# Critical role of collagen XII in cell- and matrix-mediated mechanisms regulating acquisition of tendon structure and function in development and the injury response

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $348,973

## Abstract

Establishment of tendon hierarchical structure is critical to mechanical function. This tightly controlled process
requires coordinated cell-cell and cell-matrix communication. During embryogenesis, tendon progenitors
organize into linear arrays and establish cell-cell communication prior to assembling ECM, suggesting that
cells dictate ECM organization. Cells also clonally expand within linear arrays, suggesting that the ECM also
dictates cell organization. Collagen XII is known to regulate collagen fibril assembly by forming bridges
between fibrils, and our recent data show that collagen XII-deficient tendons exhibit reduced fibril packing and
loss of distinct fiber domains. Interestingly, we also found that these tendons have disordered tenocyte
arrangement and gap junction organization, indicating a novel role for collagen XII in cell organization, cell
communication, and establishing an organized tenocyte network. However, the extent to which disrupted
tendon hierarchical structure due to collagen XII deficiency is driven by disordered cellular arrangement and
communication or by the deposition of disorganized ECM remains unelucidated. Therefore, our overarching
goal is to establish the temporal roles of collagen XII in regulating tendon cell organization, hierarchical
structure, and mechanical function during tendon development and healing. Our global hypothesis is that, in
addition to ECM fibril assembly, collagen XII regulates cellular arrangement and communication prior to ECM
deposition during development and healing, which is pivotal to establishing normal tendon structure-function.
We will use novel tissue-targeted and inducible Col12a1 knockout mouse models to specifically target tendons
during development and healing. These mouse models will be used in conjunction with an innovative
multiscale approach to assess tissue level mechanics, cell organization and communication, fiber alignment,
and fibril size/organization. Aim 1 will define the temporal roles of collagen XII in regulating cell arrangement
and ECM assembly during tendon growth and development. Targeted knockdown of Col12a1 will be induced
throughout tendon development (Scx-Cre driver; Aim 1a) or following establishment of cell organization (Scx-
CreERT2 driver; Aim 1b). Temporal studies will also be conducted using 3D cell-gel constructs to evaluate
tissue formation without confounding variables found in vivo. Aim 2 will define the temporal roles of collagen XII
in regulating cell arrangement and ECM assembly during tendon healing. Using the SMA-CreERT2 driver,
Col12a1 knockdown will be targeted to peritenon-derived progenitors, the primary contributors to healing
tendon following injury. In Aim 2a, SMA-expressing cells will be targeted during the proliferative phase, while
in Aim 2b, SMA-expressing cells will be targeted at the end of the proliferative phase to isolate contributions
to ECM assembly. We will utilize sophisticated and rigorous measures of hierarchical s...

## Key facts

- **NIH application ID:** 10179664
- **Project number:** 1R01AR078790-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** LOUIS J SOSLOWSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,973
- **Award type:** 1
- **Project period:** 2021-07-20 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179664

## Citation

> US National Institutes of Health, RePORTER application 10179664, Critical role of collagen XII in cell- and matrix-mediated mechanisms regulating acquisition of tendon structure and function in development and the injury response (1R01AR078790-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179664. Licensed CC0.

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