Degenerative tendinopathy is characterized by the formation of non-tendinous tissues in the tendon matrix. This tendon disease is a leading cause of chronic disability and affects millions of Americans. Intensive research has been conducted in the past decades, but the pathogenesis of degenerative tendinopathy remains unclear and, as a result, current treatments of the tendon disease are largely palliative. Recently, we and others identified tendon/progenitor stem cells (TSCs), which exhibit multi-differentiation potential and can differentiate into adipocytes, chondrocytes, and osteocytes both in vitro and in vivo. The diverse cell types formed by TSCs correspond well with three non-tendinous tissues observed in human tendinopathic tendons: fatty tissue, cartilage-like tissue, and bony tissue. Moreover, we discovered that excessive mechanical loading alone is sufficient to induce differentiation of TSCs into non-tenocyte lineages. In light of these exciting findings, we hypothesize that TSCs are the primary contributors to the development of degenerative tendinopathy, which is a result of their aberrant differentiation into non-tenocyte lineages of cells in response to excessive mechanical loading placed on tendons. To test this innovative hypothesis, we propose two major aims in this project: (1) To define the effect of mechanical loading on TSCs by using a novel in vitro model system to analyze cell proliferation, self-renewal, and differentiation; and () to determine the effects of excessive mechanical loading conditions on mouse tendons in vivo using a well-established mouse treadmill running model.
The second aim i ncludes two sub-aims, which are to determine the effects of both over-use and over-loading on mouse tendons. The key innovation of our proposed studies is that they will uncover the mechanobiological responses of tendons by clarifying and analyzing the role of TSCs at the cellular, tissue, and functional levels under well-controlled mechanical loading conditions, which are of direct relevance to an important disease process. This study represents the initial efforts to determine the pathogenic role of TSCs in the development of degenerative tendinopathy. The successful completion of this study will reveal the stem-cell based mechanism of degenerative tendinopathy. This will lead to new prevention and treatment strategies such as targeting TSCs by blocking their differentiation into non-tenocytes and altering training regimens for athletes and laymen alike that will be more effective than current tendinopathy treatment methods, which mostly rely on the use of anti- inflammatory drugs.

Public Health Relevance

The treatment of tendinopathy, a chronic tendon injury, is difficult for orthopaedic surgeons and sports medicine physicians alike. The challenge stems from our insufficient understanding of the precise pathogenic mechanisms of tendinopathy. This project aims to test an innovative hypothesis that degenerative tendinopathy results from the abnormal differentiation of tendon stem cells in response to excessive mechanical loading ('overuse' and 'overloading') placed on tendons. The new scientific data from this project will help develop new, more effective treatment protocols for tendinopathy, thus benefiting millions of tendinopathic patients in the United States alone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR065949-04
Application #
9442678
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Washabaugh, Charles H
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Orthopedics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Thampatty, Bhavani P; Wang, James H-C (2017) Mechanobiology of young and aging tendons: In vivo studies with treadmill running. J Orthop Res :
Jia, Haoruo; Ma, Xiaoyuan; Wei, Yulong et al. (2017) Loading-Induced Reduction in Sclerostin as a Mechanism of Subchondral Bone Plate Sclerosis in Mouse Knee Joints During Late-Stage Osteoarthritis. Arthritis Rheumatol :
Wang, James H-C; Zhao, Guangyi; Li, Bin (2016) Measurement of Cell Motility Using Microgrooved Substrates. Methods Mol Biol 1365:293-9
Zhang, Jianying; Yuan, Ting; Wang, James H-C (2016) Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats. Oncotarget 7:8498-512
Yuan, Ting; Zhang, Jianying; Zhao, Guangyi et al. (2016) Creating an Animal Model of Tendinopathy by Inducing Chondrogenic Differentiation with Kartogenin. PLoS One 11:e0148557
Wang, James H-C; Zhao, Guangyi; Li, Bin (2016) The Study of Cell Motility by Cell Traction Force Microscopy (CTFM). Methods Mol Biol 1365:301-13
Zhou, Yiqin; Wang, James H-C (2016) PRP Treatment Efficacy for Tendinopathy: A Review of Basic Science Studies. Biomed Res Int 2016:9103792
Wu, Huiyan; Zhao, Guangyi; Zu, Hongfei et al. (2016) Real-Time Monitoring of Platelet Activation Using Quartz Thickness-Shear Mode Resonator Sensors. Biophys J 110:669-679
Wang, James H-C; Nirmala, Xavier (2016) Application of Tendon Stem/Progenitor Cells and Platelet-Rich Plasma to Treat Tendon Injuries. Oper Tech Orthop 26:68-72
Zhang, Jianying; Wang, James H-C (2015) Moderate Exercise Mitigates the Detrimental Effects of Aging on Tendon Stem Cells. PLoS One 10:e0130454

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