Tendons and ligaments are dense connective tissues of mesodermal origin, which connect muscles to bones or bone to bone, and transmit mechanical force. The extracellular matrix (ECM) consists mainly of collagen type 1, organized as triple-helix polypeptide chains, which unite into fibrils, fibers, fascicles, tertiary bundles, forming the tendon and ligament architecture. Damage to tendons and ligaments caused by overuse or injuries is not healed and rarely recovers completely. In addition, to injury, aging-related changes in cells and ECM of ligaments and tendons represent an important risk factor for the development of knee osteoarthritis or rotator cuff syndrome. Obstacles in the development of approaches to address tendon and ligament damage are partly due to the limited knowledge about mechanisms that regulate development, adult tissue homoeostasis and regenerative responses following injury. We recently identified Mohawk (Mkx) as a key regulator of tendon and ligament development. Mkx is a member of the Three Amino acid Loop Extension superclass of atypical homeobox genes. Mkx-/- mice had hypoplastic tendons throughout the body, clearly demonstrating an essential function of Mkx in tendon development. Importantly, Mkx is highly expressed in adult human and mouse tenocytes and ligament cells but its expression is decreased in aging or in arthritis-affected joints and in response to inflammatory stimuli such as interleukin-1. These observations support our hypothesis that Mkx is a central regulator of adult tendon and ligament homeostasis and that its suppression following injury or during aging and arthritis accounts for limited repair responses and leads to degenerative changes. To test this hypothesis and reveal the molecular mechanisms of Mkx to maintain and/or regenerate tendon/ligament, we will perform the following studies.
Aim 1 : Determine Mkx targets and functions in tendon/ligament cells during development and after birth.
Aim 2 : Analyze mechanisms controlling tendon/ligament specific expression of Mkx.
Aim 3 : Examine role of Mkx in tenogenic differentiation of mesenchymal stem cells and its potential to enhance repair or regeneration of tendon injuries. Feasibility of this project is based on availability of several genetically modified mouse lines, including conditional Mkx TG and KO mice;access to human ligament cells from a wide range of donors across the adult age spectrum and at various stages of ACL degeneration and multiple genome-wide screening systems. The findings from this study are expected to advance our current understanding of tendon and ligament biology and serve as a basis for the development of new therapeutic approaches for tendon and ligament injuries and diseases.

Public Health Relevance

We recently discovered MKX as a novel tendon/ligament specific transcription factor. This project will examine molecular mechanisms that control MKX expression, how MKX regulates development and homeostasis of adult tendon and ligament tissues and establish proof-of-principle whether increasing MKX expression can improve healing of tendon injuries. The findings from this study are expected to advance our current understanding of tendon and ligament biology and serve as a basis for the development of new therapeutic approaches for tendon and ligament injures and diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR065379-01A1
Application #
8722781
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Tyree, Bernadette
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$416,900
Indirect Cost
$196,900
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Asahara, Hiroshi (2016) Current Status and Strategy of microRNA Research for Cartilage Development and Osteoarthritis Pathogenesis. J Bone Metab 23:121-7
Suzuki, Hidetsugu; Ito, Yoshiaki; Shinohara, Masahiro et al. (2016) Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis. Proc Natl Acad Sci U S A 113:7840-5
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