# Elucidation of the Role of Creb5 in Synovial Joint Formation

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $680,743

## Abstract

Project Summary/Abstract.
The broad, long-term goal of this project is to develop a comprehensive understanding of the developmental
events that dictate cell fate decisions in formation of the synovial joint. Within this broad area, this proposal
focuses on the differentiation of articular cartilage, which plays a central role in maintaining the low-friction
environment of the joint space. Indeed, a hallmark of cells comprising the articular cartilage is their expression
of proteoglycans, such as the protein lubricin, encoded by the Prg4 gene, that lubricates the joint and protects
against the development of arthritis. Prg4 is specifically expressed in the superficial-most layer of the articular
cartilage. Findings by both the Lassar lab and others have established that Prg4-expressing cells in the superficial
zone of articular cartilage (in embryonic and early post-natal mice) serve as a stem cell population for all deeper
regions of the articular cartilage in the adult. Thus, to elucidate how the articular cartilage stem cell population
is both generated during development and maintained in the adult, a key objective of this proposal is to identify
the factors that regulate the expression of both Prg4 and other genes that are specifically expressed in the
superficial zone of the articular cartilage. Recent findings in the Lassar lab indicate that the transcription factor
Creb5 is uniquely expressed in superficial zone articular chondrocytes (as opposed to both deeper zone articular
chondrocytes and growth plate chondrocytes) and is a crucial regulator of Prg4 expression. Most notably, ectopic
expression of Creb5 in deep zone bovine articular chondrocytes (which do not expression Prg4) enabled TGF-b2
and EGFR signals to induce Prg4 expression in these cells, to a level equal to that expressed by superficial zone
articular chondrocytes. These findings suggest that Creb5 establishes a competent state in chondrocytes to
express Prg4 in response to these signaling pathways. In addition, the Lassar lab has found that mice engineered
to lack functional Creb5 fail to form many synovial joints, and that mis-expression of Creb5 throughout the limb
bud mesenchyme (with Prx1-Cre) results in a profound loss of growth plate development in long bones. Taken
together, these findings indicate that Creb5 plays a critical role in both the formation of synovial joints and is a
both a novel and crucial regulator of Prg4/lubricin expression in articular chondrocytes. This project will identify
both Creb5-dependent genes and the regulatory elements that drive the expression of these genes in primary
bovine superficial zone articular chondrocytes; and mechanistically determine how TGFb, EGFR, and p38
signaling modulate the transcriptional activity of Creb5 in these cells. In addition, this project will determine
how Creb5 regulates the formation of synovial joints, and elucidate how Creb5 expression in the epiphyseal
perichondrium blocks extension of the growth plate ...

## Key facts

- **NIH application ID:** 10020759
- **Project number:** 5R01AR074385-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Andrew Bruce Lassar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $680,743
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020759

## Citation

> US National Institutes of Health, RePORTER application 10020759, Elucidation of the Role of Creb5 in Synovial Joint Formation (5R01AR074385-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020759. Licensed CC0.

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