Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration

Kyung Shin Kang, Jeff Lastfogel, Laurie L. Ackerman, Andrew Jea, Alexander Robling, Sunil S. Tholpady

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

OBJECTIVE Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin. A critical size calvarial defect (4 mm in diameter) was surgically created in the parietal bone in 8-week-old wild-type (n = 8) and Sost KO (n = 8) male mice. The defects were left undisturbed (no implant or scaffold) to simulate a traumatic calvariectomy model. Eight weeks later, the animals were examined at necropsy by planimetry, histological analysis of new bone growth, and micro-CT scanning of bone thickness. RESULTS Defects created in wild-type mice did not fill with bone over the study period of 2 months. Genetic downregulation of sclerostin yielded animals that were able to regenerate 40% of the initial critical size defect area 8 weeks after surgery. A thin layer of bone covered a significant portion of the original defect in all Sost KO animals. A statistically significant increase in bone volume (p < 0.05) was measured in Sost KO mice using radiodensitometric analysis. Immunohistochemical analysis also confirmed that this bone regeneration occurred through the Wnt pathway and originated from the edge of the defect; BMP signaling did not appear to be affected by sclerostin. CONCLUSIONS Mechanical loading is an important mechanism of bone formation in the cranial skeleton and is poorly understood. This is partially due to the fact that it is difficult to load bone in the craniomaxillofacial skeleton. This study suggests that modulation of the Wnt pathway, as is able to be done with monoclonal antibodies, is a potentially efficacious method for bone regeneration that requires further study.

Original languageEnglish (US)
Pages (from-to)1085-1091
Number of pages7
JournalJournal of Neurosurgery
Volume129
Issue number4
DOIs
StatePublished - Oct 1 2018

Fingerprint

Bone Regeneration
Bone Development
Bone and Bones
Wnt Signaling Pathway
Skeleton
Knockout Mice
Parietal Bone
Osteocytes
Standard of Care
Osteogenesis
Down-Regulation
Monoclonal Antibodies
Wounds and Injuries
Infection
Genes

Keywords

  • bone regeneration
  • cranial reconstruction
  • critical size defect
  • sclerostin
  • tissue engineering

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration. / Kang, Kyung Shin; Lastfogel, Jeff; Ackerman, Laurie L.; Jea, Andrew; Robling, Alexander; Tholpady, Sunil S.

In: Journal of Neurosurgery, Vol. 129, No. 4, 01.10.2018, p. 1085-1091.

Research output: Contribution to journalArticle

Kang, Kyung Shin ; Lastfogel, Jeff ; Ackerman, Laurie L. ; Jea, Andrew ; Robling, Alexander ; Tholpady, Sunil S. / Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration. In: Journal of Neurosurgery. 2018 ; Vol. 129, No. 4. pp. 1085-1091.
@article{22ebeea49bc5429ab17dff251b0f0758,
title = "Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration",
abstract = "OBJECTIVE Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin. A critical size calvarial defect (4 mm in diameter) was surgically created in the parietal bone in 8-week-old wild-type (n = 8) and Sost KO (n = 8) male mice. The defects were left undisturbed (no implant or scaffold) to simulate a traumatic calvariectomy model. Eight weeks later, the animals were examined at necropsy by planimetry, histological analysis of new bone growth, and micro-CT scanning of bone thickness. RESULTS Defects created in wild-type mice did not fill with bone over the study period of 2 months. Genetic downregulation of sclerostin yielded animals that were able to regenerate 40{\%} of the initial critical size defect area 8 weeks after surgery. A thin layer of bone covered a significant portion of the original defect in all Sost KO animals. A statistically significant increase in bone volume (p < 0.05) was measured in Sost KO mice using radiodensitometric analysis. Immunohistochemical analysis also confirmed that this bone regeneration occurred through the Wnt pathway and originated from the edge of the defect; BMP signaling did not appear to be affected by sclerostin. CONCLUSIONS Mechanical loading is an important mechanism of bone formation in the cranial skeleton and is poorly understood. This is partially due to the fact that it is difficult to load bone in the craniomaxillofacial skeleton. This study suggests that modulation of the Wnt pathway, as is able to be done with monoclonal antibodies, is a potentially efficacious method for bone regeneration that requires further study.",
keywords = "bone regeneration, cranial reconstruction, critical size defect, sclerostin, tissue engineering",
author = "Kang, {Kyung Shin} and Jeff Lastfogel and Ackerman, {Laurie L.} and Andrew Jea and Alexander Robling and Tholpady, {Sunil S.}",
year = "2018",
month = "10",
day = "1",
doi = "10.3171/2017.5.JNS17219",
language = "English (US)",
volume = "129",
pages = "1085--1091",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
number = "4",

}

TY - JOUR

T1 - Loss of mechanosensitive sclerostin may accelerate cranial bone growth and regeneration

AU - Kang, Kyung Shin

AU - Lastfogel, Jeff

AU - Ackerman, Laurie L.

