# Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $85,628

## Abstract

ABSTRACT
While it is undisputed that extracellular matrix and soft tissues influence skeletal growth, few specific pathways
explaining this effect have been uncovered. In Marfan syndrome, which affects 1-2 in 5000 individuals, skeletal
overgrowth, long digits, poorly developed musculature and lax joints result from fibrillin-1 (FBN1) mutations.
Strikingly, specific mutations in FBN1 can also cause the “opposite” of Marfan syndrome, i.e. short stature,
disproportionally short digits (brachydactyly), stiff joints, and a “pseudomuscular” build, which are the hallmarks
of acromelic dysplasias, comprising a group of Mendelian disorders. Identical acromelic dysplasias can also be
caused by genes encoding ADAMTS proteases, ADAMTS-like (ADAMTSL) proteins, latent transforming
growth factor- (TGF) binding protein-3 (LTBP3), and SMAD4. The overlapping phenotypes of different gene
mutations underlying acromelic dysplasias strongly support my hypothesis that a fibrillin-ADAMTS-TGF axis
constitutes a novel extracellular matrix (ECM) network regulating postnatal limb growth.
Mutations in ADAMTSL2 or FBN1 lead to geleophysic dysplasia (GD), a severe, frequently lethal human
acromelic dysplasia. ADAMTSL2 is a secreted glycoprotein that binds to FBN1 and FBN2, and is implicated in
TGF signaling. Intriguingly, ADAMTSL2 mRNA is not expressed in growth plate cartilage or bone, but has its
strongest expression in tendon. My studies show that FBN2 microfibrils are increased at sites of Adamtsl2
expression in a mouse knockout model of GD, suggesting a role for ADAMTSL2 in switching from prenatal
FBN2-dominated microfibrils to postnatal FBN1-dominated microfibrils. Furthermore, skeletal growth is
impaired upon limb-specific ADAMTSL2 deletion (Prx1-Cre) or tendon and ligament specific deletion (Scx-
Cre). I observed disproportionate distal limb shortening (i.e. acromelic dysplasia) and a reduction in Achilles
tendon length in both conditional deletions. A model for skeletal growth in geleophysic dysplasia provides an
opportunity to determine how tissue non-autonomous regulation of skeletal growth occurs via mechanical or
regulatory input from tendon ECM. In aim 1, I will test the hypothesis by analyzing postnatal limb growth and
ECM alterations in the microfibril system after Adamtsl2 deletion in tendons with Scx-Cre. In aim 2, I will
investigate how ADAMTSL2 interacts with FBN1 and FBN2 and how ADAMTSL2 executes its role in the
isoform switch from FBN2 to FBN1. I will analyze the genetic interaction of Adamtsl2 with Fbn1 and Fbn2 in
mice and I will use protein-protein interaction studies and cell culture assays to gain mechanistic insights in the
function of ADAMTSL2 in regulating the fibrillin isoform switch.
Impact: The anticipated results will provide novel insights into the pathophysiology of acromelic dysplasias and
other fibrillinopathies. These insights could be translated for targeting tendon ECM in regenerative strategies.
The proposal addresses fundamental ...

## Key facts

- **NIH application ID:** 10437366
- **Project number:** 3R01AR070748-06S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dirk Hubmacher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $85,628
- **Award type:** 3
- **Project period:** 2018-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437366

## Citation

> US National Institutes of Health, RePORTER application 10437366, Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix (3R01AR070748-06S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10437366. Licensed CC0.

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