Regulatory Mechanisms of Collagen XII in Establishing Achilles Tendon Hierarchical Structure and Function in Postnatal Development and with Altered Loading Michael Steven DiStefano

Format:

Book

Thesis/Dissertation

Author/Creator:

DiStefano, Michael Steven, author.

Contributor:

University of Pennsylvania. Bioengineering., degree granting institution.

Language:

English

Subjects (All):

0202.

0379.

0719.

0758.

Local Subjects:

0202.

0379.

0719.

0758.

Physical Description:

1 electronic resource (116 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Tendons transmit tensile forces from muscle to bone via their hierarchical extracellular matrix (ECM). Formation of this structure is reliant on multiscale processes such as formation of fibrils, assembly of fibril bundles into fibers, and recruitment of fibers into fascicles. Establishment of tendon structure and function is dependent on applied loading at physiological levels. Collagen XII is a Fibril-Associated Collagen with Interrupted Triple Helices (FACIT), primarily expressed in tendon during growth and development. It is responsive to mechanical stress and forms ECM complexes that transduce mechanical signals to interact and localize with collagen I fibrils. This is critical in its ability to form bridges between collagen fibrils implicating it in having roles in regulating collagen I fibrillogenesis, fibril organization, and interactions with ECM constituents. However, the mechanisms by which collagen XII deficiency disrupt formation of tendon hierarchical structure during development and how altered loading influences collagen XII-mediated mechanotransduction on tendon development remains unknown. The dissertation objectives were to establish the mechanisms involving collagen XII regulation of tendon hierarchical structure, mechanical function, and composition throughout development (Aim 1) and to understand the role of altered loading on collagen XII-mediated mechanotransduction throughout tendon development (Aim 2). In Aim 1, we used our tendon-targeted Col12a1 knockout (KO) mouse model and demonstrated reductions in mechanical properties and collagen fiber realignment, increased tendon length and cell density, reduced nuclear aspect ratio, altered fibril diameter distributions, and altered gene expression profiles in KO Achilles tendons relative to wild type (WT). In Aim 2, we performed unilateral sciatic nerve resection (SNR) in WT and KO mice and demonstrated reductions in mechanical properties in SNR relative to contralateral tendons. Interestingly, the mechanical deficits and reductions in cell density between SNR and contralateral tendons were consistent across WT and KO mice. Distinct gene expression profiles between SNR and contralateral limbs were observed between genotypes, suggesting that collagen XII is not required for macroscale mechanical adaptation to unloading, but may play a role in matrix remodeling during tendon development under altered loading. Our findings indicate roles of collagen XII and loading in establishment of tendon structure, function, and gene expression during postnatal development

Notes:

Advisors: Soslowsky, Louis J. Committee members: Mauck, Robert L.; Dyment, Nathaniel A.; Boerckel, Joel D.; Connizzo, Brianne K.; Birk, David E.

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276001135

Access Restriction:

Restricted for use by site license