Regulation of Skeletal Growth by Soft Tissue Extracellular Matrix

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.