Cartilage is an essential tissue in developing and adult humans. Sadly, this is best illustrated by the prevalence and severity of birth defects due to cartilage malformations, growth retardations due to growth plate defects in children, and articular cartilage degeneration diseases in adults. Today, however, no suitable treatments exist for most of these diseases, and this is largely due to incomplete understanding of the mechanisms underlying chondrogenesis. The main goal of this project is to help lift this barrier by increasing knowledge of the action and regulation of Sox9, a master transcription factor in chondrogenesis. Sox9 is well known to activate the early chondrocyte differentiation program, and our recent data reveal that it remains a master transcription factor in the growth plate throughout chondrocyte hypertrophy. It sustains columnar chondrocyte proliferation, delays prehypertrophy, and ensures hypertrophy. Based on these data, we propose that important mechanisms must exist to determine the specific activity of Sox9 at each chondrocyte developmental stage from early to hypertrophic differentiation.
Aim 1 is to test the hypothesis that the redundant proteins Sox5 and Sox6 boost the ability of Sox9 to activate the differentiation program of early chondrocytes by increasing the efficiency of Sox9 binding to gene enhancers.
Aim 2 is to test the hypothesis that Sox9 phosphorylation by the cAMP-dependent protein kinase A critically contributes to delaying chondrocyte maturation downstream of parathyroid hormone-related protein signaling.
Aim 3 is to test the hypothesis that specific transcriptional mechanisms allow Sox9 to activate the hypertrophic chondrocyte program and most specifically the Col10a1 gene.
All aims will be reached using genetic approaches in the developing mouse and state-of-the-art genomics, cellular and molecular approaches in vitro. We anticipate that the achievement of this project will lead to a deeper knowledge of the mechanisms that govern the multi-step differentiation pathway of chondrocytes. This knowledge will provide novel insights into mechanisms underlying cartilage malformation and degeneration diseases and will help find suitable treatments.

Public Health Relevance

This project is relevant to multiple types of cartilage malformation diseases (chondrodysplasias) and cartilage degeneration diseases (mainly osteoarthritis). Together, these diseases are highly prevalent in the human population and can have devastating consequences on life expectancy and quality from birth until senior age. Our studies are designed to increase understanding of the modes of action and regulation of Sox9, a protein with master roles in the control of genes required for cartilage development and function. We anticipate that the results of our studies will provide important new insights into mechanisms underlying cartilage diseases and will suggest novel, efficient ways to prevent and cure these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046249-13
Application #
8334423
Study Section
Special Emphasis Panel (ZRG1-MOSS-S (03))
Program Officer
Tyree, Bernadette
Project Start
1999-07-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$510,456
Indirect Cost
$185,325
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Lefebvre, Véronique; Bhattaram, Pallavi (2016) SOXC Genes and the Control of Skeletogenesis. Curr Osteoporos Rep 14:32-8
Liu, Chia-Feng; Samsa, William E; Zhou, Guang et al. (2016) Transcriptional control of chondrocyte specification and differentiation. Semin Cell Dev Biol :
Liu, Chia-Feng; Lefebvre, Véronique (2015) The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic Acids Res 43:8183-203
Lefebvre, Véronique; Bhattaram, Pallavi (2015) Prg4-expressing cells: articular stem cells or differentiated progeny in the articular chondrocyte lineage? Arthritis Rheumatol 67:1151-4
Kato, Kenji; Bhattaram, Pallavi; Penzo-Méndez, Alfredo et al. (2015) SOXC Transcription Factors Induce Cartilage Growth Plate Formation in Mouse Embryos by Promoting Noncanonical WNT Signaling. J Bone Miner Res 30:1560-71
Huang, Alice H; Riordan, Timothy J; Pryce, Brian et al. (2015) Musculoskeletal integration at the wrist underlies the modular development of limb tendons. Development 142:2431-41
Yao, Baojin; Wang, Qiuqing; Liu, Chia-Feng et al. (2015) The SOX9 upstream region prone to chromosomal aberrations causing campomelic dysplasia contains multiple cartilage enhancers. Nucleic Acids Res 43:5394-408
Mead, Timothy J; Lefebvre, Véronique (2014) Proliferation assays (BrdU and EdU) on skeletal tissue sections. Methods Mol Biol 1130:233-43
Bhattaram, Pallavi; Penzo-Méndez, Alfredo; Kato, Kenji et al. (2014) SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis. J Cell Biol 207:657-71
Mead, Timothy J; Wang, Qiuqing; Bhattaram, Pallavi et al. (2013) A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. Nucleic Acids Res 41:4459-69

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