The role of angiogenesis in a murine tibial model of distraction osteogenesis

Carvalho, Roberto S.; Einhorn, Thomas A.; Lehmann, Wolfgang; Edgar, Cory; Alyamani, Ahmed; Apazidis, Athina; Pacicca, Donna M.; Clemens, Thomas L.; Gerstenfeld, Louis C.

doi:10.1016/j.bone.2003.12.027

Cited by 141 publications

(110 citation statements)

References 48 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…This technique can be used clinically for leg lengthening (96) as well as the correction of pseudoarthroses (97), but has also been implemented in animal models to study the controlled formation of bone (98). The large increases in vascularity, associated with significant increases in pro-angiogenic gene transcription, were hypothesized to play an important role in bone formation during distraction (99). Treatment with the anti-angiogenic agent TNP-470 (100) as well as with antibodies against VEGF receptors (101) confirmed this theory-inhibition of angiogenesis blocks bone formation in the distraction gap.…”

Section: Blood Flow During Distraction Osteogenesismentioning

confidence: 99%

Skeletal Blood Flow in Bone Repair and Maintenance

2013

View full text Add to dashboard Cite

Bone is a highly vascularized tissue, although this aspect of bone is often overlooked. In this article, the importance of blood flow in bone repair and regeneration will be reviewed. First, the skeletal vascular anatomy, with an emphasis on long bones, the distinct mechanisms for vascularizing bone tissue, and methods for remodeling existing vasculature are discussed. Next, techniques for quantifying bone blood flow are briefly summarized. Finally, the body of experimental work that demonstrates the role of bone blood flow in fracture healing, distraction osteogenesis, osteoporosis, disuse osteopenia, and bone grafting is examined. These results illustrate that adequate bone blood flow is an important clinical consideration, particularly during bone regeneration and in at-risk patient groups. IntroductionThe rate at which blood vessels deliver oxygen, nutrients, growth factors, and circulating cells to boneis tightly regulated as a function of blood pressure and vascularizaAll biological tissues, including bone, require vascular support to survive. However, a frequently overlooked feature of bone is its extensive vascular network. Many studies have demonstrated that the blood vessels in bone are necessary for nearly all skeletal functions, including development, homeostasis, and repair (1). In addition, blood vessels lost due to trauma are regenerated, and new bone tissue formed in response to injury is vascularized. As a consequence of this environment, the blood vessels in bone are highly active, not simply a passive source for the delivery of nutrients (2). Readers are referred to recent publications for more information about the active processes of the vasculature not covered in this review, including the vascular niche and hypoxia-driven signaling pathways (3-4). tion. Given that blood pressure is generally maintained, the number and size of blood vessels determines the local blood flow rate. These two factors are regulated through the processes of angiogenesis and vasomotor function, respectively. Although a variety of skeletal disorders are associated with general vascular dysfunction (5-7), this review will focus on the regulation of bone blood flow, through the number and size of vessels, during bone repair and regeneration. To introduce this topic, the skeletal vascular anatomy and techniques for measuring bone blood flow are briefly discussed. Blood supply in boneA dense vascular network delivers oxygen and nutrients to all 206 bones in the human body. In general, this requires a substantial portion of the total cardiac output. Experimental work in various animal species has demonstrated that a significant portion of the resting cardiac output is directed to the skeleton, likely between 10% and 15% (8-12).For some time, the blood flow pattern in bones has been described as primarily centrifugal: blood is supplied to the cortical bone through the nutrient arteries in the (Figure 1), and returned by the periosteal veins (13). Particularly in long bones, the vascular anatomy is well characterized, wi...

show abstract

Section: Blood Flow During Distraction Osteogenesismentioning

confidence: 99%

Skeletal Blood Flow in Bone Repair and Maintenance

2013

View full text Add to dashboard Cite

show abstract

“…DO models indicate that 14 days of consolidation is enough for mineralized bone to fill in the osteotomy gap [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Short-Term Exercise in Mice Increases Tibial Post-Yield Mechanical Properties While Two Weeks of Latency Following Exercise Increases Tissue-Level Strength

2009

View full text Add to dashboard Cite

We have previously shown that exercise during growth increases post-yield deformation in C57BL6/129 (B6;129) male tibiae at the expense of reduced pre-yield deformation and structural and tissue strength. Other research in the literature indicates that increased mineral, cross-sectional geometry and structural strength due to exercise can be maintained or increased after exercise ends for as long as 14 weeks. It was therefore hypothesized that after our exercise protocol ends, effects of exercise on mechanical properties would persist, resulting in increased post-yield behavior and rescued strength versus age-matched control mice. Beginning at 8 weeks of age, exercise consisted of running on a treadmill (30 min/day, 12 m/min, 5° incline) for 21 consecutive days. At the end of running and 2 weeks later, in the cortical bone of the tibial mid-diaphyses of B6;129 male mice, changes due to exercise and latency following exercise were assayed by mechanical tests and analyses of cross-sectional geometry. Exercise increased structural post-yield deformation compared with weight-matched control mice, without changes in bone size or shape, suggesting that exercised-induced changes in pre-existing bone quality were responsible. Over the two week latency period, no growth related changes were noted in control mice, but exercise-induced changes resulted in increased tissue stiffness and strength versus mice sacrificed immediately after exercise ended. Our data indicate that periods of exercise followed by latency can alter strength, stiffness and ductility of bone independent of changes in size or shape, suggesting that exercise may be a practical way to increase the quality of the bone extracellular matrix.

show abstract

“…PHD enzyme activity is also required for HIFα degradation, oxidatively "tagging" HIFα for recognition by pVHL. In addition to low oxygen levels (as shown here), mechanical stimuli, TNF-α, and reactive oxygen species can also upregulate HIFα expression (29). Strategies that augment osteoblast HIFα/VEGF signaling by selectively inhibiting skeletal PHD may increase bone formation and enhance fracture healing.…”

Section: Figurementioning

confidence: 54%

“…In the developing skull, it is probable that cranial suture and dural mechanical tension organize angiogenesis necessary for intramembranous ossification (26)(27)(28). VEGF expression in osteoblasts is mechanically very responsive (29). Distraction osteogenesis - an orthopedic mechanical manipulation that promotes robust angiogenesis and bone formation via nonendochondral mechanisms - upregulates both HIF-1α and VEGF (29).…”

Section: Location Location Locationmentioning

confidence: 99%

Vascular biology and bone formation: hints from HIF

Towler

2007

J. Clin. Invest.

View full text Add to dashboard Cite

In this issue of the JCI, Wang, Clemens, and colleagues demonstrate that hypoxia-inducible factor α (HIFα) signaling in bone-building osteoblasts is central to the coupling of angiogenesis and long bone development in mice (see the related article beginning on page 1616). They show that bone formation controlled by osteoblast HIFα signaling is not cell autonomous but is coupled to skeletal angiogenesis dependent upon VEGF signaling. Thus, strategies that promote HIFα signaling in osteoblasts may augment bone formation and accelerate fracture repair.

show abstract

The role of angiogenesis in a murine tibial model of distraction osteogenesis

Cited by 141 publications

References 48 publications

Skeletal Blood Flow in Bone Repair and Maintenance

Skeletal Blood Flow in Bone Repair and Maintenance

Short-Term Exercise in Mice Increases Tibial Post-Yield Mechanical Properties While Two Weeks of Latency Following Exercise Increases Tissue-Level Strength

Vascular biology and bone formation: hints from HIF

Contact Info

Product

Resources

About