Fracture healing as a post‐natal developmental process: molecular, spatial, and temporal aspects of its regulation

wbldb

Gerstenfeld, Louis C.¹; Cullinane, Dennis M.¹; Barnes, George L.¹; Graves, Dana T.¹; Einhorn, Thomas A.¹

Fracture healing as a post‐natal developmental process: molecular, spatial, and temporal aspects of its regulation

J Cell Biochem. April 2003;88(5):873-884

©2003 Wiley-Liss, Inc

Affiliations

¹Department of Orthopaedic Surgery, Orthopaedic Research Laboratory, Boston University Medical Center, Boston, Massachusetts 02118-2526
Abstract and keywords

Fracture healing is a specialized post‐natal repair process that recapitulates aspects of embryological skeletal development. While many of the molecular mechanisms that control cellular differentiation and growth during embryogenesis recur during fracture healing, these processes take place in a post‐natal environment that is unique and distinct from those which exist during embryogenesis. This Prospect Article will highlight a number of central biological processes that are believed to be crucial in the embryonic differentiation and growth of skeletal tissues and review the functional role of these processes during fracture healing. Specific aspects of fracture healing that will be considered in relation to embryological development are: (1) the anatomic structure of the fracture callus as it evolves during healing; (2) the origins of stem cells and morphogenetic signals that facilitate the repair process; (3) the role of the biomechanical environment in controlling cellular differentiation during repair; (4) the role of three key groups of soluble factors, pro‐inflammatory cytokines, the TGF‐β superfamily, and angiogenic factors, during repair; and (5) the relationship of the genetic components that control bone mass and remodeling to the mechanisms that control skeletal tissue repair in response to fracture.

Keywords: fracture healing; BMP; angiogenesis; inﬂammatory cytokines
Links

DOI: 10.1002/jcb.10435

PubMed: 12616527

WoS: 000181601700003
History

Received: 2002-10-25

Accepted: 2002-10-28

Cited Works (11)

Year	Entry
1997	Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP. Osteogenic differentiation of purified, culture‐expanded human mesenchymal stem cells in vitro. J Cell Biochem. February 1997;64(2):295-312.
2002	Deckers MML, van Bezooijen RL, van der Horst G, Hoogendam J, van der Bent C, Papapoulos SE, Löwik CWGM. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology. April 2002;143(4):1545-1553.
2001	Le AX, Miclau T, Hu D, Helms JA. Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res. January 2001;19(1):78-84.
2002	Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor–related protein 5. NEJM. May 16, 2002;346(20):1513-1521.
2002	Cho T-J, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing. J Bone Miner Res. March 2002;17(3):513-520.
2002	Street J, Bao M, deGuzman L, Bunting S, Peale FV Jr, Ferrara N, Steinmetz H, Hoeffel J, Cleland JL, Daugherty A, van Bruggen N, Redmond HP, Carano RAD, Filvaroff EH. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci USA. July 23, 2002;99(15):9656-9661.
1988	Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. December 16, 1988;242(4885):1528-1534.
1999	Gerber H-P, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. June 1999;5(6):623-628.
2001	Kon T, Cho T-J, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC, Einhorn TA. Expression of osteoprotegerin, receptor activator of NF-κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res. June 2001;16(6):1004-1014.
1999	Ferguson C, Alpern E, Miclau T, Helms JA. Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev. September 1999;87(1-2):57-66.
1965	Urist MR. Bone: formation by autoinduction. Science. November 12, 1965;150(3698):893-899.

Cited By (60)

