Soslowsky Laboratory

Mouse models for SLRP roles in tendon aging and impaired healing in aging tendons

Interactions between extracellular matrix (ECM) molecules are known to regulate ECM assembly and function. Two class I small leucine-rich proteoglycans (SLRPs), decorin and biglycan, have been implicated in the regulation of tissue-specific ECM assembly during vital processes such as tendon development, healing, and repair. The expression and accumulation of these SLRPs in tendon differ dramatically throughout these processes. For example, immediately after injury expression of these SLRPs recapitulates what is seen during development, when biglycan is highly expressed initially, followed by a rapid decline, and decorin expression remains relatively consistent.

Figure 1 – We’ve demonstrated successful knockdown of decorin and biglycan in mature mice using TM-inducible models.

However, our previous work that has examined the roles of decorin and biglycan during these processes have utilized conventional knockout models that have an absence of decorin and biglycan throughout the life of the animal. This leads to cumulative effects due to altered development, growth, and maturation in addition to changing how the tendon responds to injury and aging. To address this, we were awarded an R01 grant (R01AR068057) from the National Institute of Arthritis and Musculoskeletal Skin Diseases (NIAMS) at the National Institutes of Health (NIH) to utilize murine inducible knockdown models for decorin and biglycan to determine the influence of SLRPs during aging and the mechanisms by which aging alters the regulatory roles of SLRPs during the tendon injury response.
To achieve our goal, we are using tamoxifen-inducible knockdown models that allows for precise control of Cre expression and, subsequently, decorin and/or biglycan knockout (Fig. 1). Three different mouse models will be used: inducible decorin knockdown (I-Dcn-/-), inducible biglycan knockdown (I-Bgn-/-), and an inducible decorin and biglycan compound knockdown (I-Dcn-/-/Bgn--/-). Our aging study will induce SLRP knockdown after the animals have reached skeletal maturity, then allow them to age with reduced SLRP expression. Our injury study will induce SLRP knockdown at three different phases throughout the repair process: inflammation, proliferation, and remodeling, to see how the roles of decorin and biglycan may change during each of these phases.

Figure 2 – Transmission electron microscopy (TEM) helps determine tendon structural parameters, such as collagen fibril diameter and fibril density.

 To evaluate the changes in tendon after SLRP knockdown, our innovative viscoelastic mechanical testing protocol will be utilized alongside additional structural (Fig. 2), histological, and compositional analyses to determine a comprehensive picture of the roles of decorin and biglycan in tendon aging and repair. Our viscoelastic analysis allows us to the tissue response over a range of strain levels and loading frequencies, which is critical for determining how the tendons would function in vivo (Fig. 3).


Figure 3 – Stress relaxation is one viscoelastic parameter used to determine tendon mechanics. Viscoelastic tendon mechanics are sensitive to strain and rate of loading.

Additionally, we can combine the viscoelastic analysis with the more commonly used “ramp to failure”, which provides useful data on tendon elastic modulus and failure properties. Our viscoelastic analysis is vital for the SLRP study since previous work has demonstrated few changes to elastic modulus and failure mechanics after knockout of decorin and biglycan, while the viscoelastic mechanics are more sensitive to the changes associated with SLRP knockout.


Robinson, K. A., Sun, M., Barnum, C. E., Weiss, S. N., Huegel, J., Shetye, S. S., Lin, L., Saez, D., Adams, S. M., Iozzo, R. V., Soslowsky, L. J., & Birk, D. E. (2017). Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons. Matrix Biology.

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