The role of microvasculature in normal and perturbed bone healing as revealed by intravital microscopy

Winet, Howard

doi:10.1016/s8756-3282(96)00133-0

Cited by 90 publications

(67 citation statements)

References 47 publications

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“…Neovascularization is indispensable for bone fracture repair, during which a coordinated cross-talk between osteoblasts and endothelial cells needs to take place in the local microenvironment (3)(4)(5)(6). Here, we have demonstrated that VEGF and CCN1 may synergize in coupling osteoblasts and endothelial cells functionally.…”

Section: Discussionmentioning

confidence: 99%

“…During bone growth, vascular structures invade the growth plate regions of the bone, providing a conduit for the entry of chondroclasts and osteoclasts that are involved in resorptive processes, whereas following bone injury, angiogenesis is transiently stimulated to promote repair mechanisms (3)(4)(5). Fracture repair is a multistep process involving migration, proliferation, and differentiation of several cell types such as endothelial cells, fibroblasts, chondroblasts, osteoblasts, and osteoclasts.…”

mentioning

confidence: 99%

“…Among a variety of proangiogenic growth factors, the vascular endothelial growth factor (VEGF) 3 (2) plays a pivotal role in bone remodeling and healing. VEGF is produced by many cells in the bone environment and stimulates the invasion of new blood vessels into the cartilage, thereby playing a crucial role in regulating resorption of cartilage and bone formation (10).…”

mentioning

confidence: 99%

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Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing

Athanasopoulos

Schneider

Keiper

et al. 2007

Journal of Biological Chemistry

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Angiogenesis is indispensable during fracture repair, and vascular endothelial growth factor (VEGF) is critical in this process. CCN1 (CYR61) is an extracellular matrix signaling molecule that has been implicated in neovascularization through its interactions with several endothelial integrin receptors. CCN1 has been shown to be up-regulated during the reparative phase of fracture healing; however, the role of CCN1 therein remains unclear. Here, the regulation of CCN1 expression in osteoblasts and the functional consequences thereof were studied. Stimulation of osteoblasts with VEGF resulted in a dose-and time-dependent up-regulation of CCN1 mRNA and protein. An up-regulation of both cell surface-associated CCN1 as well as extracellular matrix-associated CCN1 in osteoblasts was found. The supernatant of VEGF-prestimulated osteoblasts was chemotactic for endothelial cells, increasing their migration and stimulated capillary-like sprout formation. These effects could be attributed to the presence of CCN1 in the osteoblast supernatant as they were prevented by an antibody against CCN1 or by small interfering RNA-mediated knockdown of osteoblast CCN1. Moreover, the supernatant of VEGF-prestimulated osteoblasts induced angiogenesis in Matrigel plugs in vivo in a CCN1-dependent manner. In addition, blockade of CCN1 prevented bone fracture healing in mice. Taken together, the present work demonstrates a potential paracrine loop consisting of the VEGF-mediated up-regulation of CCN1 in osteoblasts that attracts endothelial cells and promotes angiogenesis. Such a loop could be operative during fracture healing.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing

Athanasopoulos

Schneider

Keiper

et al. 2007

Journal of Biological Chemistry

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“…Several studies have shown that there is a reciprocal regulation and functional relationship between endothelial cells and osteoblast-like cells during osteogenesis, in which systemic hormones and paracrine growth factors or cytokines play an active role (4,24,53,55). In a previous study (51), we showed that osteoblast progenitor cells [human bone marrow stromal cells (HBMSC)] behave differently in terms of proliferation and differentiation when cultured in association with endothelial cells [human umbilical vein endothelial cells (HUVEC)] in various coculture models (coculture with or without direct contact, conditioned medium) than when they are cultured alone.…”

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confidence: 99%

Effect of HUVEC on human osteoprogenitor cell differentiation needs heterotypic gap junction communication

