# Pathogenesis of Enthesopathy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $356,648

## Abstract

Project Summary
Over half of sports injuries involve tendons and entheses, the insertion sites of tendons or ligaments to bones.
A common enthesis disorder enthesophathy, representing one fourth of tendon diseases, results in a long-term
disturbance of the load transfer and is a major cause of pain and disability. The exact pathogenesis of
enthesopathy is largely unknown, and there is no effective disease modifying treatment for this disorder. The
proposed project aims to elucidate the pathogenic mechanisms of enthesopathy and develop potential
therapeutic solutions to prevent/treat this disease. Our preliminary studies suggest that TGFβ activation in bone
tissue of the enthesis, in response to aberrant mechanical loading after enthesis injury, is an early change in the
progression of enthesopathy. In a mouse model of enthesopathy, we observed upregulated TGFβ activity at the
bone-fibrocartilage junction earlier, and entheses progressive degradation later after entheses injury. Moreover,
transgenic mice with active TGFβ overexpression in bone recapitulated the enthesopathy phenotype, whereas
the enthesopathy mice treated with a TGFβ neutralizing antibody had decelerated enthesis degeneration. To
achieve bone-targeting delivery and slow release in bone tissue, we generated a new drug that conjugates a
TGFβ inhibitor to Alendronate through a metabolically hydrolysable linker. The conjugate effectively inhibited
TGFβ activity in bone in the active TGFβ transgenic mice. The central hypothesis of this study is that aberrant
TGFβ activation at the bone-fibrocartilage junction initiates enthesopathy by recruiting stem/progenitor cells for
blood vessel invasion and ossification in the fibrocartilage zone. To test this hypothesis, we will examine the role
of elevated active TGFβ in the progression of enthesopathy using different mouse models (Aim 1). We will also
determine the role of TGFβ-recruited stem/progenitor cells in the progression of enthesopathy using two genetic
lineage tracing mice and an inducible tissue-specific TGFβ receptor-ablation mice (Aim 2). Finally, we will
examine the therapeutic potential of the TGFβ inhibitor–Alendronate conjugate in enthesopathy (Aim 3). Results
will provide evidence for clinical application of this conjugate as a therapy for enthesopathy.

## Key facts

- **NIH application ID:** 10474352
- **Project number:** 5R01AR072730-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xu Cao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,648
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474352

## Citation

> US National Institutes of Health, RePORTER application 10474352, Pathogenesis of Enthesopathy (5R01AR072730-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10474352. Licensed CC0.

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