WNT-activated bone grafts repair osteonecrotic lesions in aged animals

B. Salmon, B. Liu, E. Shen, T. Chen, J. Li, M. Gillette, R. C. Ransom, M. Ezran, C. A. Johnson, Alesha Castillo, W. J. Shen, F. B. Kraemer, A. A. Smith, J. A. Helms

Research output: Contribution to journalArticle

Abstract

The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo μCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

Original languageEnglish (US)
Article number14254
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Autografts
Transplants
Bone and Bones
Tissue Donors
Diaphyses
Cryosurgery
Wnt Signaling Pathway
Osteonecrosis
Therapeutics
Liposomes
Stem Cells
Immunohistochemistry
Wounds and Injuries
Proteins

ASJC Scopus subject areas

  • General

Cite this

Salmon, B., Liu, B., Shen, E., Chen, T., Li, J., Gillette, M., ... Helms, J. A. (2017). WNT-activated bone grafts repair osteonecrotic lesions in aged animals. Scientific Reports, 7(1), [14254]. https://doi.org/10.1038/s41598-017-14395-9

WNT-activated bone grafts repair osteonecrotic lesions in aged animals. / Salmon, B.; Liu, B.; Shen, E.; Chen, T.; Li, J.; Gillette, M.; Ransom, R. C.; Ezran, M.; Johnson, C. A.; Castillo, Alesha; Shen, W. J.; Kraemer, F. B.; Smith, A. A.; Helms, J. A.

In: Scientific Reports, Vol. 7, No. 1, 14254, 01.12.2017.

Research output: Contribution to journalArticle

Salmon, B, Liu, B, Shen, E, Chen, T, Li, J, Gillette, M, Ransom, RC, Ezran, M, Johnson, CA, Castillo, A, Shen, WJ, Kraemer, FB, Smith, AA & Helms, JA 2017, 'WNT-activated bone grafts repair osteonecrotic lesions in aged animals', Scientific Reports, vol. 7, no. 1, 14254. https://doi.org/10.1038/s41598-017-14395-9
Salmon, B. ; Liu, B. ; Shen, E. ; Chen, T. ; Li, J. ; Gillette, M. ; Ransom, R. C. ; Ezran, M. ; Johnson, C. A. ; Castillo, Alesha ; Shen, W. J. ; Kraemer, F. B. ; Smith, A. A. ; Helms, J. A. / WNT-activated bone grafts repair osteonecrotic lesions in aged animals. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{5ad85d5ad7d743b284238eb0472e3b76,
title = "WNT-activated bone grafts repair osteonecrotic lesions in aged animals",
abstract = "The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo μCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.",
author = "B. Salmon and B. Liu and E. Shen and T. Chen and J. Li and M. Gillette and Ransom, {R. C.} and M. Ezran and Johnson, {C. A.} and Alesha Castillo and Shen, {W. J.} and Kraemer, {F. B.} and Smith, {A. A.} and Helms, {J. A.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-14395-9",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - WNT-activated bone grafts repair osteonecrotic lesions in aged animals

AU - Salmon, B.

AU - Liu, B.

AU - Shen, E.

AU - Chen, T.

AU - Li, J.

AU - Gillette, M.

AU - Ransom, R. C.

AU - Ezran, M.

AU - Johnson, C. A.

AU - Castillo, Alesha

AU - Shen, W. J.

AU - Kraemer, F. B.

AU - Smith, A. A.

AU - Helms, J. A.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo μCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

AB - The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo μCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

UR - http://www.scopus.com/inward/record.url?scp=85032509398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032509398&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-14395-9

DO - 10.1038/s41598-017-14395-9

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 14254

ER -