The cell and molecular biology of fracture healing
01 Oct 1998-Clinical Orthopaedics and Related Research (Clin Orthop Relat Res)-Vol. 355, Iss: 355, pp 7-21
TL;DR: Using a reproducible model of experimental fracture healing in the rat, the integrated cellular responses that signal the pathways and the role of the extracellular matrix components in orchestrating the events of fracture healing are elucidated.
Abstract: Fracture healing is a complex physiologic process that involves the coordinated participation of several cell types. By using a reproducible model of experimental fracture healing in the rat, it is possible to elucidate the integrated cellular responses that signal the pathways and the role of the extracellular matrix components in orchestrating the events of fracture healing. Histologic characterization of fracture healing shows that intramembranous ossification occurs under the periosteum within a few days after an injury. Events of endochondral ossification occur adjacent to the fracture site and span a period of up to 28 days. Remodeling of the woven bone formed by intramembranous and endochondral ossification proceeds for several weeks. Spatial and temporal expression of genes for major collagens (Types I and II), minor fibrillar collagens (Types IV and XI), and several extracellular matrix components (osteocalcin, osteonectin, osteopontin, fibronectin and CD44) are detected by in situ hybridization. Immunohistochemical studies show that expression of proliferating cell nuclear antigen is both time and space dependent and differentially expressed in the callus tissues formed by the intramembranous and endochondral processes. Chondrocytes involved in endochondral ossification undergo apoptosis (programmed cell death), and early events in fracture healing may be initiated by the expression of early response genes such as c-fos. Additional characterization and elucidation of fracture healing will lay the foundation for subsequent studies aimed at identifying mechanisms for enhancing skeletal repair.
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TL;DR: In this paper, the basic principles involved in designing hierarchical biological materials, such as cellular and composite architectures, adapative growth and as well as remodeling, are discussed, and examples that are found to utilize these strategies include wood, bone, tendon, and glass sponges.
2,274 citations
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...In addition to biological factors [321], such as the importance of restoring the vascularization to avoid cell death due to lack of oxygen and the overwhelming presence of signaling molecules, the mechanical loading within the fracture site plays a crucial role for the healing [322,323]....
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TL;DR: The basic biology of fracture healing is summarized, which includes an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus.
Abstract: The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. Although there is still much to be learned to fully comprehend the pathways of bone regeneration, the over-all pathways of both the anatomical and biochemical events have been thoroughly investigated. These efforts have provided a general understanding of how fracture healing occurs. Following the initial trauma, bone heals by either direct intramembranous or indirect fracture healing, which consists of both intramembranous and endochondral bone formation. The most common pathway is indirect healing, since direct bone healing requires an anatomical reduction and rigidly stable conditions, commonly only obtained by open reduction and internal fixation. However, when such conditions are achieved, the direct healing cascade allows the bone structure to immediately regenerate anatomical lamellar bone and the Haversian systems without any remodelling steps necessary. In all other non-stable conditions, bone healing follows a specific biological pathway. It involves an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus. This primary callus later undergoes revascularisation and calcification, and is finally remodelled to fully restore a normal bone structure. In this article we summarise the basic biology of fracture healing.
1,379 citations
TL;DR: Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible.
Abstract: Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis.
1,373 citations
Cites background from "The cell and molecular biology of f..."
...Unlike in other tissues, the majority of bony injuries (fractures) heal without the formation of scar tissue, and bone is regenerated with its pre-existing properties largely restored, and with the newly formed bone being eventually indistinguishable from the adjacent uninjured bone [2]....
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...Bone possesses the intrinsic capacity for regeneration as part of the repair process in response to injury, as well as during skeletal development or continuous remodelling throughout adult life [1,2]....
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...Bone regeneration is comprised of a well-orchestrated series of biological events of bone induction and conduction, involving a number of cell types and intracellular and extracellular molecularsignalling pathways, with a definable temporal and spatial sequence, in an effort to optimise skeletal repair and restore skeletal function [2,3]....
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TL;DR: The currently available bone grafts and bone substitutes as well as the biological and bio-inorganic factors for the treatments of bone defect are reviewed.
1,109 citations
Cites background from "The cell and molecular biology of f..."
...versial due to the lack of neither histological evidence [35] and clinical cases [38]....
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TL;DR: The developmental progression of fracture healing at the tissue, cellular and molecular levels is reviewed and strategies for fracture treatment that have been tested in animal models and in clinical trials or case series are presented.
Abstract: Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed.
1,069 citations
References
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TL;DR: Results identify Fos as a key regulator of osteoclast-macrophage lineage determination in vivo and provide insights into the molecular mechanisms underlying metabolic bone diseases.
Abstract: Mice lacking the proto-oncogene c-fos develop the bone disease osteopetrosis. Fos mutant mice were found to have a block in the differentiation of bone-resorbing osteoclasts that was intrinsic to hematopoietic cells. Bone marrow transplantation rescued the osteopetrosis, and ectopic c-fos expression overcame this differentiation block. The lack of Fos also caused a lineage shift between osteoclasts and macrophages that resulted in increased numbers of bone marrow macrophages. These results identify Fos as a key regulator of osteoclast-macrophage lineage determination in vivo and provide insights into the molecular mechanisms underlying metabolic bone diseases.
1,212 citations
TL;DR: This review is primarily concerned with those features which have direct clinical relevance and it is fortunately possible to treat fractures successfully without a complete understanding of the cellular mechanisms involved without at the same time relying entirely on empiricism.
Abstract: The healing of a fracture is one of the most remarkable of all the repair processes in the body since it results, not in a scar, but in the actual reconstitution of the injured tissue in something very like its original form. It is not to be expected therefore that the mechanisms controlling such a process will be easily elucidated and indeed they involve problems of cellular homeostasis which are among the most fundamental in biology. If it is not quite the “cunning’st pattern of excelling nature” then it is something quite close to it and a great deal of that pattern at present stands unrevealed. However, this review is primarily concerned with those features which have direct clinical relevance and it is fortunately possible to treat fractures successfully without a complete understanding of the cellular mechanisms involved without at the same time relying entirely on empiricism. A number of factors influence the healing which can be identified from both clinical and experimental work and may be taken into consideration to put treatment on a more rational basis. It is with these observations that we shall be particularly concerned and cellular mechanisms will be discussed only if they appear to have clinical implications. Such an account must necessarily include details of the healing process as it is modified by contemporary methods of treatment but first it is necessary to consider the events that occur in the healing of a simple fracture in an unsplinted long bone.
1,109 citations
TL;DR: The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44, and may be exploited by tumor cells to promote metastasis formation.
Abstract: The CD44 family of surface receptors regulates adhesion, movement, and activation of normal and neoplastic cells. The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44. Osteopontin induces cellular chemotaxis but not homotypic aggregation, whereas the inverse is true for the interaction between CD44 and a carbohydrate ligand, hyaluronate. The different responses of cells after CD44 ligation by either osteopontin or hyaluronate may account for the independent effects of CD44 on cell migration and growth. This mechanism may also be exploited by tumor cells to promote metastasis formation.
938 citations
TL;DR: To develop a technique for the production of a standard closed experimental fracture, a new apparatus was designed and tested on 40 male Sprague‐Dawley rats and resulted in a highly reproducible transverse fracture.
731 citations