Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model

James P. Foley; Elianna J. Fred; Silvia Minardi; Jonathan T. Yamaguchi; Allison C. Greene; Andrew A. Furman; Joseph G. Lyons; Jonathan T. Paul; Tejas S. Nandurkar; Kenneth R. Blank; Robert M. Havey; Muturi Muriuki; Avinash G. Patwardhan; Wellington K. Hsu; Stuart R. Stock; Erin L. Hsu

doi:10.1097/BRS.0000000000004454

Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model

James P. Foley, Elianna J. Fred, Silvia Minardi, Jonathan T. Yamaguchi, Allison C. Greene, Andrew A. Furman, Joseph G. Lyons, Jonathan T. Paul, Tejas S. Nandurkar, Kenneth R. Blank, Robert M. Havey, Muturi Muriuki, Avinash G. Patwardhan, Wellington K. Hsu, Stuart R. Stock, Erin L. Hsu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Study Design. This was a preclinical study. Objective. Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. Summary of Background Data. Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. Materials and Methods. Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 μg of bone morphogenetic protein-2 (10 μg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 μm level. Results. Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males (P<0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P<0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm³, respectively, P<0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P<0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm^-1, respectively, P<0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. Conclusions. This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.

Original language	English (US)
Pages (from-to)	1627-1636
Number of pages	10
Journal	Spine
Volume	47
Issue number	23
DOIs	https://doi.org/10.1097/BRS.0000000000004454
State	Published - Dec 1 2022

Funding

The laboratory microCT data were collected at the Rush University microcomputed tomography/histology core facility. Visualization was performed in the Analytical bioNanoTechnology (ANTEC) Core Facility of the Simpson Querrey Institute at Northwestern University. ANTEC is currently supported by the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). Visualization also utilized the Northwestern University Center for Advanced Molecular Imaging, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (grant number R01AR069580), and by the Women’s research Health Institute of Northwestern University. The funding agencies had no input in the design, execution, and interpretation of this study.

Keywords

BMP
BMP-2
bone
healing
regeneration
rhBMP-2
sex
sex-dependent differences
spinal fusion
spine

ASJC Scopus subject areas

Orthopedics and Sports Medicine
Clinical Neurology

Access to Document

10.1097/BRS.0000000000004454

Cite this

Foley, J. P., Fred, E. J., Minardi, S., Yamaguchi, J. T., Greene, A. C., Furman, A. A., Lyons, J. G., Paul, J. T., Nandurkar, T. S., Blank, K. R., Havey, R. M., Muriuki, M., Patwardhan, A. G., Hsu, W. K., Stock, S. R., & Hsu, E. L. (2022). Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model. Spine, 47(23), 1627-1636. https://doi.org/10.1097/BRS.0000000000004454

@article{0783866ad7f749c5a62e9106949c4f4b,

title = "Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model",

abstract = "Study Design. This was a preclinical study. Objective. Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. Summary of Background Data. Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. Materials and Methods. Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 μg of bone morphogenetic protein-2 (10 μg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 μm level. Results. Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males (P<0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P<0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm3, respectively, P<0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P<0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm-1, respectively, P<0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. Conclusions. This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.",

keywords = "BMP, BMP-2, bone, healing, regeneration, rhBMP-2, sex, sex-dependent differences, spinal fusion, spine",

author = "Foley, {James P.} and Fred, {Elianna J.} and Silvia Minardi and Yamaguchi, {Jonathan T.} and Greene, {Allison C.} and Furman, {Andrew A.} and Lyons, {Joseph G.} and Paul, {Jonathan T.} and Nandurkar, {Tejas S.} and Blank, {Kenneth R.} and Havey, {Robert M.} and Muturi Muriuki and Patwardhan, {Avinash G.} and Hsu, {Wellington K.} and Stock, {Stuart R.} and Hsu, {Erin L.}",

note = "Funding Information: The laboratory microCT data were collected at the Rush University microcomputed tomography/histology core facility. Visualization was performed in the Analytical bioNanoTechnology (ANTEC) Core Facility of the Simpson Querrey Institute at Northwestern University. ANTEC is currently supported by the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). Visualization also utilized the Northwestern University Center for Advanced Molecular Imaging, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Funding Information: Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (grant number R01AR069580), and by the Women{\textquoteright}s research Health Institute of Northwestern University. The funding agencies had no input in the design, execution, and interpretation of this study. Publisher Copyright: {\textcopyright} 2022 Lippincott Williams and Wilkins. All rights reserved.",

year = "2022",

month = dec,

day = "1",

doi = "10.1097/BRS.0000000000004454",

language = "English (US)",

volume = "47",

pages = "1627--1636",

journal = "Spine",

issn = "0362-2436",

publisher = "Lippincott Williams and Wilkins",

number = "23",

}

Foley, JP, Fred, EJ, Minardi, S, Yamaguchi, JT, Greene, AC, Furman, AA, Lyons, JG, Paul, JT, Nandurkar, TS, Blank, KR, Havey, RM, Muriuki, M, Patwardhan, AG, Hsu, WK , Stock, SR & Hsu, EL 2022, 'Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model', Spine, vol. 47, no. 23, pp. 1627-1636. https://doi.org/10.1097/BRS.0000000000004454

TY - JOUR

T1 - Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model

AU - Foley, James P.

