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Author Notes:

Address correspondence to: Robert E Guldberg, PhD, 315 Ferst Drive, Georgia Institute of Technology, Atlanta, GA 30332-0363, USA. E-mail: robert.guldberg@me.gatech.edu

AC and LK contributed equally to this work.

Conception and study design: AC, LK, LT, JW, GG, and REG.

Study conduct: AC, LK, LT, and HYS.

Data collection: AC, LK, HYS, BX, and NL.

Data analysis: AC, LK, and GG.

Data interpretation: AC, LK, LT, HYS, GG, and REG.

Drafting manuscript: AC.

Revising manuscript content: AC, LK, HYS, GG, and REG.

Approving final version of manuscript: all authors.

AC and LK take responsibility for the integrity of the data analysis.

The authors thank all members of the Guldberg lab for assistance with surgeries and Dalia Arafat for help running the Fluidigm microarrays.

The collagen sponges and BMP‐2 used in this study were provided by Kensey Nash (now DSM) and Pfizer Inc., respectively.

All authors state that they have no conflicts of interest.

Subjects:

Research Funding:

This work was supported by a research partnership between Children's Healthcare of Atlanta and the Georgia Institute of Technology, as well as the Oral and Maxillofacial Surgery Foundation (OMSF).

This work was also supported under the AFIRM II (U.S. Armed Forces Institute of Regenerative Medicine) effort, award no. W81XWH‐14‐2‐0003.

The U.S. Army Medical Research Acquisition Activity is the awarding and administering acquisition office.

Keywords:

  • AGING
  • BMPS
  • BONE QCT/μCT
  • INJURY/FRACTURE HEALING
  • PRECLINICAL STUDIES

The Effects of Age and Dose on Gene Expression and Segmental Bone Defect Repair After BMP-2 Delivery.

Tools:

Journal Title:

JBMR Plus

Volume:

Volume 3, Number 2

Publisher:

, Pages e10068-e10068

Type of Work:

Article | Final Publisher PDF

Abstract:

Age is a well-known influential factor in bone healing, with younger patients generally healing bone fractures more rapidly and suffering fewer complications compared with older patients. Yet the impact age has on the response to current bone healing treatments, such as delivery of bone morphogenetic protein 2 (BMP-2), remains poorly characterized. It remains unclear how or if therapeutic dosing of BMP-2 should be modified to account for age-related differences in order to minimize potential adverse effects and consequently improve patient bone-healing outcomes. For this study, we sought to address this issue by using a preclinical critically sized segmental bone defect model in rats to investigate age-related differences in bone repair after delivery of BMP-2 in a collagen sponge, the current clinical standard. Femoral defects were created in young (7-week-old) and adult (8-month-old) rats, and healing was assessed using gene expression analyses, longitudinal radiography, ex vivo micro-computed tomography (µCT), as well as torsional testing. We found that young rats demonstrated elevated expression of genes related to osteogenesis, chondrogenesis, and matrix remodeling at the early 1-week time point compared with adult rats. These early gene expression differences may have impacted long-term healing as the regenerated bones of young rats exhibited higher bone mineral densities compared with those of adult rats after 12 weeks. Furthermore, the young rats demonstrated significantly more bone formation and increased mechanical strength when BMP-2 dose was increased from 1 µg to 10 µg, a finding not observed in adult rats. Overall, these results indicate there are age-related differences in BMP-2-mediated bone regeneration, including relative dose sensitivity, suggesting that age is an important consideration when implementing a BMP-2 treatment strategy.

Copyright information:

© 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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