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Review
, 11 (1), 45-54

Fracture Healing: Mechanisms and Interventions

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Review

Fracture Healing: Mechanisms and Interventions

Thomas A Einhorn et al. Nat Rev Rheumatol.

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.

Figures

Figure 1
Figure 1
Histology of early stages of mouse femur fracture repair. a | The inflammatory stage of fracture repair 24 h after injury. Sections were immunoreacted with anti-TNF antibodies to show innate immune responses to the injury of both the periosteum and marrow cell populations (brown) with haematoxylin counterstaining (blue). b | Late inflammatory stage 3 days after injury, cellular streaming of undefined fibrous cells and early angiogenic cells forming small vessels are evident at the fracture site. Stained with haematoxylin and eosin. c | The late endochondral stage, 14 days after injury. The section was stained for tartrate-resistant acid phosphatase to show the recruitment of resorptive osteoclasts (bright red).
Figure 2
Figure 2
Femur fracture repair. The major metabolic phases (blue bars) of fracture healing overlap with biological stages (brown bars). The primary metabolic phases (anabolic and catabolic) of fracture healing are presented in the context of three major biological stages (inflammatory, endochondral bone formation and coupled remodelling) that encompass these phases. The primary cell types that are found at each stage, and the time span of their prevalence in each stage, are denoted. The time scale of healing is equivalent to a mouse closed femur fracture fixed with an intramedullary rod. Abbreviations: BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; DKK1, Dickkopf-related protein 1; LRP, LDL-receptor-related protein; MSC, mesenchymal stem cell; PMN, polymorphonuclear leukocyte; PTH, parathyroid hormone; PTHrP, parathyroid-hormone-related protein; RANKL, receptor activator of nuclear factor κB ligand.
Figure 3
Figure 3
Crosstalk between Wnt, PTH and BMP signalling in cartilage and bone cell lineages. Wnt ligands mediate canonical signalling through β-catenin and BMP signalling can be mediated by SMAD1, SMAD3 and SMAD5. The LRP5 and LRP6 antagonists sclerostin and DKK1 are a central focus of targeted antibody-based therapeutics. The primary stages in the lineage progression of cartilage and bone cells as they differentiate from skeletogenic stem cells are depicted. Major stimulatory and inhibitory effects on the differentiation and proliferation of the two lineages are denoted. Primary effects of the BMP, PTH and Wnt pathway on osteoclast differentiation are indirectly mediated by differing pathway activities that regulate paracrine factor expression in osteocytes, which in turn regulate osteoclast differentiation and function. Abbreviations: BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; DKK1, Dickkopf-related protein 1; LRP, LDL receptor-related protein; MSC, mesenchymal stem cell; PTH, parathyroid hormone; PTH1R, parathyroid hormone 1 receptor; PTHrP, parathyroid-hormone-related protein; RANKL, receptor activator of nuclear factor κB ligand; SMAD, mothers against decapentaplegic homologue.

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