In the original RFA (Gene Expression Studies in Arthritis and Musculoskeletal and Skin Diseases), funded in 2003, gene expression studies were conducted in adult articular chondrocytes, sets of co-regulated genes were established and these genes were computationally analyzed for co-regulatory motifs. Arising from this proposal was the discovery of a new transcriptional pathway involved in chondrocyte metabolism: the pathway leading to the generation of the transcription factors steroid regulatory element binding proteins (SREBPs). In this grant renewal proposal, we describe plans to focus our work on this pathway, studying the phenotype generated by tissue-specific knock out of the enzyme Site-1 Protease, an enzyme necessary for activation of SREBPs. Mutation of Site-1 protease or knock-out of the gene results in a severe chondrodysplasia with no endochondral bone formation. Our results point to the possibility that Site-1 protease, in addition to its function in the SREBP pathway, may have a function in chondrogenesis that is independent of its ability to activate the transcription factor. These studies provide an entirely new direction in cartilage research and have the potential to impact both the transcriptional regulation of cartilage genes, the formation of endochondral bone and articular cartilage repair. Therefore, SPECIFIC AIM 1 is designed to investigate the role of Site-1 protease in chondrogenesis and in maintenance of the chondrocyte phenotype in vivo while SPECIFIC AIM 2 is designed to pursue the mechanism of this phenotype on a molecular basis in vitro. Cartilage-specific knock out mice have been made that have severe chondrodysplasia and no endochondral bone formation. Studies will be undertaken to determine the mechanism of the defect by analysis of this cartilage-specific knockout and other knock-out phenotypes, including more focused knock out in the growth plate and an inducible knock out system. In vitro studies will include organ culture of whole tibias, analysis of biosynthetic mechanisms of the cells and analysis of the extracellular matrix of the cartilage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050847-08
Application #
8118791
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2003-09-26
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2011
Total Cost
$254,432
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Takebe, K; Rai, M F; Schmidt, E J et al. (2015) The chemokine receptor CCR5 plays a role in post-traumatic cartilage loss in mice, but does not affect synovium and bone. Osteoarthritis Cartilage 23:454-61
Zhang, Ziji; Zhang, Zhiqi; Kang, Yan et al. (2014) Resistin stimulates expression of chemokine genes in chondrocytes via combinatorial regulation of C/EBP? and NF-?B. Int J Mol Sci 15:17242-55
Wu, P; Holguin, N; Silva, M J et al. (2014) Early response of mouse joint tissue to noninvasive knee injury suggests treatment targets. Arthritis Rheumatol 66:1256-65
Patra, Debabrata; DeLassus, Elizabeth; McAlinden, Audrey et al. (2014) Characterization of a murine type IIB procollagen-specific antibody. Matrix Biol 34:154-60
Patra, Debabrata; DeLassus, Elizabeth; Liang, Guosheng et al. (2014) Cartilage-specific ablation of site-1 protease in mice results in the endoplasmic reticulum entrapment of type IIb procollagen and down-regulation of cholesterol and lipid homeostasis. PLoS One 9:e105674
Rai, Muhammad Farooq; Patra, Debabrata; Sandell, Linda J et al. (2014) Relationship of gene expression in the injured human meniscus to body mass index: a biologic connection between obesity and osteoarthritis. Arthritis Rheumatol 66:2152-64
Rai, Muhammad Farooq; Patra, Debabrata; Sandell, Linda J et al. (2013) Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. Arthritis Rheum 65:2090-101
Hashimoto, Shingo; Rai, Muhammad Farooq; Gill, Corey S et al. (2013) Molecular characterization of articular cartilage from young adults with femoroacetabular impingement. J Bone Joint Surg Am 95:1457-64
Patra, Debabrata; Sandell, Linda J (2012) Antiangiogenic and anticancer molecules in cartilage. Expert Rev Mol Med 14:e10
Hashimoto, S; Rai, M F; Janiszak, K L et al. (2012) Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis Cartilage 20:562-71

Showing the most recent 10 out of 22 publications