. The central interaction of barrier pore size and cell maturation. J Clin Invest. 1973;52(5):1154–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature. 2016;532:323–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ellis S, Grassinger J, Jones A, Borg J, Camenisch T, Haylock D, et al. The relationship between bone, hemopoietic stem cells, and vasculature. Blood. 2011;118:1516–24.

    Article  CAS  PubMed  Google Scholar 

  120. Haylock D, Nilsson SK. The role of hyaluronic acid in hemopoietic stem cell biology. Regen Med. 2006;1:437–45.

    Article  CAS  PubMed  Google Scholar 

  121. Füreder W, Krauth MT, Sperr WR, Sonneck K, Simonitsch-Klupp I, Müllauer L, et al. Evaluation of angiogenesis and vascular endothelial growth factor expression in the bone marrow of patients with aplastic anemia. Am J Pathol. 2006;168(1):123–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. 2005;106:1901–10.

    Article  CAS  PubMed  Google Scholar 

  123. Dabrowski Z, Szyguła Z, Miszta H. Do changes in bone marrow pressure contribute to the egress of cell from bone marrow? Acta Phys Pol A. 1981;32:729–36.

    CAS  Google Scholar 

  124. Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity. 2003;19(4):583–93.

    Article  CAS  PubMed  Google Scholar 

  125. Penninx B, Guralnik JM, Onder G, Ferrucci L, Wallace RB, Pahor M. Anemia and decline in physical performance among older persons. Am J Med. 2003;115(2):104–10.

    Article  PubMed  Google Scholar 

  126. Makovey J, Macara M, Chen JS, Hayward CS, March L, Sambrook PN. High osteoporotic fracture risk and CVD risk co-exist in postmenopausal women. Bone. 2013;52:120–5.

    Article  PubMed  Google Scholar 

  127. Gaudio A, Xourafa A, Rapisarda R, Castellino P, Signorelli SS. Peripheral artery disease and osteoporosis: not only age-related (review). Mol Med Rep. 2018. https://doi.org/10.3892/mmr.2018.9512.

  128. Bridgeman G, Brookes M. Blood supply to the human femoral diaphysis in youth and senescence. J Anat. 1996;188:611–21.

    PubMed  PubMed Central  Google Scholar 

  129. Spencer H, Hausinger A, Laszlo D. The calcium tolerance test in senile osteoporosis. J Am Geriatr Soc. 1954;2(1):19–25.

    Article  CAS  PubMed  Google Scholar 

  130. Vogt M, Cauley JA, Kuller LH, Nevitt MC. Bone mineral density and blood flow to the lower extremities: the study of osteoporotic fractures. J Bone Miner Res. 1997;12(2):283–9.

    Article  CAS  PubMed  Google Scholar 

  131. Trueta J, Little K. The vascular contribution to osteogenesis. II. Studies with the electron microscope. J Bone Joint Surg Br. 1960;42-B:367–76.

    Article  CAS  PubMed  Google Scholar 

  132. Trueta J, Morgan JD. The vascular contribution to osteogenesis. I. Studies by the injection method. J Bone Joint Surg Br. 1960;42-B(1):97–109.

    Article  CAS  PubMed  Google Scholar 

  133. Griffith J, Wang YX, Zhou H, Kwong WH, Wong WT, Sun YL, et al. Reduced bone perfusion in osteoporosis: likely causes in an ovariectomy rat model. Radiology. 2010;254:739–46.

    Article  PubMed  Google Scholar 

  134. Bick E, Copel JW. The senescent human vertebra; contribution to human osteogeny. III J Bone Joint Surg Am. 1952;34-A(1):110–4.

    Article  CAS  PubMed  Google Scholar 

  135. Lu C, Hansen E, Sapozhnikova A, Hu D, Miclau T, Marcucio RS. Effect of age on vascularization during fracture repair. J Orthop Res. 2008;26:1384–9.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Brenneise CV, Squier CA. Blood flow in maxilla and mandible of normal and atherosclerotic rhesus monkeys. J Oral Pathol. 1985;14(10):800–8.

    Article  CAS  PubMed  Google Scholar 

  137. Mahlknecht U, Kaiser S. Age-related changes in peripheral blood counts in humans. Exp Ther Med. 2010;1(6):1019–25.

    Article  PubMed  PubMed Central  Google Scholar 

  138. den Elzen W, Willems JM, Westendorp RC, de Craen AJ, Assendelft WJ, Gussekloo J. Effect of anemia and comorbidity on functional status and mortality in old age: results from the Leiden 85-plus study. CMAJ. 2009;181(3-4):151–7.

