Tendons transmit the force generated by muscle contraction to the skeleton, through robust and highly organized bundles of collagen fibrils that establish the biomechanical properties of tendons. In the tendons, cellular extensions engulf bundles of collagen fibrils and generate the microenvironment for fibril growth. Growth of the collagen fibrils in tendons is the single most significant factor that determines biomechanical properties and tensile strength of tendons. Collagen fibril growth occurs in two phases, slow fibril assembly in embryonic stages and a much faster pace of fibril growth that likely occurs through fibril fusion in postnatal stages. Nothing, however, is known about the genetic program that regulates these processes. We have previously shown that the bHLH transcription factor Scleraxis is essential for early tendon differentiation and that it likely also plays an important role in collagen fibrillogenesis. In mutants of a second tendon transcription factor, Mohawk, we now find a failure of the later postnatal phase of collagen fibril growth. This project focuses on the role of Scleraxis and Mohawk in collagen fibrillogenesis and tendon maturation. The first specific aim focuses on tendon assembly in embryonic tendons and the second aim looks at the regulation of tendon maturation and rapid collagen fibril growth in postnatal stages. These processes will be addressed following a similar approach in both stages. Normal tendon growth and tendon phenotypes will initially be evaluated with an enhanced set of structural parameters and the effects of overexpression of Scx or Mkx on tendon growth will be examined. Molecular mediators of Scleraxis and Mohawk functions will be identified by microarray profiling and the regulatory roles of a small number of target genes will be determined by a transgenic rescue of the Scx or Mkx phenotypes reintroducing the expression of a single or multiple target genes into the mutant background. We recently identified ZFP185, a Zinc Finger Transcription factor as the first promising candidate for which we plan to proceed with a transgenic rescue. Identifying regulatory pathways that control fibril growth will likely contribute to the ability to enhance and regulate these processes in clinical settings.

Public Health Relevance

Sports and age related tendon or ligament injuries are of the most common causes for orthopedic treatments and the long healing periods for these injuries translate to considerable hardship to the affected individuals and a significant economic burden for society. The capacity to return these tissues to their original strength is tightly linked to the quality of the collagen matrix that develops in the treated tissue. Considerable attention has therefore been directed to the proteins that make up the collagen fibrils in tendons and to the extracellular proteins that regulate fibril growth. Nothing however is known about the higher levels of regulation of these processes. The long term goal of this project is to decipher the transcriptional network that governs collagen fibrillogenesis and fibril growth in tendons and ligaments. Identifying the key regulatory players in this process is likely to open new avenues for enhancement of the clinical outcomes of tendon and ligament injury or replacement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055973-03
Application #
8212156
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$332,640
Indirect Cost
$116,640
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239