Inherited and acquired defects in the formation or adult maintenance of cartilage cause many types of skeletal dysplasias and joint degeneration diseases, namely osteoarthritis. Sox9 encodes a transcription factor that is absolutely required for cartilage formation. The mechanisms underlying Sox9 transcription in chondrocytes, however, remain largely unknown. Sox9 enhancers have been identified for developing gonad, neural crest, and spinal cord, but none have been discovered for chondrocytes. The overarching goal of the research project is to identify the mechanisms underlying Sox9 expression in chondrocytes. We have identified a highly conserved enhancer located far upstream of the Sox9 promoter. Preliminary results in transgenic mice indicate that this enhancer is active in proliferative chondrocytes in cartilage primordia and growth plates. I propose that this enhancer binds proteins that have a key role in ensuring Sox9 expression in these cells and are thereby required to maintain chondrocyte differentiation and ensure skeletal growth and timely ossification. The main goal of this project is to test this hypothesis by pursuing the following three specific aims: (1) define the domain of activity of the enhancer in vivo, (2) test whether th enhancer is required for Sox9 expression in vivo, and (3) identify the transcription factors that bind to and activate the Sox9 enhancer, and to determine their importance in chondrogenesis. Understanding the molecular basis of Sox9 expression in chondrogenesis will identify potential pharmacological therapeutic targets, which may have clinical implications for the treatment of skeletal dysplasias and degenerative cartilage diseases such as osteoarthritis.

Public Health Relevance

Defects in cartilage components and regulatory factors cause many types of skeletal malformation diseases (skeletal dysplasias) and prevalent joint degeneration diseases, such as osteoarthritis. This novel study aims to identify the mechanisms that are required for Sox9 expression, a gene that is required for cartilage development. Knowledge obtained from this study will allow major progress to be made to generate functional cartilage for therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR063548-02
Application #
8546681
Study Section
Special Emphasis Panel (ZRG1-F10B-S (20))
Program Officer
Tyree, Bernadette
Project Start
2013-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$52,190
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195