The hierarchical assembly of proteoglycan and collagen types II, IX and XI networks leads to the formation of an organized cartilage matrix. Mutations of the components of the collagen fibrils are associated with a wide spectrum of clinical conditions that range from mild osteoarthritis to lethal chondrodysplasia. Genetic evidence in the mouse has revealed that incorporation of collagen XI in the heterotypic fibrils is a prerequisite for the development and differentiation of the skeleton. It has also suggested that this role is mediated by the alpha subunit through a mechanism yet to be determined. It is the main goal of this application to clarify the nature of this mechanism. Previous work has documented that the structural diversity of the N-terminal domain of alpha1(XI collagen is due to tissue- and stage-specific alternative splicing. This evolutionarily conserved pattern gives rise to four major isoforms, each of which is predominantly expressed at different times of differentiation and in distinct areas of cartilage. This proposal wishes to test the hypothesis that the alpha1(XI) isoforms modulate fibril growth, stabilize the matrix, and delineate areas destined to become bone. Toward this end, the structural-functional relationships of the polymorphic sequences will be examined within the context of the developing mouse. The long-term goal of the project is to elucidate the contribution of collagen XI to matrix function and to the physiomechanical properties of cartilage and bone. It is suggested (by the applicant) that this information will advance our understanding of the pathogenesis of disorders that impair skeletal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR045581-03S1
Application #
6457609
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1998-09-30
Project End
2002-08-31
Budget Start
2001-06-15
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$33,900
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Laub, F; Aldabe, R; Ramirez, F et al. (2001) Embryonic expression of Kruppel-like factor 6 in neural and non-neural tissues. Mech Dev 106:167-70
Laub, F; Aldabe, R; Friedrich Jr, V et al. (2001) Developmental expression of mouse Kruppel-like transcription factor KLF7 suggests a potential role in neurogenesis. Dev Biol 233:305-18
Laub, F; Aldabe, R; Ou, J et al. (2000) Overexpression of a novel zinc-finger protein induces apoptosis in NIH3T3 fibroblasts. Genomics 70:375-80
Ohnishi, S; Laub, F; Matsumoto, N et al. (2000) Developmental expression of the mouse gene coding for the Kruppel-like transcription factor KLF5. Dev Dyn 217:421-9