Angiogenesis is required for stress fracture healing in rats

Tomlinson, Ryan E.; McKenzie, Janice M.; Schmieder, Anne H.; Wohl, Gregory R.; Lanza, Gregory M.; Silva, Matthew J.

doi:10.1016/j.bone.2012.09.035

Cited by 41 publications

(49 citation statements)

References 43 publications

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“…Previous studies have shown that HIF-1α is critical for angiogenesis and subsequent bone formation during murine distraction osteogenesis [19, 44]. Additionally, inhibition of angiogenesis led to diminished woven bone formation following damaging mechanical loading in rats [27]. Here, a significant decrease in periosteal vascularity due to decreased HIF-1 expression was associated with less woven bone formation.…”

Section: Discussionmentioning

confidence: 86%

“…Robust expression of HIF-1α has been observed in the inflammatory cells located in the expanded periosteal region as soon as 1 day after loading, with a peak in gene expression at day 7 [22, 25]. Additionally, woven bone formation after stress fracture is preceded by increased periosteal vascularity [25, 26] and is impaired by angiogenic inhibition [27]. In contrast to fatigue loading, mechanical loading applied near physiological strain levels for fewer cycles does not produce damage, and stimulates lamellar bone formation.…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α regulates bone formation after osteogenic mechanical loading

Tomlinson

Silva

2015

Bone

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HIF-1 is a transcription factor typically associated with angiogenic gene transcription under hypoxic conditions. In this study, mice with HIF-1α deleted in the osteoblast lineage (ΔHIF-1α) were subjected to damaging or non-damaging mechanical loading known to produce woven or lamellar bone, respectively, at the ulnar diaphysis. By microCT, ΔHIF-1α mice produced significantly less woven bone than wild type (WT) mice 7 days after damaging loading. This decrease in woven bone volume and extent was accompanied by a significant decrease in vascularity measured by immunohistochemistry against vWF. Additionally, osteocytes, rather than osteoblasts, appear to be the main bone cell expressing HIF-1α following damaging loading. In contrast, 10 days after non-damaging mechanical loading, dynamic histomorphometry measurements demonstrated no impairment in loading-induced lamellar bone formation in ΔHIF-1α mice. In fact, both non-loaded and loaded ulnae from ΔHIF-1α mice had increased bone formation compared to WT ulnae. When comparing the relative increase in periosteal bone formation in loaded vs. non-loaded ulnae, it was not different between ΔHIF-1α mice and controls. There were no significant differences observed between WT and ΔHIF-1α mice in endosteal bone formation parameters. The increases in periosteal lamellar bone formation in ΔHIF-1α mice are attributed to non-angiogenic effects of the knockout. In conclusion, these results demonstrate that HIF-1α is a pro-osteogenic factor for woven bone formation after damaging loading, but an anti-osteogenic factor for lamellar bone formation under basal conditions and after non-damaging loading.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

HIF-1α regulates bone formation after osteogenic mechanical loading

Tomlinson

Silva

2015

Bone

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“…In rodent models, stress fracture healing has been shown to recapitulate the intramembranous portion of fracture repair (88), with the hallmark of stress fracture healing being the rapid formation of a hard periosteal callus of woven bone without a cartilaginous template (89). As shown in Figure 3, significant periosteal angiogenesis is associated with healing (90-91), and angiogenic inhibition attenuates the healing response (92). By quantifying gold microspheres, an immediate increase in blood flow rate was observed following the generation of a stress fracture in rats (18), consistent with reports that inflammatory markers, including IL-1, IL-6, and NOS2, are upregulated as early as 1 hour after the injury (93)(94).…”

Section: Blood Flow During Fracturementioning

confidence: 99%

Skeletal Blood Flow in Bone Repair and Maintenance

2013

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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...

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“…Intramembranous ossification primarily takes place at both ends of bony callus, and new bones are formed by proliferation of periosteal osteoblasts [2, 3]. The process of fracture healing is completed as callus is remodeled, with functions of both osteoclasts and osteoblasts according to appropriate mechanical requirements [4, 5]. …”

Section: Introductionmentioning

confidence: 99%

Endogenous Parathyroid Hormone Promotes Fracture Healing by Increasing Expression of BMPR2 through cAMP/PKA/CREB Pathway in Mice

Zhou

Jin

et al. 2017

Cell Physiol Biochem

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Background/Aims: Endogenous parathyroid hormone (PTH) plays an important role in fracture healing. This study investigated whether endogenous PTH regulates fracture healing by bone morphogenetic protein (BMP) and/or the transforming growth factor-β (TGF-β) signaling pathway. Methods: Eight-week-old wild-type (WT) and PTH-knockout (PTH KO) male mice were selected, and models of open right-femoral fracture were constructed. Fracture healing and callus characteristics of mice in the two groups were compared by X-ray, micro-computed tomography, histological, and immunohistochemical examinations. Bone marrow mesenchymal stem cells (BMMSCs) of 8-week-old WT and PTHKO male mice were obtained and induced into osteoblasts and chondrocytes. Results: We found that expression levels of Runt-related transcription factor (RUNX2), bone morphogenetic protein-receptor-type Ⅱ (BMPR2), phosphorylated Smad 1/5/8, and phosphorylated cyclic adenosine monophosphate-responsive element binding protein (CREB) in the callus of PTHKO mice were significantly decreased, whereas no significant difference in expression of SOX9, TGF-βR2,or pSMAD2/3 was observed between PTHKO and WT mice. Additionally, the activity of osteoblast alkaline phosphatase was low at 7 days post-induction, and was upregulated by addition of PTH or dibutyryl cyclic adenosine monophosphate (dbcAMP) to the cell culture. Furthermore, H89 (protein kinase A inhibitor)eliminated the simulating effects of PTH and dbcAMP, and a low concentration of cyclic adenosine monophosphate (cAMP) was observed in PTHKO mouse BMMSCs. Conclusion: These results suggested that endogenous PTH enhanced BMPR2 expression by a cAMP/PKA/CREB pathway in osteoblasts, and increased RUNX2 expression through transduction of the BMP/pSMAD1/5/8 signaling pathway.

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Angiogenesis is required for stress fracture healing in rats

Cited by 41 publications

References 43 publications

HIF-1α regulates bone formation after osteogenic mechanical loading

HIF-1α regulates bone formation after osteogenic mechanical loading

Skeletal Blood Flow in Bone Repair and Maintenance

Endogenous Parathyroid Hormone Promotes Fracture Healing by Increasing Expression of BMPR2 through cAMP/PKA/CREB Pathway in Mice

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