AU - Fred, Elianna J.

AU - Minardi, Silvia

AU - Yamaguchi, Jonathan T.

AU - Greene, Allison C.

AU - Furman, Andrew A.

AU - Lyons, Joseph G.

AU - Paul, Jonathan T.

AU - Nandurkar, Tejas S.

AU - Blank, Kenneth R.

AU - Havey, Robert M.

AU - Muriuki, Muturi

AU - Patwardhan, Avinash G.

AU - Hsu, Wellington K.

AU - Stock, Stuart R.

AU - Hsu, Erin L.

N1 - Funding Information: The laboratory microCT data were collected at the Rush University microcomputed tomography/histology core facility. Visualization was performed in the Analytical bioNanoTechnology (ANTEC) Core Facility of the Simpson Querrey Institute at Northwestern University. ANTEC is currently supported by the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). Visualization also utilized the Northwestern University Center for Advanced Molecular Imaging, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. This research also used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Funding Information: Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (grant number R01AR069580), and by the Women’s research Health Institute of Northwestern University. The funding agencies had no input in the design, execution, and interpretation of this study. Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Study Design. This was a preclinical study. Objective. Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. Summary of Background Data. Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. Materials and Methods. Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 μg of bone morphogenetic protein-2 (10 μg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 μm level. Results. Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males (P<0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P<0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm3, respectively, P<0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P<0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm-1, respectively, P<0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. Conclusions. This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.

AB - Study Design. This was a preclinical study. Objective. Evaluate sex-dependent differences in the bone healing response to recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat posterolateral spinal fusion model. Summary of Background Data. Minimal and conflicting data exist concerning potential sex-dependent differences in rhBMP-2-mediated bone regeneration in the context of spinal fusion. Materials and Methods. Forty-eight female and male Sprague-Dawley rats (N=24/group), underwent L4-L5 posterolateral fusion with bilateral placement of an absorbable collagen sponge, each loaded with 5 μg of bone morphogenetic protein-2 (10 μg/animal). At eight weeks postoperative, 10 specimens of each sex were tested in flexion-extension with quantification of range of motion and stiffness. The remaining specimens were evaluated for new bone growth and successful fusion via radiography, blinded manual palpation and microcomputed tomography (microCT). Laboratory microCT quantified bone microarchitecture, and synchrotron microCT examined bone microstructure at the 1 μm level. Results. Manual palpation scores differed significantly between sexes, with mean fusion scores of 2.4±0.4 in females versus 3.1±0.6 in males (P<0.001). Biomechanical stiffness did not differ between sexes, but range of motion was significantly greater and more variable for females versus males (3.7±5.6° vs. 0.27±0.15°, P<0.005, respectively). Laboratory microCT showed significantly smaller volumes of fusion masses in females versus males (262±87 vs. 732±238 mm3, respectively, P<0.001) but significantly higher bone volume fraction (0.27±0.08 vs. 0.12±0.05, respectively, P<0.001). Mean trabecular thickness was not different, but trabecular number was significantly greater in females (3.1±0.5 vs. 1.5±0.4 mm-1, respectively, P<0.001). Synchrotron microCT showed fine bone structures developing in both sexes at the eight-week time point. Conclusions. This study demonstrates sex-dependent differences in bone regeneration induced by rhBMP-2. Further investigation is needed to uncover the extent of and mechanisms underlying these sex differences, particularly at different doses of rhBMP-2.

KW - BMP

KW - BMP-2

KW - bone

KW - healing

KW - regeneration

KW - rhBMP-2

KW - sex

KW - sex-dependent differences

KW - spinal fusion

KW - spine

UR - http://www.scopus.com/inward/record.url?scp=85141893075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85141893075&partnerID=8YFLogxK

U2 - 10.1097/BRS.0000000000004454

DO - 10.1097/BRS.0000000000004454

M3 - Article

C2 - 35943241

AN - SCOPUS:85141893075

SN - 0362-2436

VL - 47

SP - 1627

EP - 1636

JO - Spine

JF - Spine

IS - 23

ER -

Sex-based Difference in Response to Recombinant Human Bone Morphogenetic Protein-2 in a Rat Posterolateral Fusion Model

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this