# FGF signaling during growth and mechanical adaptation of tendon-bone interfaces

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $410,620

## Abstract

ABSTRACT
The tendon-bone interface is a structurally graded fibrocartilage interface that is critical for transducing
mechanical loads from muscle to the skeleton. Reduced muscle loading can lead to impaired interface growth
and skeletal deformities. Recently, we have shown that the size of tendon-bone interfaces in the embryonic
mouse limb are negatively regulated by fibroblast growth factor 9 (FGF9), and skeletal muscle-specific knockout
of FGF9 phenocopies the effects we see in global FGF9 mutants. These strong preliminary findings have led us
to hypothesize that FGF signaling, mediated by muscle specific FGF9, contributes to interface growth in a non-
cell autonomous manner. However, it remains unclear if and how FGF signaling between adjacent muscle,
tendon, and bone alters the behavior of interface progenitor cells, or whether interface growth is secondary to
FGF-mediated changes to mechanical loading from muscle. In this proposal, we will use innovative mouse
models for FGF ligand- and receptor-loss of function (LOF) and gain-of-function (GOF) in tissue-specific Cre
alleles to isolate the cell population required for FGF-induced changes. We will rigorously compare the structural
(i.e., microcomputed tomography), cellular/ECM (i.e., histomorphology) and biomechanical properties (i.e.,
tensile, indentation tests) of the tendon-bone interface in LOF/GOF genotypes and controls. We will test FGFR-
dependent mechanoresponsive structural adaptation of interfaces following muscle unloading using chemical
denervation or increased muscle loading using optogenetic stimulation. In this project, we will use innovative, in
vivo optogenetics to induce repetitive skeletal muscle contraction in neonatal mice using pulsed blue light, a
technique we established with recent NIH R03 support. This approach, combined with novel FGFR LOF/GOF
mouse models, will allow us to determine the role of FGF signaling in muscle loading induced adaptation of the
tendon-bone interface. We aim to (1) demonstrate muscle-derived Fgf9 is responsible for regulating the
development of tendon-bone interfaces during embryonic and postnatal growth and (2) Establish the mechanism
by which cell-specific FGF signaling regulates loading-induced structural adaptations of tendon-bone interfaces.
This R01 proposal will establish the non-cell autonomous contributions of Fgf9 in interface growth and
structure/function of tendon-bone interfaces as well as the cell autonomous roles of FGFR signaling in interface
growth and mechanical adaptation. Additionally, findings from this work will identify both conserved and unique
downstream signaling pathways associated with FGF receptors that guide postnatal growth of tendon-bone
interfaces.

## Key facts

- **NIH application ID:** 10469630
- **Project number:** 5R01AR079367-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Megan L. Killian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,620
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469630

## Citation

> US National Institutes of Health, RePORTER application 10469630, FGF signaling during growth and mechanical adaptation of tendon-bone interfaces (5R01AR079367-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469630. Licensed CC0.

---

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