# Etiology of musculoskeletal maladies in NF1

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $341,440

## Abstract

Project Summary/Abstract
Children with Neurofibromatosis Type 1 (NF1) are predisposed to cancer but can also present
with unilateral bowing of the tibia that often progresses to fracture. Unlike the robust bone
healing of most children, bone healing in these patients fails, leading to invasive and repeated
surgeries, and often amputation of the leg. Research focused on identifying the cause of this
refractory bone healing revealed that Nf1 deficiency in bone mesenchymal progenitors blunts
their osteogenic potential and triggers chronic and uncontrolled RAS/ERK signaling, although
blocking this pathway failed to rescue osteoprogenitor differentiation and the delayed bone
healing of mice lacking Nf1 is osteoprogenitors. It has now become clear that multiple signaling
pathways and compensatory mechanisms are involved in the abnormal differentiation of Nf1-
null osteoprogenitors, and that targeting them to promote bone union in children with NF1 will be
very challenging. This proposal steers away from this strategy, thanks to the observation of
early senescence in Nf1-null osteoprogenitors, which should make them sensitive to “senolytic”
drugs. Our hypothesis is thus that eliminating Nf1-null osteoprogenitors - rather than correcting
their multiple defects – with senolytics will promote bone union in children with NF1
pseudarthrosis. We propose to determine if clearance of Nf1-null senescent osteoprogenitors,
genetically or pharmacologically, improves the poor healing potential of mice lacking Nf1 in
osteoprogenitors, and whether the senescence associated secretory phenotype (SASP) from
these cells alters the behavior of lineages contributing to bone repair. A second major premise
of this work is the observation that mice deficient for Nf1 selectively in adult osteoprogenitors
lose muscle mass. This finding and other in vitro and in vivo results led us to challenge the
current view of a muscle-intrinsic defect and to address the hypothesis that bone-derived
factor(s) from Nf1-null osteoprogenitors contribute to the muscle weakness observed in children
with NF1, which could also be alleviated by the clearance of Nf1-null osteoprogenitors with
senolytics. Overall, this work has the potential to improve the clinical management of NF1
pseudarthrosis with a strategy that will pharmacologically clear faulty Nf1-null osteoprogenitors
and relieve their inhibitory influence on other cells contributing to bone repair, thus restoring
robust bone regeneration. Mechanistically, this study may support senescence in Nf1-null
osteoprogenitors as a mechanism to prevent the spread of RAS-induced mutational damage
and preclude potential malignant transformation at the cost of a deleterious bystander effect on
bone repair and muscle function.

## Key facts

- **NIH application ID:** 10795677
- **Project number:** 5R01AR077949-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Florent Elefteriou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $341,440
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795677

## Citation

> US National Institutes of Health, RePORTER application 10795677, Etiology of musculoskeletal maladies in NF1 (5R01AR077949-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795677. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*