# Application of SHP2 PROTAC to Mitigate Articular Cartilage Degeneration

> **NIH NIH R21** · RHODE ISLAND HOSPITAL · 2022 · $213,664

## Abstract

PROJECT SUMMARY:
 It has been known for years that somatic SHP2 deletion in chondroid cells causes cartilage tumor
formation associated with elevated SOX9 expression. However, it remains incompletely understood
mechanistically how SHP2 depletion increases SOX9 and promotes chondroid cell proliferation. The work
outlined in this proposal builds on our novel discovery that the genetic deletion of SHP2 in cartilage cells
increases SOX9 abundance associated with SOX9 phosphorylation and sumoylation. These findings together
stimulate the hypothesis that SHP2 physiologically limits SOX9 level in cartilage via posttranslational
modifications. Therefore, intraarticular SHP2 depletion increases SOX9 protein abundance and transcriptional
activity, promoting chondrocyte anabolism and protecting AC from injury-evoked degeneration. To test this
novel hypothesis, we proposed two specific Aims. In Aim #1 we will determine to what extent intraarticular
SHP2 degradation, using the first SHP2 PROTAC drug SHP2D26, mitigates injury-evoked articular cartilage
degeneration. In Aim #2, we will interrogate the molecular mechanism through which SHP2 depletion
enhances SOX9 abundance by focusing on SHP2’s regulation of SOX9 posttranslational modifications. This
innovative study will result in the first-ever description of the mechanisms by which SHP2 modulates cartilage
anabolism through SOX9 and provide instrumental information on the translational application of SHP2D26 in
countering cartilage degeneration. Successful completion of the work proposed will have a significant impact
on cartilage biology and OA prevention.

## Key facts

- **NIH application ID:** 10535540
- **Project number:** 1R21AR081642-01
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Wentian Yang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $213,664
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535540

## Citation

> US National Institutes of Health, RePORTER application 10535540, Application of SHP2 PROTAC to Mitigate Articular Cartilage Degeneration (1R21AR081642-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10535540. Licensed CC0.

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