Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation

Hebb, John; Ashley, Jason W.; McDaniel, L. D.; Lopas, Luke A.; Tobias, John W.; Hankenson, Kurt D.; Ahn, Jaimo

doi:10.1002/jor.23652

Cited by 37 publications

(34 citation statements)

References 37 publications

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“…Proliferation is a key measurement, as it has been shown to correlate with an age-related decline in bone healing. (41) We did not observe an increase in proliferating Osxþ cells; therefore, during bone repair, the mechanoresponsive cells appear to be the more primitive Prrx1þ Sca-1þ osteogenic progenitors, compared to the less primitive Prrx1þ Sca-1-cells and Osxþ cells. This may explain why the periosteum, which is a rich source of Sca-1þ (25) and Prrx1þ (22) cells, is vital in bone repair.…”

Section: Discussionmentioning

confidence: 49%

“…Our results suggest that this expansion was the result of increased proliferation of the Prrx1+ Sca‐1+ within the defect site, as indicated by the increased population of Prrx1+ Sca‐1+ cells that are also Ki‐67+. Proliferation is a key measurement, as it has been shown to correlate with an age‐related decline in bone healing . We did not observe an increase in proliferating Osx+ cells; therefore, during bone repair, the mechanoresponsive cells appear to be the more primitive Prrx1+ Sca‐1+ osteogenic progenitors, compared to the less primitive Prrx1+ Sca‐1– cells and Osx+ cells.…”

Section: Discussionmentioning

confidence: 53%

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Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Liu

Cabahug‐Zuckerman

Stubbs

et al. 2019

Journal of Bone and Mineral Research

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Elucidating the effects of mechanical stimulation on bone repair is crucial for optimization of the healing process. Specifically, the regulatory role that mechanical loading exerts on the osteogenic stem cell pool and vascular morphology during healing is incompletely understood. Because dynamic loading has been shown to enhance osteogenesis and repair, we hypothesized that loading induces the expansion of the osteoprogenitor cell population within a healing bone defect, leading to an increased presence of osteogenic cells. We further hypothesized that loading during the repair process regulates vascular and collagen matrix morphology and spatial interactions between vessels and osteogenic cells. To address these hypotheses, we used a mechanobiological bone repair model, which produces a consistent and reproducible intramembranous repair response confined in time and space. Bilateral tibial defects were created in adult C57BL/6 mice, which were subjected to axial compressive dynamic loading either during the early cellular invasion phase on postsurgical days (PSDs) 2 to 5 or during the matrix deposition phase on PSD 5 to 8. Confocal and two‐photon microscopy was used to generate high‐resolution three‐dimensional (3D) renderings of longitudinal thick sections of the defect on PSD 10. Endomucin (EMCN)‐positive vessels, Paired related homeobox 1 (Prrx1+) stem cell antigen‐1 positive (Sca‐1+) primitive osteoprogenitors (OPCs), and osterix positive (Osx+) preosteoblasts were visualized and quantified using deep tissue immunohistochemistry. New bone matrix was visualized with second harmonic generation autofluorescence of collagen fibers. We found that mechanical loading during the matrix deposition phase (PSD 5 to 8) increased vessel volume and number, and aligned vessels and collagen fibers to the load‐bearing direction of bone. Furthermore, loading led to a significant increase in the proliferation and number of Prrx1+ Sca‐1+ primitive OPCs, but not Osx+ preosteoblasts within the defect. Together, these data illustrate the adaptation of both collagen matrix and vascular morphology to better withstand mechanical load during bone repair, and that the mechanoresponsive cell population consists of the primitive osteogenic progenitors. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 53%

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Liu

Cabahug‐Zuckerman

Stubbs

et al. 2019

Journal of Bone and Mineral Research

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“…For example, inflammation induced with lipopolysaccharide led to decreased callus strength in young animals (Reikerås et al, 2005). Also, delayed healing in aged animals has been directly associated with inflammatory dysregulation within the callus (Hebb et al, 2018;Xing, Lu, Hu, Miclau, et al, 2010;Xing, Lu, Hu, Yu, et al, 2010). Other studies have demonstrated an association of systemic inflammatory dysregulation, as a result of increased age or disease, with poor fracture healing outcomes in humans and animal experiments (Clark, Nakamura, Miclau, Marcucio, & Marcucio Ralph, 2017;Loder, 1988).…”

Section: Discussionmentioning

confidence: 99%

Age‐related changes to macrophages are detrimental to fracture healing in mice

et al. 2020

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The elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age‐related diseases. Therefore, we investigated age‐related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA‐seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an up‐regulation of M1/pro‐inflammatory genes in macrophages from old mice as well as dysregulation of other immune‐related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age‐matched controls. After preventing infiltration by macrophages, the macrophages remaining within the fracture callus were collected and examined via RNA‐seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age‐related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

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“…Thus, the functional capacity of juvenile macrophages appears to be more beneficial for healing than that of elderly macrophages. Compared to young mice, the innate and adaptive immunity cells of aged mice are more highly enriched during fracture healing . Bone regeneration is inhibited by increased CD8+ T cells which produce interferon‐gamma and TNF‐alpha and increased expression of CXCL8, CXCL9, and CXCL5 cytokines.…”

Section: Inflammatory Phase—inflammatory Cellsmentioning

confidence: 99%

Cellular biology of fracture healing

Bahney

Zondervan²,

Allison³

et al. 2018

Journal Orthopaedic Research

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382

353

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The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing— coupled with the heterogeneity of animal models—renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment.

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Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation

Abstract: Greater understanding of age-dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149-158, 2018.

Cited by 37 publications

References 37 publications

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Age‐related changes to macrophages are detrimental to fracture healing in mice

Cellular biology of fracture healing

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