    Article  Google Scholar 

  139. Chaves P. Functional outcomes of anemia in older adults. Semin Hematol. 2008;45(4):255–60.

    Article  PubMed  Google Scholar 

  140. Balducci L. Epidemiology of anemia in the elderly: information on diagnostic evaluation. J Am Geriatr Soc. 2003;51:S2–9.

    Article  PubMed  Google Scholar 

  141. Gabrilove J. Anemia and the elderly: clinical considerations. Best Pract Res Clin Haematol. 2005;3:417–22.

    Article  Google Scholar 

  142. Ohta M. Management of anemia in the elderly. JMAJ. 2009;52:219–23.

    Google Scholar 

  143. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.

    Article  CAS  PubMed  Google Scholar 

  144. Lipschitz D, Udupa KB, Milton KY, Thompson CO. Effect of age on hematopoiesis in man. Blood. 1984;63(3):502–9.

    CAS  PubMed  Google Scholar 

  145. Nilsson-Ehle H, Jagenburg R, Landahl S, Svanborg A. Blood haemoglobin declines in the elderly: implications for reference intervals from age 70 to 88. Eur J Haematol. 2000;65:297–305.

    Article  CAS  PubMed  Google Scholar 

  146. Young D. Pre-analytical variability in the elderly. Geriatr Clin Chem. 1994:19–39.

  147. Carpenter M, Kendall RG, O'Brien AE, Chapman C, Sebastian JP, Belfield PW, et al. Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia. Eur J Haematol. 1992;49(3):119–21.

    Article  CAS  PubMed  Google Scholar 

  148. Kario K, Matsuo T, Kodama K, Nakao K, Asada R. Reduced erythropoietin secretion in senile anemia. Am J Hematol. 1992;41(4):252–7.

    Article  CAS  PubMed  Google Scholar 

  149. Nafziger J, Pailla K, Luciani L, Andreux JP, Saint-Jean O, Casadevall N. Decreased erythropoietin responsiveness to iron deficiency anemia in the elderly. Am J Hematol. 1993;43(3):172–6.

    Article  CAS  PubMed  Google Scholar 

  150. Timaffy M. A comparative study of bone marrow function in young and old individuals. Gerontol Clin (Basel). 1962;4:13–8.

    Article  CAS  Google Scholar 

  151. Compston JE. Bone marrow and bone: a functional unit. J Endocrinol. 2002;173(3):387–94.

    Article  CAS  PubMed  Google Scholar 

  152. Kita K, Kawai K, Hirohata K. Changes in bone marrow blood flow with aging. J Orthop Res. 1987;5(4):569–75.

    Article  CAS  PubMed  Google Scholar 

  153. Vogel J. Hematologic problems of the aged. Mt Sinai J Med. 1980;47:150–65.

    CAS  PubMed  Google Scholar 

  154. Kusumbe A, Ramasamy SK, Itkin T, Mäe MA, Langen UH, Betsholtz C, et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature. 2016;532:380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Zsebo K, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990;63:213–24.

    Article  CAS  PubMed  Google Scholar 

  158. Chambers S, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 2007;5(8):e201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011;208:2691–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Davis TRC, Wood MB. Bone blood flow. In: Wood MB, Gilber A, editors. Microvascular bone reconstruction. London: The Livery House; 1997. p. 13–7.

    Google Scholar 

  161. Mazo I, von Andrian UA. Adhesion and homing of blood-borne cells in bone marrow microvessels. J Leukoc Biol. 1999;66:25–32.

    Article  CAS  PubMed  Google Scholar 

  162. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211(2):144–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cauley J, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures. Osteoporos Int. 2000;11:556–61.

    Article  CAS  PubMed  Google Scholar 

  164. Bak B, Andreassen TT. The effect of aging on fracture healing in the rat. Calcif Tissue Int. 1989;45:292–7.

    Article  CAS  PubMed  Google Scholar 

  165. Meyer RJ, Meyer MH, Tenholder M, Wondracek S, Wasserman R, Garges P. Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am. 2003;85-A(7):1243–54.

    Article  Google Scholar 

  166. Lu C, Miclau T, Hu D, Hansen E, Tsui K, Puttlitz C, et al. Cellular basis for age-related changes in fracture repair. J Orthop Res. 2005;23:1300–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Stabley J, Prisby RD, Behnke BJ, Delp MD. Type 2 diabetes alters bone and marrow blood flow and vascular control mechanisms in the ZDF rat. J Endocrinol. 2015;225(1):47–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Prisby R, Swift JM, Bloomfield SA, Hogan HA, Delp MD. Altered bone mass, geometry and mechanical properties during the development and progression of type 2 diabetes in the Zucker diabetic fatty rat. J Endocrinol. 2008;199:379–88.

