-
Journal of Orthopaedic Research :... Jan 2019The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of... (Review)
Review
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. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
Topics: Animals; Bony Callus; Chondrocytes; Endothelial Progenitor Cells; Fracture Healing; Humans; Mesenchymal Stem Cells; Neovascularization, Physiologic; Osteoblasts; Osteoclasts; Osteogenesis; Signal Transduction
PubMed: 30370699
DOI: 10.1002/jor.24170 -
Endocrine Reviews Nov 2022More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration... (Review)
Review
More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes, and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of "inflammaging" results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
Topics: Humans; Fracture Healing; Bony Callus; Osteogenesis; Fractures, Bone; Cellular Senescence; Aging; Endocrine System Diseases
PubMed: 35182420
DOI: 10.1210/endrev/bnac008 -
International Journal of Biological... 2022The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1...
The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1 in fracture healing is not yet well characterized. In this study, we first delineated that Piezo1 is highly expressed in periosteal stem cells (PSCs) and their derived osteoblastic lineage cells and chondrocytes. Furthermore, downregulation of Piezo1 in callus leads to impaired fracture healing, while activation by its specific agonist promotes fracture healing through stimulation of PSC-modulated chondrogenesis and osteogenesis, along with accelerated cartilage-to-bone transformation. Interestingly, vascular endothelial growth factor A is upregulated after Yoda1 treatment of PSCs, indicating an indirect role of Piezo1 in angiogenesis. Mechanistically, activation of Piezo1 promotes expression of Yes-associated protein (YAP) and its nuclear localization in PSCs, which in turn increases the expression and nuclear localization of β-catenin. In detail, YAP directly interacts with β-catenin in the nucleus and forms a transcriptional YAP/β-catenin complex, which upregulates osteogenic, chondrogenic and angiogenic factors. Lastly, Yoda1 treatment significantly improves fracture healing in a delayed union mouse model generated by tail suspension. These findings indicate that Piezo1 is a potential therapeutic target for fracture delayed union or nonunion.
Topics: Animals; Bony Callus; Fracture Healing; Ion Channels; Mice; Osteogenesis; Stem Cells; Vascular Endothelial Growth Factor A; beta Catenin
PubMed: 35844802
DOI: 10.7150/ijbs.71390 -
Injury Jun 2021
Topics: Biomechanical Phenomena; Bony Callus; Fracture Healing; Humans
PubMed: 34099104
DOI: 10.1016/j.injury.2021.05.023 -
BMC Musculoskeletal Disorders May 2022The manual monitoring of callus with digital radiography (X-ray) is the primary bone healing evaluation, assessing the number of bridged callus formations. However, this... (Review)
Review
The manual monitoring of callus with digital radiography (X-ray) is the primary bone healing evaluation, assessing the number of bridged callus formations. However, this method is subjective and nonquantitative. Recently, several quantitative monitoring methods, which could assess the recovery of the structure and biomechanical properties of the callus at different stages and the process of bone healing, have been extensively investigated. These methods could reflect the bone mineral content (BMC), bone mineral density (BMD), stiffness, callus and bone metabolism at the site of bone lengthening. In this review, we comprehensively summarized the latest techniques for evaluating bone healing during distraction osteogenesis (DO): 1) digital radiography; 2) dual-energy X-ray scanning; 3) ultrasound; 4) quantitative computed tomography; 5) biomechanical evaluation; and 6) biochemical markers. This evidence will provide novel and significant information for evaluating bone healing during DO in the future.
Topics: Bone Density; Bony Callus; Humans; Osteogenesis; Osteogenesis, Distraction; Tibia; Tomography, X-Ray Computed
PubMed: 35610718
DOI: 10.1186/s12891-022-05458-8 -
The Journal of Clinical Investigation Apr 2023Immune cells play an important functional role in bone fracture healing. Fracture repair is a well-choreographed process that takes approximately 21 days in healthy...
Immune cells play an important functional role in bone fracture healing. Fracture repair is a well-choreographed process that takes approximately 21 days in healthy mice. While the process is complex, conceptually it can be divided into four overlapping stages: inflammation, cartilaginous callus formation, bony callus formation, and remodeling. T cells play a key role in both the cartilaginous and bony callus phases by producing IL-17A. In this issue of the JCI, Dar et al. showed that T cells were recruited from the gut, where the gut microbiota determined the pool of T cells that expressed IL-17A. Treatment with antibiotics and dysbiosis reduced the expansion of IL-17-expressing CD4+ T cells (Th17) and impaired callus formation. These findings demonstrate crosstalk among the gut microbiota, the adaptive immune system, and bone that has clinical implications for fracture healing.
Topics: Mice; Animals; Gastrointestinal Microbiome; Interleukin-17; Fractures, Bone; Bony Callus; Fracture Healing
PubMed: 37066879
DOI: 10.1172/JCI167311 -
Current Osteoporosis Reports Apr 2018Bone fracture healing is a complex physiological process relying on numerous cell types and signals. Inflammatory factors secreted by immune cells help to control... (Review)
Review
PURPOSE OF REVIEW
Bone fracture healing is a complex physiological process relying on numerous cell types and signals. Inflammatory factors secreted by immune cells help to control recruitment, proliferation, differentiation, and activation of hematopoietic and mesenchymal cells. Within this review we will discuss the functional role of immune cells as it pertains to bone fracture healing. In doing so, we will outline the cytokines secreted and their effects within the healing fracture callus.
