Hubmacher Laboratory

Research

  1. How is skeletal growth regulated by soft-tissue extracellular matrix

Short stature is a hallmark of several human Mendelian disorders caused by mutations in genes encoding extracellular matrix (ECM) proteins. Domain-specific mutations in fibrillin-1 (FBN1) cause acromelic dysplasias, presenting with short stature, short digits (brachydactyly) and stiff joints. Acromelic dysplasias are also caused by recessive mutations in ADAMTS-like (ADAMTSL) proteins and ADAMTS proteases, such as ADAMTS10 (Weill-Marchesani syndrome), ADAMTS17 (Weill-Marchesani-like syndrome), and ADAMTSL2 (geleophysic dysplasia). We use a mouse model of geleophysic dysplasia as an example to define a novel ECM pathway of skeletal growth regulation by soft tissue ECM. Because Adamtsl2 is not expressed in the growth plate or the perichondrium, but is strongly expressed in tendon, we propose that in the absence of ADAMTSL2, fibrillin microfibril function is compromised. The compromised microfibrils alter the biochemical and biomechanical properties of tendon resulting in postnatal skeletal limb growth restriction. The project is funded by NIH/NIAMS (RO1AR070748)

  1. What is the role of the ADAMTS / ADAMTSL / fibrillin microfibril network in the extracellular matrix of musculoskeletal tissue

In several future research projects we will delineate how ADAMTS protease and ADAMTS-like proteins cooperate in forming a functional fibrillin microfibril network in the ECM and how mutations in these genes may cause the musculoskeletal phenotypes observed in humans. The projects are designed to study the concept that tissue-specific ECM defines the formation and function of musculoskeletal tissues, such as tendon, ligaments, muscle, and bone and that these matrices are altered in disease conditions. Despite the fact that mutations in genes coding for ECM proteins cause a large number of human genetic disorders, our understanding of how the encoded proteins are involved in normal tissue formation and repair is fairly limited. Understanding the function of these proteins on a molecular level will foster novel approaches in tissue engineering and regenerative medicine. Some of the future research projects are listed below:

  • Define the function of the ADAMTS17 protease by generating a knock-out mouse model and by determining the substrates of the protease.
  • Define differential protein-protein interactions of the fibrillin isoforms in humans using yeast-2-hybrid technology

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