The overall aim of this study is to determine the coordinate regulatory role(s) of decorin and biglycan in the re- establishment of structure and function during the repair response to injury in mature tendons and to define the effects of aging on decorin/biglycan mediated regulation of tendon repair. The analysis of tendon structure- function relationships provides a framework where the regulatory roles of extracellular matrix molecules and their interactions can be quantitatively evaluated. We hypothesize that the injury response in tendon involves a partial recapitulation of the normal developmental sequence. This includes the differential expression of biglycan and decorin providing the coordinate regulatory interactions required for re-establishment of structure and function. In addition, during aging, the tendon is unable to recapitulate the normal SLRP expression patterns thereby compromising the re-establishment of structure and function (i.e., the aged tendons will not be able to faithfully recapitulate the normal differential expression pattern). To test these hypotheses, we will analyze the effects of changes in decorin and biglycan expression on repair of flexor digitorum longus (FDL) tendon wounds in mature, aging and aged mice. These studies will utilize our novel injury model of the FDL tendon. SLRP expression will be manipulated using decorin-null, biglycan-null, compound mutant and wild type mice. The mechanical and organizational properties, as well as profiles of matrix proteins and cytokines will be quantitatively evaluated using biomechanical, biochemical, immunochemical and structural analyses, providing significant new data.
The specific aims are to:
Aim 1 : Determine the differential regulatory function(s) of biglycan and decorin on restoration of biomechanical properties during the repair response to FDL tendon injury in mature, aging and aged tendons;
Aim 2 : Define injury-associated expression patterns of biglycan and decorin;organizational and compositional measures of tendons after injury;and the regulatory roles of decorin and biglycan in re-establishment of tendon structure after injury in mature, aging and aged mice;
Aim 3 : Identify relationships between biomechanical properties and organizational and compositional measures in response to injury using multiple regression analyses in mature, aging and aged FDL tendons. These analyses will provide a fundamental understanding of the regulatory roles of decorin and bigylcan in the repair response to injury. In addition, we will define a quantitative structure-function model of interactions involving these SLRPs in mature, aging and aged tendons. This information will not only elucidate mechanisms responsible for the changes, but will also provide a framework for further investigation into the contrasting and potentially compensatory roles of these SLRPs that may aid in the design of improved treatment modalities for tendon injuries. In addition, defining the regulatory interactions involved in the regeneration of a functional tendon will provide a foundation for the tissue engineering of functional replacements.

Public Health Relevance

The focus of this application is to elucidate the regulatory role(s) of interactions involving specific extracellular matrix components in the response to tendon injury as well as in their functional alterations with tendon aging. In sports, at work, or due to aging processes, tendon injuries cause significant pain and disability, resulting in enormous healthcare costs, loss of work, and a decrease in the quality of life.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
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Tyree, Bernadette
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University of Pennsylvania
Schools of Medicine
United States
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Mienaltowski, Michael J; Dunkman, Andrew A; Buckley, Mark R et al. (2016) Injury response of geriatric mouse patellar tendons. J Orthop Res 34:1256-63
Dunkman, Andrew A; Buckley, Mark R; Mienaltowski, Michael J et al. (2014) The injury response of aged tendons in the absence of biglycan and decorin. Matrix Biol 35:232-8
Dunkman, Andrew A; Buckley, Mark R; Mienaltowski, Michael J et al. (2014) The tendon injury response is influenced by decorin and biglycan. Ann Biomed Eng 42:619-30
Buckley, Mark R; Sarver, Joseph J; Freedman, Benjamin R et al. (2013) The dynamics of collagen uncrimping and lateral contraction in tendon and the effect of ionic concentration. J Biomech 46:2242-9
Connizzo, Brianne K; Sarver, Joseph J; Birk, David E et al. (2013) Effect of age and proteoglycan deficiency on collagen fiber re-alignment and mechanical properties in mouse supraspinatus tendon. J Biomech Eng 135:021019
Dunkman, Andrew A; Buckley, Mark R; Mienaltowski, Michael J et al. (2013) Decorin expression is important for age-related changes in tendon structure and mechanical properties. Matrix Biol 32:3-13
Dourte, Leann M; Pathmanathan, Lydia; Mienaltowski, Michael J et al. (2013) Mechanical, compositional, and structural properties of the mouse patellar tendon with changes in biglycan gene expression. J Orthop Res 31:1430-7
Buckley, Mark R; Huffman, George R; Iozzo, Renato V et al. (2013) The location-specific role of proteoglycans in the flexor carpi ulnaris tendon. Connect Tissue Res 54:367-73
Buckley, Mark R; Dunkman, Andrew A; Reuther, Katherine E et al. (2013) Validation of an empirical damage model for aging and in vivo injury of the murine patellar tendon. J Biomech Eng 135:041005
Beason, David P; Kuntz, Andrew F; Hsu, Jason E et al. (2012) Development and evaluation of multiple tendon injury models in the mouse. J Biomech 45:1550-3

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