Is Senescence Involved in NF1 Recalcitrant Bone Healing?
Abstract
Recalcitrant bone healing following tibia bowing and fracture, also called pseudarthrosis (PA), is a clinically challenging skeletal manifestation associated with high morbidity in children with NF1. Affected children often undergo several surgeries associated with pain, risk of infection, long hospitalization, and reduced quality of life and, overall, face a limited success for bone healing, leading in some cases to amputation of the limb at an early age. Current treatment relies on the generic bone building property of Bone Morphogenic Protein 2 (BMP2); however, bone-forming cells with NF1 loss-of-function mutations that cause NF1 PA do not respond to this drug like normal cells. Other therapeutic options more recently identified are associated with risk of promoting tumors in patients already at great risk for this. It is thus imperative to determine why bone cells with NF1 loss-of-function mutations are not able to differentiate into bone-forming cells and efficiently respond to BMP2. It is also critical to figure out whether and how they might negatively affect other cells that participate to the multi-step process of bone healing if we want to identify new and more potent therapeutic interventions that specifically treat NF1 PA. Our laboratory pioneered research into the underlying causes of NF1 PA and relied on modeling of this manifestation in mice to identify an impairment of bone mineralization and osteogenic differentiation in skeletal progenitor stem cells that give rise to bone-forming cells. I discovered that these progenitor cells exhibit traits of senescent cells, which are characterized by their secretion of factors that can negatively impact other cells of their environment. In this proposal, I wish to follow up on these exciting new data to (1) characterize this senescence phenotype in both mouse and human cells deficient for Nf1 and then (2) use drugs known to eliminate senescent cells or inhibit the action of the factor they produce to determine whether this senescence phenotype plays a critical role in the inability of Nf1-deficent skeletal progenitor cells to differentiate and heal bone. These experiments will be performed in mouse but also human cells previously isolated from two patients with NF1 PA, thus raising the clinical relevance of our findings and increasing possibility for faster transition to future trials. The majority of the “senotherapeutic” drugs to be tested have already shown success in improving bone health during aging and are currently meeting success in clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010352
Entities
People
- Efrosini Cuko
Organizations
- Baylor College of Medicine
- United States Army