Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that lead to tendinopathies and to translate these studies to the clinic. Tendon diseases can be painful, debilitating and significantly detract from the quality of one's life. Much of what we know about tendon fibroblast cell biology comes from in vitro cell culture studies or descriptive histological studies of diseased and healthy tissue. There has been a lack of in vivo, mechanism driven studies that combine contemporary molecular biology and genetics with precise tissue mechanics and functional measures. The long-term goal of this project is to better understand tendon fibroblast biology in the context of injury and disease, and to improve the treatment of tendinopathies. For many tissues in the body, the genes that control embryonic tissue development are also important in the repair and regeneration of adult tissues. Scleraxis is a bHLH transcription factor that is critical for the embryonic development of limb tendons, but little is known about scleraxis function in adult tendons. Our overall hypotheses are that scleraxis is important for the adaptation of tendons to mechanical loading, scleraxis is regulated by TGF- and IGF-1 signaling pathways, and that dysregulation of scleraxis is a central factor in the development of tendinosis. These hypotheses are rigorously tested in three Specific Aims that use a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in adult wild type mice (ScxWT), adult transgenic mice with a postnatal inducible knockdown of scleraxis (ScxKD), and in cultured primary tendon fibroblast cells from humans and mice. These studies will provide important insight into adult tendon fibroblast physiology, and lay the groundwork for future translational studies focused on scleraxis to improve the treatment of patients suffering from tendinopathies.

Public Health Relevance

to public health is based upon the tremendous impact that tendon injuries and diseases have on mobility and quality of life. There is a substantial lack in our understanding of how tendons adapt to new stresses placed upon them, and how tendons recover from injuries. Increasing our understanding of fundamental adult tendon biology and translating this to patients is highly relevant to the NIH's mission to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
4R01AR063649-04
Application #
9115032
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sugg, Kristoffer B; Markworth, James F; Disser, Nathaniel P et al. (2018) Postnatal tendon growth and remodeling require platelet-derived growth factor receptor signaling. Am J Physiol Cell Physiol 314:C389-C403
Dueweke, Jeffrey J; Awan, Tariq M; Mendias, Christopher L (2017) Regeneration of Skeletal Muscle After Eccentric Injury. J Sport Rehabil 26:171-179
Sarver, Dylan C; Kharaz, Yalda Ashraf; Sugg, Kristoffer B et al. (2017) Sex differences in tendon structure and function. J Orthop Res 35:2117-2126
Lee, Simon; Gumucio, Jonathan; Mendias, Christopher et al. (2017) What is the role of systemic conditions and options for manipulation of bone formation and bone resorption in rotator cuff tendon healing and repair? Tech Shoulder Elb Surg 18:113-120
Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C et al. (2017) Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy. FEBS Lett 591:801-809
Mendias, Christopher L; Schwartz, Andrew J; Grekin, Jeremy A et al. (2017) Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy. J Appl Physiol (1985) 122:571-579
Garcia, Stefan C; Dueweke, Jeffrey J; Mendias, Christopher L (2016) Optimal Joint Positions for Manual Isometric Muscle Testing. J Sport Rehabil 25:
Hudgens, Joshua L; Sugg, Kristoffer B; Grekin, Jeremy A et al. (2016) Platelet-Rich Plasma Activates Proinflammatory Signaling Pathways and Induces Oxidative Stress in Tendon Fibroblasts. Am J Sports Med 44:1931-40
Claflin, Dennis R; Roche, Stuart M; Gumucio, Jonathan P et al. (2016) Assessment of the Contractile Properties of Permeabilized Skeletal Muscle Fibers. Methods Mol Biol 1460:321-36
Gumucio, Jonathan P; Flood, Michael D; Roche, Stuart M et al. (2016) Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int Orthop 40:759-64

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