The Effects of Age and Dose on Gene Expression and Segmental Bone Defect Repair After BMP‐2 Delivery
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. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 16, 2018
- Source ID
- 10.1002/jbm4.10068
Entities
People
- Albert Cheng
- Boao Xia
- Greg Gibson
- Hazel Y. Stevens
- Joseph K. Williams
- Laxminarayanan Krishnan
- Lisa Tran
- Nari Lee
- Robert E Guldberg
Organizations
- Armed Forces Institute of Regenerative Medicine
- Children's Healthcare of Atlanta
- Emory University
- Georgia Tech
- Oral and Maxillofacial Surgery Foundation