Villars

Guillotin

Amédée

et al. 2002

American Journal of Physiology-Cell Physiology

295

238

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Villars, F., B. Guillotin, T. Amé dé e, S. Dutoya, L. Bordenave, R. Bareille, and J. Amé dé e. Effect of HUVEC on human osteoprogenitor cell differentiation needs heterotypic gap junction communication. Am J Physiol Cell Physiol 282: C775-C785, 2002; 10.1152/ajpcell.00310.2001.-Bone development and remodeling depend on complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Our aim was to investigate the interaction between human umbilical vein endothelial cells (HUVEC) and human bone marrow stromal cells (HBMSC). Cell differentiation analysis performed with different cell culture models revealed that alkaline phosphatase activity and type I collagen synthesis were increased only by the direct contact of HUVEC with HBMSC. This "juxtacrine signaling" could involve a number of different heterotypic connexions that require adhesion molecules or gap junctions. A dye coupling assay with Lucifer yellow demonstrated a functional coupling between HUVEC and HBMSC. Immunocytochemistry revealed that connexin43 (Cx43), a specific gap junction protein, is expressed not only in HBMSC but also in the endothelial cell network and that these two cell types can communicate via a gap junctional channel constituted at least by Cx43. Moreover, functional inhibition of the gap junction by 18␣-glycyrrhetinic acid treatment or inhibition of Cx43 synthesis with oligodeoxyribonucleotide antisense decreased the effect of HUVEC cocultures on HBMSC differentiation. This stimulation could be mediated by the intercellular diffusion of signaling molecules that permeate the junctional channel.coupling; intercellular messenger; connexin43; osteoblast; endothelial cells ANGIOGENESIS is a tightly regulated process involved in growth, repair, and bone remodeling (9, 11-13, 23, 28, 50, 54, 56). Several studies have shown that there is a reciprocal regulation and functional relationship between endothelial cells and osteoblast-like cells during osteogenesis, in which systemic hormones and paracrine growth factors or cytokines play an active role (4,24,53,55). In a previous study (51), we showed that osteoblast progenitor cells [human bone marrow stromal cells (HBMSC)] behave differently in terms of proliferation and differentiation when cultured in association with endothelial cells [human umbilical vein endothelial cells (HUVEC)] in various coculture models (coculture with or without direct contact, conditioned medium) than when they are cultured alone. An increase in alkaline phosphatase activity (Al-P) was observed only when HBMSC were cocultured in direct contact with HUVEC. The enhancement of this early osteoblastic marker is not provided when HBMSC and HUVEC are cocultured separately with the use of a semipermeable membrane (51) or when HBMSC are seeded onto a matrix obtained from HUVEC cultures (51).Therefore, the intercommunication between endothelial cells and os...

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“…Like other organs, the regulation of bone blood flow (osteohemodynamics) is complex and involves numerous physiologic mechanisms including the sympathetic nervous system, circulating hormones, and local metabolic factors [Winet, 1996;Brookes and Revelle, 1998]. Others have clearly demonstrated that exogenous norepinephrine [Stein et al 1958;Ye et al, 1993] and endothelin [Coessens et al 1996;Briggs et al, 1998] constrict the bone vasculature, confirming the presence of functional alpha-adrenergic and endothelin receptors.…”

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confidence: 99%

Bone Blood Flow and Vascular Reactivity

Fleming

Barati

Beck

et al. 2001

Cells Tissues Organs

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Blood flow is essential for normal bone growth and bone repair. Like other organs, the regulation of blood flow to bone is complex and involves numerous physiologic mechanisms including the sympathetic nervous system, circulating hormones, and local metabolic factors. Our studies addressed the following questions: (1) Which endogenous vasoconstrictor agents regulate in vivo blood flow to bone? (2) Does a decrease in bone vascular reactivity to vasoconstrictor hormones account for the increase in blood flow during bone healing? (3) Does the endothelium influence bone arteriolar function? An intact bone model was developed in the rat to assess hormonal regulation of in vivo bone blood flow and in vivo bone vascular reactivity. An isolated, perfused bone arteriole preparation was employed to characterize the responsiveness of small resistance-size arterioles (diameter < 100 µm) to vasoconstrictor hormones and to evaluate the role of the vascular endothelium to modulate vascular smooth muscle reactivity. Our results indicate that: (1) though exogenous endothelin is a potent constrictor of the in vivo bone vasculature, endogenous endothelin does not actively regulate in vivo blood flow; (2) the increase in blood flow to a bone injury site is not due to a decrease in bone vascular sensitivity to norepinephrine, and (3) isolated bone arterioles of young rats are very sensitive to vasoconstrictor hormones but exhibit only modest endothelium-mediated vasodilation.

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The role of microvasculature in normal and perturbed bone healing as revealed by intravital microscopy

Cited by 90 publications

References 47 publications

Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing

Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing

Effect of HUVEC on human osteoprogenitor cell differentiation needs heterotypic gap junction communication

Bone Blood Flow and Vascular Reactivity

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