Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing

Soonchul Lee, Chenchao Wang, Hsin Chuan Pan, Swati Shrestha, Carolyn Meyers, Catherine Ding, Jia Shen, Eric Chen, Min Lee, Chia Soo, Kang Ting, Aaron James

Research output: Contribution to journalArticle

Abstract

Background: Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model. Methods: A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold. Results: Results at 4 and 8 weeks showed increased bone formation by micro-computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization. Conclusions: In summary, the authors' results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.

Original languageEnglish (US)
Pages (from-to)1385-1396
Number of pages12
JournalPlastic and Reconstructive Surgery
Volume139
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Bone and Bones
Proteins
Hedgehogs
Osteogenesis
Parietal Bone
Bone Morphogenetic Protein 7
SAG compound
Bone Morphogenetic Protein 2
Bone Regeneration
Durapatite
Mesenchymal Stromal Cells
Safety
Control Groups
Therapeutics

ASJC Scopus subject areas

  • Surgery

Cite this

Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing. / Lee, Soonchul; Wang, Chenchao; Pan, Hsin Chuan; Shrestha, Swati; Meyers, Carolyn; Ding, Catherine; Shen, Jia; Chen, Eric; Lee, Min; Soo, Chia; Ting, Kang; James, Aaron.

In: Plastic and Reconstructive Surgery, Vol. 139, No. 6, 01.06.2017, p. 1385-1396.

Research output: Contribution to journalArticle

Lee, S, Wang, C, Pan, HC, Shrestha, S, Meyers, C, Ding, C, Shen, J, Chen, E, Lee, M, Soo, C, Ting, K & James, A 2017, 'Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing', Plastic and Reconstructive Surgery, vol. 139, no. 6, pp. 1385-1396. https://doi.org/10.1097/PRS.0000000000003367
Lee, Soonchul ; Wang, Chenchao ; Pan, Hsin Chuan ; Shrestha, Swati ; Meyers, Carolyn ; Ding, Catherine ; Shen, Jia ; Chen, Eric ; Lee, Min ; Soo, Chia ; Ting, Kang ; James, Aaron. / Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing. In: Plastic and Reconstructive Surgery. 2017 ; Vol. 139, No. 6. pp. 1385-1396.
@article{0c0c202dc86b4bf38a8eedef97d36756,
title = "Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing",
abstract = "Background: Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model. Methods: A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold. Results: Results at 4 and 8 weeks showed increased bone formation by micro-computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization. Conclusions: In summary, the authors' results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.",
author = "Soonchul Lee and Chenchao Wang and Pan, {Hsin Chuan} and Swati Shrestha and Carolyn Meyers and Catherine Ding and Jia Shen and Eric Chen and Min Lee and Chia Soo and Kang Ting and Aaron James",
year = "2017",
month = "6",
day = "1",
doi = "10.1097/PRS.0000000000003367",
language = "English (US)",
volume = "139",
pages = "1385--1396",
journal = "Plastic and Reconstructive Surgery",
issn = "0032-1052",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing

AU - Lee, Soonchul

AU - Wang, Chenchao

AU - Pan, Hsin Chuan

AU - Shrestha, Swati

AU - Meyers, Carolyn

AU - Ding, Catherine

AU - Shen, Jia

AU - Chen, Eric

AU - Lee, Min

AU - Soo, Chia

AU - Ting, Kang

AU - James, Aaron

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background: Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model. Methods: A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold. Results: Results at 4 and 8 weeks showed increased bone formation by micro-computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization. Conclusions: In summary, the authors' results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.

AB - Background: Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro. In this study, the authors sought to leverage their previous findings by applying the combination of Smoothened agonist (SAG), hedgehog signal activator, and NELL-1 to an in vivo critical-size bone defect model. Methods: A 4-mm parietal bone defect was created in mixed-gender CD-1 mice. Treatment groups included control (n = 6), SAG (n = 7), NELL-1 (n = 7), and SAG plus NELL-1 (n = 7). A custom fabricated poly(lactic-co-glycolic acid) disk with hydroxyapatite coating was used as an osteoinductive scaffold. Results: Results at 4 and 8 weeks showed increased bone formation by micro-computed tomographic analyses with either stimulus alone (SAG or NELL-1), but significantly greater bone formation with both components combined (SAG plus NELL-1). This included greater bone healing scores and increased bone volume and bone thickness. Histologic analyses confirmed a significant increase in new bone formation with the combination therapy SAG plus NELL-1, accompanied by increased defect vascularization. Conclusions: In summary, the authors' results suggest that combining the hedgehog signaling agonist SAG and NELL-1 has potential as a novel therapeutic strategy for the healing of critical-size bone defects. Future directions will include optimization of dosage and delivery strategy for an SAG and NELL-1 combination product.

UR - http://www.scopus.com/inward/record.url?scp=85012867432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012867432&partnerID=8YFLogxK

U2 - 10.1097/PRS.0000000000003367

DO - 10.1097/PRS.0000000000003367

M3 - Article

C2 - 28198775

AN - SCOPUS:85012867432

VL - 139

SP - 1385

EP - 1396

JO - Plastic and Reconstructive Surgery

JF - Plastic and Reconstructive Surgery

SN - 0032-1052

IS - 6

ER -