AU - Jea, Andrew

AU - Robling, Alexander

AU - Tholpady, Sunil S.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - OBJECTIVE Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin. A critical size calvarial defect (4 mm in diameter) was surgically created in the parietal bone in 8-week-old wild-type (n = 8) and Sost KO (n = 8) male mice. The defects were left undisturbed (no implant or scaffold) to simulate a traumatic calvariectomy model. Eight weeks later, the animals were examined at necropsy by planimetry, histological analysis of new bone growth, and micro-CT scanning of bone thickness. RESULTS Defects created in wild-type mice did not fill with bone over the study period of 2 months. Genetic downregulation of sclerostin yielded animals that were able to regenerate 40% of the initial critical size defect area 8 weeks after surgery. A thin layer of bone covered a significant portion of the original defect in all Sost KO animals. A statistically significant increase in bone volume (p < 0.05) was measured in Sost KO mice using radiodensitometric analysis. Immunohistochemical analysis also confirmed that this bone regeneration occurred through the Wnt pathway and originated from the edge of the defect; BMP signaling did not appear to be affected by sclerostin. CONCLUSIONS Mechanical loading is an important mechanism of bone formation in the cranial skeleton and is poorly understood. This is partially due to the fact that it is difficult to load bone in the craniomaxillofacial skeleton. This study suggests that modulation of the Wnt pathway, as is able to be done with monoclonal antibodies, is a potentially efficacious method for bone regeneration that requires further study.

AB - OBJECTIVE Cranial defects can result from trauma, infection, congenital malformations, and iatrogenic causes and represent a surgical challenge. The current standard of care is cranioplasty, with either autologous or allogeneic material. In either case, the intrinsic vascularity of the surrounding tissues allows for bone healing. The objective of this study was to determine if mechanotransductive gene manipulation would yield non-weight-bearing bone regeneration in a critical size calvarial defect in mice. METHODS A mouse model of Sost deletion in Sost knockout (KO) mice was created in which the osteocytes do not express sclerostin. A critical size calvarial defect (4 mm in diameter) was surgically created in the parietal bone in 8-week-old wild-type (n = 8) and Sost KO (n = 8) male mice. The defects were left undisturbed (no implant or scaffold) to simulate a traumatic calvariectomy model. Eight weeks later, the animals were examined at necropsy by planimetry, histological analysis of new bone growth, and micro-CT scanning of bone thickness. RESULTS Defects created in wild-type mice did not fill with bone over the study period of 2 months. Genetic downregulation of sclerostin yielded animals that were able to regenerate 40% of the initial critical size defect area 8 weeks after surgery. A thin layer of bone covered a significant portion of the original defect in all Sost KO animals. A statistically significant increase in bone volume (p < 0.05) was measured in Sost KO mice using radiodensitometric analysis. Immunohistochemical analysis also confirmed that this bone regeneration occurred through the Wnt pathway and originated from the edge of the defect; BMP signaling did not appear to be affected by sclerostin. CONCLUSIONS Mechanical loading is an important mechanism of bone formation in the cranial skeleton and is poorly understood. This is partially due to the fact that it is difficult to load bone in the craniomaxillofacial skeleton. This study suggests that modulation of the Wnt pathway, as is able to be done with monoclonal antibodies, is a potentially efficacious method for bone regeneration that requires further study.

KW - bone regeneration

KW - cranial reconstruction

KW - critical size defect

KW - sclerostin

KW - tissue engineering

UR - http://www.scopus.com/inward/record.url?scp=85054342553&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054342553&partnerID=8YFLogxK

U2 - 10.3171/2017.5.JNS17219

DO - 10.3171/2017.5.JNS17219

M3 - Article

C2 - 29125417

AN - SCOPUS:85054342553

VL - 129

SP - 1085

EP - 1091

JO - Journal of Neurosurgery

JF - Journal of Neurosurgery

SN - 0022-3085

IS - 4

ER -