RECENT FINDINGS
Macrophages have been found to play an important role in fracture healing. These immune cells signal to other cells of the fracture callus, modulating bone healing. Cytokines and cellular signals within fracture healing continue to be studied. The findings from this work have helped to reinforce the importance of osteoimmunity in bone fracture healing. Owing to these efforts, immunomodulation is emerging as a potential therapeutic target to improve bone fracture healing.
Topics: Bony Callus; Cell Differentiation; Cell Proliferation; Cytokines; Fracture Healing; Hematopoietic Stem Cells; Humans; Macrophages; Mesenchymal Stem Cells
PubMed: 29508143
DOI: 10.1007/s11914-018-0423-2 -
Journal of Orthopaedic Science :... Mar 2012
Topics: Bone and Bones; Bony Callus; Electric Impedance; Electricity; History, 18th Century; History, 19th Century; History, 20th Century; History, Ancient; Humans; Japan; Orthopedics
PubMed: 22422052
DOI: 10.1007/s00776-012-0219-7 -
Annals of Biomedical Engineering Apr 2021Bone lengthening and bone transport are regeneration processes that commonly rely on distraction osteogenesis, a widely accepted surgical procedure to deal with numerous...
Bone lengthening and bone transport are regeneration processes that commonly rely on distraction osteogenesis, a widely accepted surgical procedure to deal with numerous bony pathologies. Despite the extensive study in the literature of the influence of biomechanical factors, a lack of knowledge about their mechanobiological differences prevents a clinical particularization. Bone lengthening treatments were performed on sheep metatarsus by reproducing the surgical and biomechanical protocol of previous bone transport experiments. Several in vivo monitoring techniques were employed to build an exhaustive comparison: gait analysis, radiographic and CT assessment, force measures through the fixation, or mechanical characterization of the new tissue. A significant initial loss of the bearing capacity, quantified by the ground reaction forces and the limb contact time with the ground, is suffered by the bone lengthening specimens. The potential effects of this anomaly on the musculoskeletal force distribution and the evolution of the bone callus elastic modulus over time are also analyzed. Imaging techniques also seem to reveal lower bone volume in the bone lengthening callus than in the bone transport one, but an equivalent mineralization rate. The simultaneous quantification of biological and mechanical parameters provides valuable information for the daily clinical routine and numerical tools development.
Topics: Animals; Biomechanical Phenomena; Bone Regeneration; Bony Callus; Elastic Modulus; Female; Gait; Metatarsal Bones; Osteogenesis, Distraction; Sheep; Tomography, X-Ray Computed
PubMed: 33111968
DOI: 10.1007/s10439-020-02665-z -
Journal of Bone and Mineral Research :... May 2023Despite considerable improvement in fracture care, 5%-10% of all fractures still heal poorly or result in nonunion formation. Therefore, there is an urgent need to...
Despite considerable improvement in fracture care, 5%-10% of all fractures still heal poorly or result in nonunion formation. Therefore, there is an urgent need to identify new molecules that can be used to improve bone fracture healing. One activator of the Wnt-signaling cascade, Wnt1, has recently gained attention for its intense osteoanabolic effect on the intact skeleton. The aim of the present study was to investigate whether Wnt1 might be a promising molecule to accelerate fracture healing both in skeletally healthy and osteoporotic mice that display a diminished healing capacity. Transgenic mice for a temporary induction of Wnt1 specifically in osteoblasts (Wnt1-tg) were subjected to femur osteotomy. Non-ovariectomized and ovariectomized Wnt1-tg mice displayed significantly accelerated fracture healing based on a strong increase in bone formation in the fracture callus. Transcriptome profiling revealed that Hippo/yes1-associated transcriptional regulator (YAP)-signaling and bone morphogenetic protein (BMP) signaling pathways were highly enriched in the fracture callus of Wnt1-tg animals. Immunohistochemical staining confirmed increased activation of YAP1 and expression of BMP2 in osteoblasts in the fracture callus. Therefore, our data indicate that Wnt1 boosts bone formation during fracture healing via YAP/BMP signaling both under healthy and osteoporotic conditions. To further test a potential translational application of Wnt1, we applied recombinant Wnt1 embedded into a collagen gel during critical-size bone-defect repair. Mice treated with Wnt1 displayed increased bone regeneration compared to control mice accompanied by increased YAP1/BMP2 expression in the defect area. These findings are of high clinical relevance because they indicate that Wnt1 could be used as a new therapeutic agent to treat orthopedic complications in the clinic. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Mice; Animals; Fracture Healing; Osteogenesis; Fractures, Bone; Bony Callus; Mice, Transgenic; Wnt Signaling Pathway
PubMed: 36891752
DOI: 10.1002/jbmr.4797