    Article  CAS  PubMed  Google Scholar 

  169. Kapitola J, Kubícková J. Estradiol benzoate decreases the blood flow through the tibia of female rats. Exp Clin Endocrinol. 1990;96(1):117–20.

    CAS  PubMed  Google Scholar 

  170. Kapitola J, Andrle J, Kubícková J. Possible participation of prostaglandins in the increase in the bone blood flow in oophorectomized female rats. Exp Clin Endocrinol. 1994;102:414–6.

    Article  CAS  PubMed  Google Scholar 

  171. Egrise D, Martin D, Neve P, Vienne A, Verhas M, Schoutens A. Bone blood flow and in vitro proliferation of bone marrow and trabecular bone osteoblast-like cells in ovariectomized rats. Calc Tissue Int. 1992;50(4):336–41.

    Article  CAS  Google Scholar 

  172. Hansen VB, Forman A, Lundgaard A, Aalkjær C, Skajaa K, Hansen ES. Effects of oophorectomy on functional properties of resistance arteries isolated from the cancellous bone of the rabbit femur. J Orthop Res. 2001;19(3):391–7.

    Article  CAS  PubMed  Google Scholar 

  173. Roche B, Vanden-Bossche A, Malaval L, Normand M, Jannot M, Chaux R, et al. Parathyroid hormone 1-84 targets bone vascular structure and perfusion in mice: impacts of its administration regimen and of ovariectomy. J Bone Miner Res. 2014;29(7):1608–18.

    Article  CAS  PubMed  Google Scholar 

  174. Prisby R, Behnke BJ, Allen MR, Delp MD. Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery. J Appl Physiol. 2015;118(8):980–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Stabley J, Prisby RD, Behnke BJ, Delp MD. Chronic skeletal unloading of the rat femur: mechanisms and functional consequences of vascular remodeling. Bone. 2013;57(2):355–60.

    Article  PubMed  Google Scholar 

  176. Prisby R, Menezes T, Campbell J. Vasodilation to PTH (1-84) in bone arteries is dependent upon the vascular endothelium and is mediated partially via VEGF signaling. Bone. 2013;54:68–75.

    Article  CAS  PubMed  Google Scholar 

  177. Prisby R, Guignandon A, Vanden-Bossche A, Mac-Way F, Linossier MT, Thomas M, et al. Intermittent PTH(1-84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res. 2011;26(11):2583–96.

    Article  CAS  PubMed  Google Scholar 

  178. Lee S, Prisby RD. Short-term intermittent PTH 1-34 administration and bone marrow blood vessel ossification in mature and middle-aged C57BL/6 mice. Bone Rep. 2019;10. https://doi.org/10.1016/j.bonr.2018.100193.

  179. Guers J, Prisby RD, Edwards DG, Lennon-Edwards S. Intermittent parathyroid hormone administration attenuates endothelial dysfunction in old rats. J Appl Physiol. 2017;122(1):76–81.

    Article  CAS  PubMed  Google Scholar 

  180. Yao Z, Lafage-Proust MH, Plouët J, Bloomfield S, Alexandre C, Vico L. Increase of both angiogenesis and bone mass in response to exercise depends on VEGF. J Bone Miner Res. 2004;19(9):1471–80.

    Article  CAS  PubMed  Google Scholar 

  181. Stabley J, Moningka NC, Behnke BJ, Delp MD. Exercise training augments regional bone and marrow blood flow during exercise. Med Sci Sports Exerc. 2014;46(11):2107–12.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Boss J, Misselevich I. Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals. Vet Pathol. 2003;40(4):345–54.

    Article  CAS  PubMed  Google Scholar 

  183. Yamamoto T, Irisa T, Sugioka Y, Sueishi K. Effects of pulse methylprednisolone on bone and marrow tissues: corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 1997;40:2055–64.

    Article  CAS  PubMed  Google Scholar 

  184. Wang G, Sweet DE, Reger SI, Thompson RC. Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits. J Bone Joint Surg Am. 1977;59(6):729–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bone Vascular and Microcirculation Laboratory, Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA

    Rhonda D. Prisby

Authors
  1. Rhonda D. Prisby
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rhonda D. Prisby.

Ethics declarations

Conflict of Interest

The author declares that she has no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prisby, R.D. The Clinical Relevance of the Bone Vascular System: Age-Related Implications. Clinic Rev Bone Miner Metab 17, 48–62 (2019). https://doi.org/10.1007/s12018-019-09259-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12018-019-09259-x

Keywords

Search

Navigation