Overview of Skeletal Repair (Fracture Healing and Its Assessment)

Morgan, Elise F.; Giacomo, Anthony De; Gerstenfeld, Louis C.

doi:10.1007/978-1-62703-989-5_2

Cited by 49 publications

(49 citation statements)

References 42 publications

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“…PRAB and H&E sections were imaged at 20× and 40×, respectively, on a Nanozoomer slide scanner (Hamamatsu Photonics). For fractured femurs and ulnas, the total callus, cartilage, and woven bone areas were quantified by a blinded user to mouse ID and experimental group three times and presented as previously described . Other tissue within the callus not classified as cartilage or woven bone was called periosteal fibrous tissue.…”

Section: Methodsmentioning

confidence: 99%

“…For fractured femurs and ulnas, the total callus, cartilage, and woven bone areas were quantified by a blinded user to mouse ID and experimental group three times and presented as previously described. (62) Other tissue within the callus not classified as cartilage or woven bone was called periosteal fibrous tissue. The relative proportion of each of these three tissue types is presented as a percentage of the total callus area (adding up to 100%).…”

Section: Histology and Histomorphometrymentioning

confidence: 99%

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VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Buettmann

McKenzie

Migotsky

et al. 2019

Journal of Bone and Mineral Research

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Bone formation via intramembranous and endochondral ossification is necessary for successful healing after a wide range of bone injuries. The pleiotropic cytokine, vascular endothelial growth factor A (VEGFA) has been shown, via nonspecific pharmacologic inhibition, to be indispensable for angiogenesis and ossification following bone fracture and cortical defect repair. However, the importance of VEGFA expression by different cell types during bone healing is not well understood. We sought to determine the role of VEGFA from different osteoblast cell subsets following clinically relevant models of bone fracture and cortical defect. Ubiquitin C (UBC), Osterix (Osx), or Dentin matrix protein 1 (Dmp1) Cre‐ERT2 mice (male and female) containing floxed VEGFA alleles (VEGFAfl/fl) were either given a femur full fracture, ulna stress fracture, or tibia cortical defect at 12 weeks of age. All mice received tamoxifen continuously starting 2 weeks before bone injury and throughout healing. UBC Cre‐ERT2 VEGFAfl/fl (UBC cKO) mice, which were used to mimic nonspecific inhibition, had minimal bone formation and impaired angiogenesis across all bone injury models. UBC cKO mice also exhibited impaired periosteal cell proliferation during full fracture, but not stress fracture repair. Osx Cre‐ERT2 VEGFAfl/fl (Osx cKO) mice, but not Dmp1 Cre‐ERT2 VEGFAfl/fl (Dmp1 cKO) mice, showed impaired periosteal bone formation and angiogenesis in models of full fracture and stress fracture. Neither Osx cKO nor Dmp1 cKO mice demonstrated significant impairments in intramedullary bone formation and angiogenesis following cortical defect. These data suggest that VEGFA from early osteolineage cells (Osx+), but not mature osteoblasts/osteocytes (Dmp1+), is critical at the time of bone injury for rapid periosteal angiogenesis and woven bone formation during fracture repair. Whereas VEGFA from another cell source, not from the osteoblast cell lineage, is necessary at the time of injury for maximum cortical defect intramedullary angiogenesis and osteogenesis. © 2019 American Society for Bone and Mineral Research.

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Section: Methodsmentioning

confidence: 99%

Section: Histology and Histomorphometrymentioning

confidence: 99%

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Buettmann

McKenzie

Migotsky

et al. 2019

Journal of Bone and Mineral Research

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“…In addition to signaling the resident osteoblast population to stimulate matrix formation, anabolic outcomes in response to mechanical loading also depend on recruitment of bone marrow MSC into an osteogenic lineage. For example, introducing LIV into the mechanical environment has been shown to improve the fracture repair [111], where stem cells are recruited to the callus to be re-integrated into bone tissue [112] through a processes mirroring the skeletal development in a smaller scale [113]. When physical loading is absent, MSC have a tendency to enter adipogenic lineage [114], a phenotype that predominates in paraplegic, sedentary and elderly individuals [115], achieved in a reciprocal relationship to a declining musculoskeletal system.…”

Section: Role Of Linc-nuclear Connections In Bone/osteoblast Phenomentioning

confidence: 99%

Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex

Uzer

Rubin

2016

Curr Mol Bio Rep

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Mechanoresponses in mesenchymal stem cells (MSCs) guide both differentiation and function. In this review, we focus on advances in0 our understanding of how the cytoplasmic cytoskeleton, nuclear envelope and nucleoskeleton, which are connected via LINC (Linker of Nucleoskeleton and Cytoskeleton) complexes, are emerging as an integrated dynamic signaling platform to regulate MSC mechanobiology. This dynamic interconnectivity affects mechanical signaling and transfer of signals into the nucleus. In this way, nuclear and LINC-mediated cytoskeletal connectivity play a critical role in maintaining mechanical signaling that affects MSC fate by serving as both mechanosensory and mechanoresponsive structures. We review disease and age related compromises of LINC complexes and nucleoskeleton that contribute to the etiology of musculoskeletal diseases. Finally we invite the idea that acquired dysfunctions of LINC might be a contributing factor to conditions such as aging, microgravity and osteoporosis and discuss potential mechanical strategies to modulate LINC connectivity to combat these conditions.

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“…In contrast to the paucity of quantitative tools to assess fracture healing in a clinical setting, a large number of analytical approaches have been developed for use in preclinical studies using animal models. The most common of these approaches includes structural and material property measurements obtained from computed tomography and biomechanical measurements based on various testing modalities, including three and four point bending and torsion testing to failure …”

mentioning

confidence: 99%

Correlation between RUST assessments of fracture healing to structural and biomechanical properties

Cooke

Hussein

Lybrand

et al. 2017

Journal Orthopaedic Research

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Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: A control and a phosphate restricted diet group. Micro-computed tomography (µCT) and torsion testing were carried out at post-operative days (POD) 14, 21, 35, and 42 (n = 10-16) per group time-point. Anteroposterior and lateral radiographic views were constructed from the µCT scans and scored by five raters. The raters also indicated if the fracture were healed. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density (BMD) (r = 0.85 and 0.80, p < 0.001) and bone volume fraction (BV/TV) (r = 0.86 and 0.80, p < 0.001). Both RUST scores positively correlated with callus strength (r = 0.35 and 0.26, p < 0.012) and rigidity (r = 0.50 and 0.39, p < 0.001). Radiographically healed calluses had a mRUST ≥13 and a RUST ≥10 and had excellent relationship to structural and biomechanical metrics. Effect of delayed healing due to phosphate dietary restrictions was found at later time points with all mechanical properties (p < 0.011), however no differences found in the RUST scores (p > 0.318). Clinical relevance of this study is both RUST scores showed high correlation to physical properties of healing and generally distinguished healed vs. non-healed fractures. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:945-953, 2018.

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Overview of Skeletal Repair (Fracture Healing and Its Assessment)

Cited by 49 publications

References 42 publications

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

VEGFA From Early Osteoblast Lineage Cells (Osterix+) Is Required in Mice for Fracture Healing

Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex

Correlation between RUST assessments of fracture healing to structural and biomechanical properties

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