Year	Entry
2019	Zenzes M, Bortel EL, Fratzl P, Mundlos S, Schuetz M, Schmidt H, Duda GN, Witte F, Zaslansky P. Normal trabecular vertebral bone is formed via rapid transformation of mineralized spicules: a high-resolution 3D ex-vivo murine study. Acta Biomater. March 1, 2019;86:429-440.
2012	Vetter A, Witt F, Sander O, Duda GN, Weinkamer R. The spatio-temporal arrangement of different tissues during bone healing as a result of simple mechanobiological rules. Biomech Model Mechanobiol. January 2012;11(1-2):147-160.
2004	Simmons CA, Alsberg E, Hsiong S, Kim WJ, Mooney DJ. Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells. Bone. August 2004;35(2):562-569.
2020	Hozain S, Cottrell J. CDllb+ targeted depletion of macrophages negatively affects bone fracture healing. Bone. September 2020;138:115479.
2021	Doherty L, Wan M, Kalajzic I, Sanjay A. Diabetes impairs periosteal progenitor regenerative potential. Bone. February 2021;143:115764.
2021	Bhatti FUR, Dadwal UC, Valuch CR, Tewari NP, Awosanya OD, de Andrade Staut C, Sun S, Mendenhall SK, Perugini AJ III, Nagaraj RU, Battina HL, Nazzal MK, Blosser RJ, Maupin KA, Childress PJ, Li J, Kacena MA. The effects of high fat diet, bone healing, and BMP-2 treatment on endothelial cell growth and function. Bone. May 2021;146:115883.
2022	Moran MM, Ko FC, Mesner LD, Calabrese GM, Al-Barghouthi BM, Farber CR, Sumner DR. Intramembranous bone regeneration in diversity outbred mice is heritable. Bone. November 2022;164:116524.
2008	Shapiro F. Bone development and its relation to fracture repair: the role of mesenchymal osteoblasts and surface osteoblasts. Eur Cell Mater. 2008;15:53-76.
2011	Marsell R, Einhorn TA. The biology of fracture healing. Injury. June 2011;42(6):551-555.
2005	Shefelbine SJ, Augat P, Claes L, Simo U. Trabecular bone fracture healing simulation with finite element analysis and fuzzy logic. J Biomech. December 2005;38(12):2440-2450.
2006	Isaksson H, Wilson W, van Donkelaar CC, Huiskes R, Ito K. Comparison of biophysical stimuli for mechano-regulation of tissue differentiation during fracture healing. J Biomech. 2006;39(8):1507-1516.
2021	Kegelman CD, Nijsure MP, Moharrer Y, Pearson HB, Dawahare JH, Jordan KM, Qin L, Boerckel JD. YAP and TAZ promote periosteal osteoblast precursor expansion and differentiation for fracture repair. J Bone Miner Res. January 2021;36(1):143-157.
2023	Kajabi AW, Zbýň Š, Johnson CP, Tompkins MA, Nelson BJ, Takahashi T, Shea KG, Marette S, Carlson CS, Ellermann JM. Longitudinal 3T MRI T₂^* mapping of juvenile osteochondritis dissecans (JOCD) lesions differentiates operative from non-operative patients: pilot study. J Orthop Res. January 2023;41(1):150-160.
2023	Rundle CH, Gomez GA, Pourteymoor S, Mohan S. Sequential application of small molecule therapy enhances chondrogenesis and angiogenesis in murine segmental defect bone repair. J Orthop Res. July 2023;41(7):1471-1481.
2012	Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. March 2012;8(3):133-143.
2015	Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45-54.
2014	Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. December 2014;10(12):e1004820.
2007	Fratzl P, Weinkamer R. Nature’s hierarchical materials. Prog Mater Sci. November 2007;52(8):1263-1334.
2021	Zenzes M, Zaslansky P. Micro-CT data of early physiological cancellous bone formation in the lumbar spine of female C57BL/6 mice. Sci Data. May 14, 2021;8(1):132.
2008	Schindeler A, McDonald MM, Bokko P, Little DG. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol. October 2008;19(5):459-466.
2008	Palomares KTS. Mechanobiological Regulation of Cell Molecular Expression and Tissue Differentiation During Bone Healing [PhD thesis]. Boston University; 2008.
2011	Leong PL. Spatial Localization of Mechanical Stimuli and Cellular Responses During Bone Healing in Vivo [PhD thesis]. Boston University; 2011.
2013	Miller GJ. Mechanoregulation and Mechanotransduction in Skeletal Tissue Differentiation [Master's thesis]. Boston University; 2013.
2016	Glass KA. Combined Gene Therapy and Functional Tissue Engineering for the Treatment of Osteoarthritis [PhD thesis]. Duke University; 2016.
2016	Loebel C. Engineering Hyaluronan-Tyramine Hydrogels to Modulate Mesenchymal Stem Cell Behavior [PhD thesis]. Swiss Federal Institute of Technology Zürich; 2016.
2007	Oest ME. Dual Osteogenic and Angiogenic Growth Factor Delivery as a Treatment for Segmental Bone Defects [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2007.
2010	Johnson MR. Delivery of BMP-2 for Bone Tissue Engineering Applications [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; May 2010.
2011	Boerckel JD. Mechanical Regulation of Bone Regeneration and Vascular Growth in Vivo [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2011.
2013	Shekaran A. Beta 1 Integrins in Bone Formation During Development and Engineering Integrin-Specific Hydrogels for Enhanced Bone Healing [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; May 2013.
2013	Uhrig BA. Tissue Regeneration in Composite Injury Models of Limb Trauma [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2013.
