R01AR076562

The role of CREB5 in maintaining synovial joint homeostasis - Project Summary/Abstract.

The broad, long-term goal of this project is to develop a comprehensive understanding of the regulatory network that regulates the differentiation and maintenance 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. Furthermore, in both humans and mice lacking PRG4 (which encodes lubricin), the surface of the articular cartilage becomes damaged and precocious joint failure occurs.

Notably, decreased levels of lubricin have been observed following surgically induced osteoarthritis in sheep, and in synovial fluid from patients with either osteoarthritis or rheumatoid arthritis. Furthermore, a decrease in lubricin expression during aging correlates with increasing sensitivity of aged knees to cartilage degradation.

Thus, a key objective of the Lassar Lab has been to identify tissue-specific transcription 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 express 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. 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 determine the role of CREB5 in maintaining the health of all tissues in the mature synovial joint; will determine whether expression of CREB5 in either articular chondrocytes or synovial fibroblasts is attenuated during aging or during osteoarthritis; and finally, will determine whether sustained expression of exogenous CREB5 in the synovial joint can boost lubricin expression and block degradation of this tissue either during aging or in a murine model for post-traumatic osteoarthritis.

President And Fellows Of Harvard College

NOT APPLICABLE

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Boston, Massachusetts 021155701 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 382% from $703,905 to $3,392,822.