# Functional role and therapeutic potential of hedgehog signaling in tendon-to-bone repair

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $340,854

## Abstract

Summary
Approximately 30% of U.S. adults suffer from tendon and ligament injuries, which frequently occur near
insertion sites into bone (i.e., entheses) and do not spontaneously heal. Growth and development studies have
demonstrated a critical role for hedgehog (Hh) signaling in driving zonal enthesis formation but it's role in adult
enthesis repair is largely unknown. Zonal enthesis formation involves anchoring collagen fibers, synthesizing
proteoglycan-rich fibrocartilage, and mineralizing this fibrocartilage. Hh promotes this fibrocartilage formation.
Unfortunately, studying this pathway in traditional tendon-to-bone repair has been a challenge since these
repair models do not sufficiently anchor collagen fibers to bone, much less produce zones of fibrocartilage.
Conversely, ligament reconstructions, where a tendon graft is placed through bone tunnels, can produce zonal
attachments. Therefore, ligament reconstruction models, such as the anterior cruciate reconstruction model
proposed in this application, can be employed to study the mechanisms that regulate zonal tendon-to-bone
repair in the adult. This proposal will address this gap in knowledge by targeting the hedgehog pathway
genetically and pharmacologically during tendon-to-bone repair following ACL reconstruction in novel
transgenic mouse models. We will define the roles of the hedgehog pathway in specific stages of the repair
response from the expansion of the progenitor pool to production of fibrocartilage and bone within zonal
tendon-to-bone attachments during the tunnel integration process. By modulating the pathway
pharmacologically, we will determine the potential for this pathway to be targeted in a translational fashion that
could lead to novel therapies in the future. Our central hypothesis is that the Hh pathway is a critical positive
regulator of zonal enthesis formation in the adult and therefore stimulation of the pathway will improve tendon-
to-bone repair.

## Key facts

- **NIH application ID:** 10431935
- **Project number:** 5R01AR076381-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathaniel A. Dyment
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,854
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431935

## Citation

> US National Institutes of Health, RePORTER application 10431935, Functional role and therapeutic potential of hedgehog signaling in tendon-to-bone repair (5R01AR076381-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10431935. Licensed CC0.

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