2015	Priddy LB. Biomaterial Strategies for Improved Bone Healing With Bone Morphogenetic Protein-2 Delivery [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2015.
2016	Clark AYL. Integrin Specificity as a Novel Strategy for Enhancing Transplanted Stem Cell Survival and Tissue Repair in Vivo [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; May 2016.
2019	Klosterhoff BS. Mechanobiological Regulation of Early Stage Bone Repair [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2019.
2019	Ruehle MA. Cell-Based Vascular Therapeutics for Bone Regeneration [PhD thesis]. Atlanta, GA: Georgia Institute of Technology; August 2019.
2007	Geris L. Mathematical Modelling of Bone Regeneration During Fracture Healing and Implant Osseointegration [PhD thesis]. Leuven, Belgium: Katholieke Universiteit Leuven; May 2007.
2021	Al Hamed FSM. Role of Plasma Composition on Bone Healing and Implant Osseointegration [PhD thesis]. McGill University; March 2021.
2019	McDermott AM. Mechanical Regulation of Progenitor Cell Differentiation During Endochondral Ossification [PhD thesis]. Notre Dame, IN: University of Notre Dame; July 2019.
2020	Karali A. Multi-Scale Evaluation of Bone Combining Indentation, in Situ XCT Mechanics and Digital Volume Correlation [PhD thesis]. Portsmouth, England: University of Portsmouth; 2020.
2010	Gurkan UA. Engineering of Bone Marrow in Vitro for Investigating the Role of Growth Factors and Their Mechanoresponsiveness in Osteogenesis [PhD thesis]. Purdue University; May 2010.
2018	Yang F. The Synergistic Effect of Bone Graft Substitute Architecture and Mechanical Environment on HMSCs Responses in Vitro [PhD thesis]. Queen Mary University of London; December 2018.
2004	De Ranieri A. Morphologic, Mechanical, and Molecular Aspects of TGF-Β2 Enhanced Implant Fixation [PhD thesis]. Rush University; 2004.
2019	Rahimi A. Simulation of the Acoustic Pressure Field and Study of Cellular Responses of Osteoprogenitors Using Low-Intensity Pulsed Ultrasound Treatment in an in Vitro Ultrasound Bioreactor [PhD thesis]. St. Louis, MO: Saint Louis University; 2019.
2008	Byrne DP. Computational Modelling of Bone Regeneration Using a Three-Dimensional Lattice Approach [PhD thesis]. Trinity College Dublin; October 2008.
2012	Khayyeri H. Computational Investigations of Variability in Mechanobiological Simulations of Tissue Differentiation [PhD thesis]. Trinity College Dublin; 2012.
2014	Xue F. Computational Investigations of Mesenchymal Stem Cell Ageing in Mechanobiological Simulations of Tissue Differentiation [PhD thesis]. Trinity College Dublin; 2014.
2017	Gonzalez Fernandez T. Integrating Non-Viral Gene Therapy and 3D Bioprinting for Bone, Cartilage and Osteochondral Tissue Engineering [PhD thesis]. Trinity College Dublin; December 2017.
2007	Isaksson HE. Mechanical and Mechanobiological Influences on Bone Fracture Repair: Identifying Important Cellular Characteristics [PhD thesis]. Eindhoven, The Netherlands: Eindhoven University of Technology; 2007.
2013	Mostafa NAHZ. Tissue Engineering Therapies for Cleft Palate Reconstruction [PhD thesis]. Edmonton, AB: University of Alberta; 2013.
2019	Hsia AW. Osteophyte Formation in Post-Traumatic Osteoarthritis [PhD thesis]. Davis, University of California; 2019.
2016	Yee CSN. Determining the Role of Sost and Sostdc1 During Fracture Healing [PhD thesis]. Merced, CA: Merced, University of California; 2016.
2010	Melhus G. Molecular Studies on Bone With Focus on Fracture Healing in Experimental Osteoporosis [PhD thesis]. Oslo, Norway: University of Oslo; 2010.
2008	Weaver AS. The Effect of Mechanical Stimulation on Bone Fracture Healing: Changes in Callus Morphology and Mesenchymal Stem Cell Homing [PhD thesis]. University of Michigan; 2008.
2010	Meganck JA. Fracture Healing and Regeneration in the Context of an Altered Collagenous Extracellular Matrix [PhD thesis]. University of Michigan; 2010.
2020	Kegelman CD. Combinatorial Roles of Skeletal Cell YAP and TAZ in Bone Growth, Remodeling, and Repair [PhD thesis]. Philadelphia, PA: University of Pennsylvania; 2020.
2023	Collins JM. The Roles of YAP and TAZ in Fetal Bone Development [PhD thesis]. Philadelphia, PA: University of Pennsylvania; 2023.
2021	Lo CH. Bone Microenvironmental Control of Skeletal Malignancy [PhD thesis]. University of South Florida; 2021.
2011	Kempen DHR. Bone Regeneration Based on Growth Factor Releasing Polymer Composites [PhD thesis]. Utrecht University; 2011.
2009	McKenzie JA. Investigations Into the Ulnar Response to Mechanical Stimuli Activating Lamellar and Woven Bone Formation [PhD thesis]. St. Louis, MO: Washington University in St. Louis; December 2009.
2018	Buettmann E. The Role of Bisphosphonates and Osteoblast Lineage Cells in Promoting Osteogenic and Angiogenic Processes Necessary for Bone Repair [PhD thesis]. St. Louis, MO: Washington University in St. Louis; December 2018.
2020	Coates BA. The Role of Gene Transcription and Inflammatory Cytokines in Bone Fracture Repair [PhD thesis]. St. Louis, MO: Washington University in St. Louis; May 2020.