Tendons are dense, load-bearing tissues that transmit muscle forces to the skeleton. Upon traumatic injury or degeneration, load-bearing function is frequently compromised due to poor intrinsic healing that is dominated by fibrotic scar formation. Despite tremendous interest, the biology of tendon healing remains poorly defined and many of the cell and molecular factors that mediate these events have not been identified. One major signaling pathway with high therapeutic potential for tendon is TGF?, which has been implicated in multiple aspects of tendon cell biology including development, regeneration, and fibrosis. Despite the importance of TGF? signaling, the mechanisms by which TGF? may drive these divergent processes remain unknown, which has limited effective therapeutic application. Therefore, the goal of our proposal is to distinguish the tenogenic vs. fibrotic functions of TGF? signaling in the context of injury using a novel model of neonatal regenerative healing and a model of adult fibrotic healing. Using inducible mouse technology which enables cell-specific targeting and temporal control of gene recombination, we will determine the role of TGF? (Aim 1) and downstream Smad (Aim 2) signaling in the specific cell populations that drive healing.
Aim 3 will use a tissue engineering platform to determine whether limitations in adult tendon healing are due to poor intrinsic tenogenic capacity and identify potential Non-Smad mediators of tenogenesis. Successful completion of this project will uncover the tenogenic vs. fibrotic requirements for TGF? and Smad signaling, which will ultimately enable the development of targeted cell therapies modulating TGF? signaling to enhance tendon differentiation while attenuating fibrosis.

Public Health Relevance

Tendon ruptures and tendinopathies are painful and debilitating conditions affecting a large portion of the adult population. Due to poor intrinsic healing, tendon injuries often lead to fibrotic scarring, chronic pain and loss of function. From a regenerative standpoint, there is a pressing clinical need to identify the cell and molecular mechanisms regulating tendon differentiation vs. fibrotic scarring in order to improve repair outcomes. Since the TGF? signaling family has been implicated in both tendon differentiation and fibrosis, the objective of the proposed studies is to test TGF? family molecules in tendon healing via conditional loss of gene function in the specific cells that drive healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR069537-01
Application #
9076996
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2016-02-15
Project End
2021-01-31
Budget Start
2016-02-15
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Orthopedics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Moser, Helen L; Doe, Anton P; Meier, Kristen et al. (2018) Genetic lineage tracing of targeted cell populations during enthesis healing. J Orthop Res 36:3275-3284
Bianco, Spencer T; Moser, Helen L; Galatz, Leesa M et al. (2018) Biologics and stem cell-based therapies for rotator cuff repair. Ann N Y Acad Sci :
Torre, Olivia M; Das, Rohit; Berenblum, Ramy E et al. (2018) Neonatal mouse intervertebral discs heal with restored function following herniation injury. FASEB J 32:4753-4762
Torre, Olivia M; Mroz, Victoria; Bartelstein, Meredith K et al. (2018) Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies. Ann N Y Acad Sci :
Chien, Chun; Pryce, Brian; Tufa, Sara F et al. (2018) Optimizing a 3D model system for molecular manipulation of tenogenesis. Connect Tissue Res 59:295-308
Arvind, Varun; Huang, Alice H (2017) Mechanobiology of limb musculoskeletal development. Ann N Y Acad Sci 1409:18-32
Huang, Alice H (2017) Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton. Dev Biol 429:420-428
Howell, Kristen; Chien, Chun; Bell, Rebecca et al. (2017) Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing. Sci Rep 7:45238