Stress fracture healing: Fatigue loading of the rat ulna induces upregulation in expression of osteogenic and angiogenic genes that mimic the intramembranous portion of fracture repair

Wohl, Gregory R.; Towler, Dwight A.; Silva, Matthew J.

doi:10.1016/j.bone.2008.09.010

Cited by 65 publications

(105 citation statements)

References 66 publications

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“…In the present rat model of bone repair, the small drill hole was created at a mechanically stable site, 36 and normal gait activity started soon after the defect production. Consequently, daily or physiological mechanical stimuli, Angiogenesis along with bone regeneration T Matsumoto et al which will serve in enhancing osteogenesis and hypoxiamediated angiogenesis, [37][38][39] were induced from the very early stage of bone repair. Angiogenesis encourages bone regeneration by contributing to both the sustainment of the high metabolic activity of osteoblasts engaged in bone repair and the recruitment of osteoprogenitors to the defect Angiogenesis along with bone regeneration T Matsumoto et al zone.…”

Section: Discussionmentioning

confidence: 99%

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Matsumoto

Goto

Sato

2013

Laboratory Investigation

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Quantitative three-dimensional (3D) imaging of angiogenesis during bone repair remains an experimental challenge. We developed a novel contrast agent containing 0.07-to 0.1-mm particles of zirconium dioxide (ZrCA) and established subtraction mCT using synchrotron radiation (sSRCT) for quantitative imaging of angiogenesis and bone repair. This method was applied to a rat model of tibial bone repair 3 days (DAY3; n ¼ 2), 5 days (DAY5; n ¼ 8), or 10 days (DAY10; n ¼ 8) after drill-hole injury. Using the same drill-hole defect model, its potential use was illustrated by comparison of bone repair between hindlimbs subjected to mechanical unloading (n ¼ 6) and normal weight bearing (n ¼ 6) for 10 days. Following vascular casting with ZrCA, the defect site was scanned with 17.9-and 18.1-keV X-rays. In the latter, image contrast between ZrCA-filled vasculature and bone was enhanced owing to the sharp absorption jump of zirconium dioxide at 18.0 keV (k-edge). The two scan data sets were reconstructed with 2.74-mm voxel resolution, registered by mutual information, and digitally subtracted to extract the contrast-enhanced vascular image. K 2 HPO 4 phantom solutions were scanned at 17.9 keV for quantitative evaluation of bone mineral. Angiogenesis had already started, but new bone formation was not found on DAY3. New bone emerged near the defect boundary on DAY5 and took the form of trabecular-like structure invaded by microvessels on DAY10. Vascular and bone volume fractions, blood vessel and bone thicknesses, and mineralization were higher on DAY10 than on DAY5. All these parameters were found to be decreased after 10 days of hindlimb unloading, indicating the possible involvement of angiogenesis in bone repair impairment caused by reduced mechanical stimuli. In conclusion, the combined technique of sSRCT and ZrCA vascular casting is suitable for quantitative 3D imaging of angiogenesis and its surrounding bone regeneration. This method will be useful for better understanding the linkage between angiogenesis and bone repair.

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Section: Discussionmentioning

confidence: 99%

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Matsumoto

Goto

Sato

2013

Laboratory Investigation

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“…(69) Still, primary studies in nonskeletal tissues suggest that angiogenesis indeed may be reduced by BPs over and above the normal reduction that would occur because of the absence of effective osteoclastic tunneling. (70) Interestingly, in a rat model of stress fracture, there is upregulation of vascular endothelial growth factor (VEGF) mRNA within 1 to 4 hours of initiation of the stress fracture (71,72) and upregulation of osteogenic genes in the cambium layer of the periosteum within 3 days. Early upregulation of interleukin 6 (IL-6) and IL-11 suggest the importance of remodeling in stress fracture healing.…”

Section: Insights Into the Pathogenesis Of Atypical Femoral Fracturesmentioning

confidence: 99%

“…Early upregulation of interleukin 6 (IL-6) and IL-11 suggest the importance of remodeling in stress fracture healing. (72) These responses may well be coordinated, and any agent that suppresses angiogenesis could inhibit the repair of an impending stress fracture.…”

Section: Insights Into the Pathogenesis Of Atypical Femoral Fracturesmentioning

confidence: 99%

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

Shane

Burr

Ebeling

et al. 2010

Journal of Bone and Mineral Research

998

679

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Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. ß

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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).…”

Section: Blood Flow During Fracturementioning

confidence: 99%

Skeletal Blood Flow in Bone Repair and Maintenance

2013

Self Cite

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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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Stress fracture healing: Fatigue loading of the rat ulna induces upregulation in expression of osteogenic and angiogenic genes that mimic the intramembranous portion of fracture repair

Cited by 65 publications

References 66 publications

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

Skeletal Blood Flow in Bone Repair and Maintenance

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