Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion

There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its rece...

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Vydáno v:Scientific reports Ročník 10; číslo 1; s. 22241 - 15
Hlavní autoři: Rivera, Kevin O., Russo, Fabrizio, Boileau, Ryan M., Tomlinson, Ryan E., Miclau, Theodore, Marcucio, Ralph S., Desai, Tejal A., Bahney, Chelsea S.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 17.12.2020
Nature Publishing Group
Nature Portfolio
Témata:
631/154/51/2314
631/1647/767/2200
631/443/63
692/308/2778
692/698/1671/1354
692/698/1671/63
Animal models
Animals
Biomarkers
Bone healing
Bone mineral density
Callus
Cancellous bone
Cartilage
Cartilage - diagnostic imaging
Cartilage - drug effects
Cartilage - physiology
Disease Models, Animal
Endochondral bone
Explants
Fluorescent Antibody Technique
Fracture Healing - drug effects
Fractures
Gene expression
Gene Expression Profiling
Humanities and Social Sciences
Imaging, Three-Dimensional
Immunohistochemistry
Injections, Intralesional
Kinases
Mice
multidisciplinary
Nerve growth factor
Nerve Growth Factor - administration & dosage
Ossification
Osteogenesis - drug effects
Platelet-derived growth factor
Recombinant Proteins - administration & dosage
Science
Science (multidisciplinary)
SDF-1 protein
Tibial Fractures
Time Factors
Transcription activation
TrkA protein
Tropomyosin
Wnt protein
X-Ray Microtomography
ISSN:2045-2322, 2045-2322
On-line přístup:Získat plný text
Tagy: Přidat tag
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Abstract There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh , Alpl , and Sdf-1 . Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.
AbstractList There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.
Abstract There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.
There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF's ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF's ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.
There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local β-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from β-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh , Alpl , and Sdf-1 . Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local β-NGF injections. Finally, we demonstrate functional improvements to bone healing following local β-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate β-NGF’s ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.
ArticleNumber 22241
Author Bahney, Chelsea S.
Russo, Fabrizio
Miclau, Theodore
Boileau, Ryan M.
Desai, Tejal A.
Marcucio, Ralph S.
Tomlinson, Ryan E.
Rivera, Kevin O.
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  surname: Rivera
  fullname: Rivera, Kevin O.
  organization: Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF)
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  surname: Russo
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  organization: Department of Orthopaedics and Trauma Surgery, Campus Bio-Medico University
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  givenname: Ryan M.
  surname: Boileau
  fullname: Boileau, Ryan M.
  organization: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco (UCSF), Department of Urology, University of California, San Francisco (UCSF)
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  organization: Department of Orthopaedic Surgery, Thomas Jefferson University
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  fullname: Miclau, Theodore
  organization: Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF)
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  givenname: Ralph S.
  surname: Marcucio
  fullname: Marcucio, Ralph S.
  organization: Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF)
– sequence: 7
  givenname: Tejal A.
  surname: Desai
  fullname: Desai, Tejal A.
  organization: Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF)
– sequence: 8
  givenname: Chelsea S.
  surname: Bahney
  fullname: Bahney, Chelsea S.
  email: cbahney@sprivail.org
  organization: Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), The Steadman Philippon Research Institute (SPRI)
BackLink https://www.ncbi.nlm.nih.gov/pubmed/33335129$$D View this record in MEDLINE/PubMed
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Snippet There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test...
Abstract There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study,...
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SubjectTerms 631/154/51/2314
631/1647/767/2200
631/443/63
692/308/2778
692/698/1671/1354
692/698/1671/63
Animal models
Animals
Biomarkers
Bone healing
Bone mineral density
Callus
Cancellous bone
Cartilage
Cartilage - diagnostic imaging
Cartilage - drug effects
Cartilage - physiology
Disease Models, Animal
Endochondral bone
Explants
Fluorescent Antibody Technique
Fracture Healing - drug effects
Fractures
Gene expression
Gene Expression Profiling
Humanities and Social Sciences
Imaging, Three-Dimensional
Immunohistochemistry
Injections, Intralesional
Kinases
Mice
multidisciplinary
Nerve growth factor
Nerve Growth Factor - administration & dosage
Ossification
Osteogenesis - drug effects
Platelet-derived growth factor
Recombinant Proteins - administration & dosage
Science
Science (multidisciplinary)
SDF-1 protein
Tibial Fractures
Time Factors
Transcription activation
TrkA protein
Tropomyosin
Wnt protein
X-Ray Microtomography
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Title Local injections of β-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion
URI https://link.springer.com/article/10.1038/s41598-020-78983-y
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