# Roles of SOX8 and SOX9 in Adult Articular Cartilage

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $568,821

## Abstract

PROJECT SUMMARY
Progressive and irreversible deterioration of articular cartilage is a central event in osteoarthritis (OA) and other
forms of degenerative joint disease (DJD), but despite the high prevalence of these painful and disabling
conditions, no treatment is yet available to effectively protect and restore healthy tissue. Cartilage breakdown
occurs as a result of both increased tissue catabolism and impaired anabolism. Strategies are being developed
to block catabolism, but major knowledge gaps preclude the design of strategies to restore proper cartilage
anabolism. This project is designed to fill key gaps. One gap is on the exact roles of the SOX9 transcription
factor in adult articular cartilage. SOX9 drives chondrocyte specification and differentiation in developmental
chondrogenesis, but its roles in adult cartilage homeostasis and pathology remain unclear. Another gap is on
the role of SOX8, the closest relative of SOX9, in cartilage. New data reveal that SOX8 is co-expressed with
SOX9 in articular chondrocytes and contributes to adult articular cartilage integrity. Pro-inflammatory and other
pathways driving DJD elicit chondrocyte catabolic actions and downregulate cartilage-specific anabolism,
including SOX9 expression, and in vitro studies suggest that the catabolic response of chondrocytes to pro-
inflammatory cytokines is greatly reduced upon forced expression of SOX8 or SOX9. Together, these data
suggest the innovative hypothesis that SOX8 and SOX9 share key roles in articular chondrocytes and that their
pathogenic downregulation exacerbates cartilage anabolism repression and catabolism stimulation. Three
specific aims are proposed to test this hypothesis. Aim 1 is to define the roles of SOX8 and SOX9 in adult
articular chondrocytes in healthy conditions. Either or both genes will be knocked down in human primary
articular chondrocytes and conditionally inactivated in articular chondrocytes in adult mice, and consequences
will be assessed. Aim 2 is to test whether SOX8 and SOX9 repression impacts OA development. SOX8 and
SOX9 expression and activities will be examined for correlations with OA severity in humans. Also, OA will be
induced in adult mice and the effect of SOX8/SOX9 inactivation on disease development will be analyzed and
mechanistically dissected. Aim 3 is to test whether and how forced expression of SOX8 or SOX9 helps
maintain articular chondrocyte normalcy in OA conditions. The SOX proteins will be overexpressed in primary
human articular chondrocytes from normal and OA knees and their impact on cell behavior assessed. Mice will
be conditionally forced to express the SOX proteins in articular chondrocytes and will be tested for cartilage
fate under normal and OA conditions. A team of expert investigators and clinicians has been assembled to
ensure the successful achievement of the project. Novel discoveries are expected to transform current
understanding of key mechanisms dictating articular chondrocyte specifi...

## Key facts

- **NIH application ID:** 10198770
- **Project number:** 5R01AR072649-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** VERONIQUE M LEFEBVRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $568,821
- **Award type:** 5
- **Project period:** 2018-07-08 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198770

## Citation

> US National Institutes of Health, RePORTER application 10198770, Roles of SOX8 and SOX9 in Adult Articular Cartilage (5R01AR072649-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198770. Licensed CC0.

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