# Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $8,559

## Abstract

PROJECT SUMMARY
Mutations in several secreted ECM proteins, including ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, LTBP3,
and fibrillin-1 (FBN1), can cause acromelic dysplasias, such as geleophysic dysplasia or Weill-Marchesani
syndrome. All acromelic dysplasias share identical musculoskeletal presentations, including short stature, joint
contractures and hypermuscularity, which suggests that proteins mutated in acromelic dysplasias cooperate in
the ECM of musculoskeletal tissues, either as part of an acromelic dysplasia protein complex or as part of a
molecular pathway that regulates musculoskeletal development and homeostasis. While some functions for the
individual proteins that are mutated in acromelic dysplasias have emerged, there is very little information about
the direct interaction and interrelationship between these proteins. For example, recombinant ADAMTSL2 and
ADAMTS10 can bind to fibrillin-1. However, it is unknown, if both proteins can bind to each other or if the occupy
the same site on fibrillin-1. It is also not known how any of the proteins compromised in acromelic dysplasia,
including ADAMTSL2 and ADAMTS10, are involved in skeletal muscle formation and homeostasis. Here, we
propose to test the hypothesis that ADAMTS10 and ADAMTSL2 interact with each other, either directly or
through the fibrillin-1 microfibril scaffold, and that they cooperate in regulating skeletal muscle formation. In
specific aim 1, we will analyze the role of ADAMTS10 in skeletal muscle differentiation and investigate if
ADAMTS10 cooperates with ADAMTSL2. In specific aim 2, we will investigate if ADAMTSL2 and ADAMTS10
can interact directly and determine their spatial relationship when interacting with fibrillin-1. With the expected
results we will begin to define the functional role of the components of the acromelic dysplasia complex which
can then be extended by including additional components encoded by the genes mutated in acromelic
dysplasias. These insights will contribute to the quest to understand how proteins affected in acromelic dysplasia
work together to govern skeletal muscle and musculoskeletal tissue development and homeostasis.

## Key facts

- **NIH application ID:** 10320133
- **Project number:** 3R01AR070748-05S1
- **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:** $8,559
- **Award type:** 3
- **Project period:** 2021-01-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320133

## Citation

> US National Institutes of Health, RePORTER application 10320133, Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix (3R01AR070748-05S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10320133. Licensed CC0.

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