We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Modulation of spine fusion with BMP-2, MEK inhibitor (PD0325901), and zoledronic acid in a murine model of NF1 double inactivation.
- Authors
Bobyn, Justin D.; Deo, Nikita; Little, David G.; Schindeler, Aaron
- Abstract
<bold>Background: </bold>Spine fusion is a common procedure for the treatment of severe scoliosis, a frequent and challenging deformity associated with Neurofibromatosis type 1 (NF1). Moreover, deficiencies in NF1-Ras-MEK signaling affect bone formation and resorption that in turn impacts on spine fusion outcomes.<bold>Methods: </bold>In this study we describe a new model for AdCre virus induction of Nf1 deficiency in the spines of Nf1flox/flox mice. The virus is delivered locally to the mouse spine in a fusion procedure induced using BMP-2. Systemic adjunctive treatment with the MEK inhibitor (MEKi) PD0325901 and the bisphosphonate zoledronic acid (ZA) were next trialed in this model.<bold>Results: </bold>AdCre delivery resulted in abundant fibrous tissue (Nf1null +393%, P < 0.001) and decreased marrow space (Nf1null -67%, P < 0.001) compared to controls. While this did not significantly impact on the bone volume of the fusion mass (Nf1null -14%, P = 0.999 n.s.), the presence of fibrous tissue was anticipated to impact on the quality of spine fusion. Multinucleated TRAP + cells were observed in the fibrous tissues seen in Nf1null spines. In Nf1null spines, MEKi increased bone volume (+194%, P < 0.001) whereas ZA increased bone density (+10%, P < 0.002) versus BMP-2 alone. Both MEKi and ZA decreased TRAP + cells in the fibrous tissue (MEKi -62%, P < 0.01; ZA -43%, P = 0.054). No adverse effects were seen with either MEKi or ZA treatment including weight loss or signs of illness or distress that led to premature euthanasia.<bold>Conclusions: </bold>These data not only support the utility of an AdCre-virus induced knockout spine model, but also support further investigation of MEKi and ZA as adjunctive therapies for improving BMP-2 induced spine fusion in the context of NF1.
- Subjects
ZOLEDRONIC acid; BONE growth; SPINE; BONE density; NEUROFIBROMATOSIS 1
- Publication
Journal of Orthopaedic Science, 2021, Vol 26, Issue 4, p684
- ISSN
0949-2658
- Publication type
journal article
- DOI
10.1016/j.jos.2020.05.016