Transcriptional Mechanisms of Secondary Fracture Healing
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Purpose of Review
Growing evidence supports the critical role of transcriptional mechanisms in promoting the spatial and temporal progression of bone healing. In this review, we evaluate and discuss new transcriptional and post-transcriptional regulatory mechanisms of secondary bone repair, along with emerging evidence for epigenetic regulation of fracture healing.
Using the candidate gene approach has identified new roles for several transcription factors in mediating the reactive, reparative, and remodeling phases of fracture repair. Further characterization of the different epigenetic controls of fracture healing and fracture-driven transcriptome changes between young and aged fracture has identified key biological pathways that may yield therapeutic targets. Furthermore, exogenously delivered microRNA to post-transcriptionally control gene expression is quickly becoming an area with great therapeutic potential.
Activation of specific transcriptional networks can promote the proper progression of secondary bone healing. Targeting these key factors using small molecules or through microRNA may yield effective therapies to enhance and possibly accelerate fracture healing.
KeywordsTranscription factor Gene expression Bone MicroRNA Epigenetics Transcriptome
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Praemer AFSR, DF. Musculoskeletal conditions in the United States. Rosemount, Ill, USA1999.Google Scholar
- 13.Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, K-i I, et al. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 2004;18(8):952–63. https://doi.org/10.1101/gad.1174704.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Valavanidis A, Vlachogianni T, Fiotakis K. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int J Environ Res Public Health. 2009;6(2):445–62. https://doi.org/10.3390/ijerph6020445.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.•• Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144(2):221–34. Provides evidence of a new mechanism of endochondral ossification in which chondrocytes transdifferentiate into osteoblasts at areas of invading vasculature.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Paglia DNS, D.Y.; Gavrity, J; Scanlon, V; Sanjay, A; Awad, H; Drissi, H. Conditional deletion of Runx3 in Prx-positive cells resulted in accelerated fracture healing. Orthopaedic Research Society Annual Meeting 2015.Google Scholar
- 28.Paglia DNM S; Lorenzo J; Hansen MF, Drissi H IL17 a & b and their respective receptors are regulated by Runx3 during fracture healing. Orthopaedic Research Society 2017.Google Scholar
- 29.Paglia DN, Yang X, Kalinowski J, Jastrzebski S, Drissi H, Lorenzo J. Runx1 regulates myeloid precursor differentiation into osteoclasts without affecting differentiation into antigen presenting or phagocytic cells in both males and females. Endocrinology. 2016;157(8):3058–69. https://doi.org/10.1210/en.2015-2037.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.KS DY C, Gibson J, Lorenzo J, Hansen M, Drissi H. Gene array analyses reveal distinct expression patterns in the osteoclast and chondroclast populations within a fracture callus. J Bone Miner Res. 2012;27(Suppl 1)Google Scholar
- 35.Lefebvre V, Behringer RR, de Crombrugghe B. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthritis Cartilage. 2001;9(Supplement 1):S69-S75.Google Scholar
- 39.Mohan G, Magnitsky S, Melkus G, Subburaj K, Kazakia G, Burghardt A et al. Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: a pilot study. 2016.Google Scholar
- 40.Grimes R, Jepsen KJ, Fitch JL, Einhorn TA, Gerstenfeld LC. The transcriptome of fracture healing defines mechanisms of coordination of skeletal and vascular development during endochondral bone formation. J Bone Miner Res. 2011;26(11):2597–609. https://doi.org/10.1002/jbmr.486.CrossRefPubMedGoogle Scholar
- 42.• Ode A, Duda GN, Geissler S, Pauly S, Ode J-E, Perka C, et al. Interaction of age and mechanical stability on bone defect healing: an early transcriptional analysis of fracture hematoma in rat. Plos One. 2014;9(9):e106462. Identified a number of differentially expressed genes that were influenced by the interaction between method of fracture fixation and age of animal CrossRefPubMedPubMedCentralGoogle Scholar
- 45.del Real A, Pérez-Campo FM, Fernández AF, Sañudo C, Ibarbia CG, Pérez-Núñez MI, et al. Differential analysis of genome-wide methylation and gene expression in mesenchymal stem cells of patients with fractures and osteoarthritis. Epigenetics. 2017;12(2):113–22. https://doi.org/10.1080/15592294.2016.1271854.CrossRefPubMedGoogle Scholar
- 46.•• Hadjiargyrou M, Zhi J, Komatsu DE. Identification of the microRNA transcriptome during the early phases of mammalian fracture repair. Bone. 2016;87:78–88. This paper characterized the temporal changes in microRNA expression patterns during the early phases of femoral fracture repair CrossRefPubMedGoogle Scholar
- 48.He B, Zhang Z-K, Liu J, He Y-X, Tang T, Li J, et al. Bioinformatics and microarray analysis of miRNAs in aged female mice model implied new molecular mechanisms for impaired fracture healing. Int J Mol Sci. 2016;17(8) https://doi.org/10.3390/ijms17081260.
- 50.• Tu M, Tang J, He H, Cheng P, Chen C. MiR-142-5p promotes bone repair by maintaining osteoblast activity. J Bone Miner Metab. 2016;35(3):255-264. Doi: https://doi.org/10.1007/s00774-016-0757-8. Provides compelling evidence that locally administered microRNA can enhance secondary fracture healing.
- 52.Yoshizuka M, Nakasa T, Kawanishi Y, Hachisuka S, Furuta T, Miyaki S, et al. Inhibition of microRNA-222 expression accelerates bone healing with enhancement of osteogenesis, chondrogenesis, and angiogenesis in a rat refractory fracture model. J Orthop Sci. 2016;21(6):852–8.CrossRefPubMedGoogle Scholar
- 56.Jepsen KJ, Price C, Silkman LJ, Nicholls FH, Nasser P, Hu B, et al. Genetic variation in the patterns of skeletal progenitor cell differentiation and progression during endochondral bone formation affects the rate of fracture healing. J Bone Miner Res. 2008;23(8):1204–16. https://doi.org/10.1359/JBMR.080317.CrossRefPubMedPubMedCentralGoogle Scholar