The role of oxygen during fracture healing

Lu, Chuanyong; Saless, Neema; Wang, Xiaodong; Sinha, Arjun; Decker, Sebastian; Kazakia, Galateia J.; Hou, Huagang; Williams, Benjamin B.; Swartz, Harold M.; Hunt, Thomas K.; Miclau, Theodore; Marcucio, Ralph

doi:10.1016/j.bone.2012.09.037

Cited by 97 publications

(88 citation statements)

References 49 publications

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“…In the context of bone repair, these investigators demonstrated that 10 days of hypoxia (FiO2 = 13%) slowed down bone formation and delayed callus remodeling in a mouse model of tibial closed transverse mid-diaphyseal fractures stabilized or not with external fixator. However, the onset of the hypoxic treatment likely accounts for the discrepancy between our data and the results presented by Makley et al [24] and Lu et al [25]. In both studies, mice were housed in the hypoxic chamber during the entire recovery period, namely, between the bone lesion surgery and the sacrifice times, whereas our hypoxic mice were housed for 7 days in normoxic conditions prior to being transferred into the hypoxic chamber for a 4-day period (sacrifice at postsurgery day 11).…”

Section: Discussioncontrasting

confidence: 56%

“…Contrary to our data, Makley et al [24] demonstrated in a rat model of fibula fracture subjected to chronic hypobaric hypoxia that the efficiency of bone repair is impaired. Such an observation was granted further support by a recent investigation [25]. In the context of bone repair, these investigators demonstrated that 10 days of hypoxia (FiO2 = 13%) slowed down bone formation and delayed callus remodeling in a mouse model of tibial closed transverse mid-diaphyseal fractures stabilized or not with external fixator.…”

Section: Discussionmentioning

confidence: 83%

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In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

Durand¹,

Collombet²,

Frasca³

et al. 2014

Stem Cells Translational Medicine

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We investigated the effects of respiratory hypobaric hypoxia on femoral bone-defect repair in mice because hypoxia is believed to influence both mesenchymal stromal cell (MSC) and hematopoietic stem cell mobilization, a process involved in the bone-healing mechanism. To mimic conditions of non-weight-bearing limb immobilization in patients suffering from bone trauma, our hypoxic mouse model was further subjected to hind-limb unloading. A hole was drilled in the right femur of adult male C57/BL6J mice. Four days after surgery, mice were subjected to hind-limb unloading for 1 week. Seven days after surgery, mice were either housed for 4 days in a hypobaric room (FiO 2 at 10%) or kept under normoxic conditions. Unsuspended control mice were housed in either hypobaric or normoxic conditions. Animals were sacrificed on postsurgery day 11 to allow for collection of both contralateral and lesioned femurs, blood, and spleen. As assessed by microtomography, delayed hypoxia enhanced bone-healing efficiency by increasing the closing of the cortical defect and the newly synthesized bone volume in the cavity by 155% and 135%, respectively. Proteome analysis and histomorphometric data suggested that bone-repair improvement likely results from the acceleration of the natural bone-healing process rather than from extended mobilization of MSC-derived osteoprogenitors. Hind-limb unloading had hardly any effect beyond delayed hypoxia-enhanced bone-healing efficiency. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:958-968

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 83%

In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

Durand¹,

Collombet²,

Frasca³

et al. 2014

Stem Cells Translational Medicine

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“…The present study identified that CoCl 2 was able to significantly increase the expression of Runx2, ALP and OC. In spite of inadequate blood supply caused by hypoxia being a major cause of delayed union or non-union during fracture healing (24), an appropriate amount of hypoxia may aid in bone Figure 6. Schematic representation of the molecular mechanism of the effect of CoCl 2 on fracture healing.…”

Section: Discussionmentioning

confidence: 99%

Effect of CoCl2 on fracture repair in a rat model of bone fracture

Huang

Liu

Feng

et al. 2015

Molecular Medicine Reports

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Abstract. Low oxygen availability is known to activate the hypoxia-inducible factor-1α (HIF-1α) pathway, which is involved in the impairment of fracture healing. However, the role of low oxygen in fracture healing remains to be fully elucidated. In the present study, rats were divided into two groups and treated with CoCl 2 or saline, respectively. Rats with tibial fractures were sacrificed at 14, 28 and 42 days subsequent to fracture. Autoradiography was performed to measure healing of the bone tissue. In addition, the effects of cobalt chloride (CoCl 2 ) on the expression of two major angiogenic mediators, HIF-1α and vascular endothelial growth factor (VEGF), as well as the osteoblast markers runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC) were determined at mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Systemic administration of CoCl 2 (15 mg/ kg/day intraperitoneally) significantly promoted fracture healing and mechanical strength. The present study demonstrated that in rats treated with CoCl 2 , the expression of HIF-1α, VEGF, Runx2, ALP and OC was significantly increased at mRNA and protein levels, and that CoCl 2 treatment enhances fracture repair in vivo. IntroductionTraumatic fractures are the most common type of injury in daily life. In the majority of clinical cases, the most simple fractures heal with minimal intervention; however, in severe fractures and in certain patient populations, including diabetics and patients with splintered fractures, impaired fracture healing and bone defects occur (1,2). In spite of numerous advances in every discipline of medicine, patients with complex bone injuries of the upper and lower extremities and are required to undergo prolonged reconstructive procedures for retrieval of their limb functions (2,3).It has been reported that the hypoxia-inducible factor (HIF) pathway is the central pathway for sensing and responding to alterations in local oxygen levels in a wide variety of organisms (4). Activation of the HIF-1α pathway can act as a critical mediator of neoangiogenesis, which is required for skeletal regeneration; thus, it is suggested that the application of HIF activators may be used as therapies to improve bone healing (4). An increasing number of studies suggested that hypoxia may be a powerful stimulus for bone cells via the mediation of angiogenesis [vascular endothelial growth factor (VEGF)], cellular metabolism (glucose transporter) and the recruitment of mesenchymal cells (MSCs) to areas of matrix damage (5-7). A more thorough understanding of hypoxia in bone healing will lead to the elucidation of cellular and molecular mechanisms that may aid in the development of protective therapies. CoCl 2 , a mimic of hypoxia, directly enhances HIF-1α stabilization and downstream target genes by inhibiting prolyl hydroxylase enzymes (8). An improved understanding of the alterations in gene expression that occur during fracture he...

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“…for fracture healing, cells need oxygen (Lu et al, 2013a). In this study we have replaced the general oxygen decay term of the MOSAIC model with a cell-specific description of cellular oxygen consumption.…”

Section: Oxygen Consumptionmentioning

confidence: 99%

Oxygen as a critical determinant of bone fracture healing—A multiscale model

Carlier

Geris

Gastel

et al. 2015

Journal of Theoretical Biology

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Highlights The influence of oxygen was incorporated in a multiscale model of fracture healing.  The results of the oxygen model were compared with experimental observations.  An extensive sensitivity analysis of the oxygen model indicated its robustness.  Adequate spatiotemporal oxygen patterns appear to be critical for bone healing. Keywordsoxygen -angiogenesis -fracture healing -multiscale model -non-union AbstractA timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3 mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model 3 is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process.

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The role of oxygen during fracture healing

Cited by 97 publications

References 49 publications

In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

Effect of CoCl2 on fracture repair in a rat model of bone fracture

Oxygen as a critical determinant of bone fracture healing—A multiscale model

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