The extracellular matrix provides cartilage with its ability to undergo reversible deformation, and thus to cushion the joint during loading. Failure of competent matrix repair during aging or disease causes profound alterations in the biomechanics of cartilage; with progression, this presents clinically as osteoarthritis. The normal composition of the chondrocytic proteoglycans is complex, and changes during aging. Keratan sulfate (KS), virtually absent from fetal proteoglycans, increases to comprise roughly 25% of the glycosaminoglycan composition of mature cartilage. Despite the prominence of KS in aging cartilage, details concerning its role remain obscure. We have developed a human chondrocyte cell line, 105KC, which was derived from a malignant chondrosarcoma and which has continued to synthesize mature-type chondrocytic KS-proteoglycans for more than 4 years. This represents the first system to maintain stable production of keratan sulfate in long term culture and thus provides a unique model of human chondrocyte metabolism. Preliminary data suggest that there is non-random heterogeneity among the KS chains of the high density proteoglycans synthesized by 105KC cells, and thus that there may be regional regulation of KS chain-elongation during proteoglycan biosynthesis. We propose to perform a detailed characterization of the different populations of human skeletal KS, to analyze their substitution patterns onto aggregating proteoglycans, to compare the KS chains derived from the large aggregating proteoglycans with those derived from the small KS-proteoglycans, and to study the effects of physical factors on KS substitution. This will provide previously unavailable structural information regarding human mature chondrocytic proteoglycans, and may yield insight into the role of keratan sulfate in mature and aging cartilage matrix.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AR001878-01
Application #
3079349
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1992-03-15
Project End
1997-02-28
Budget Start
1992-03-15
Budget End
1993-02-28
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Asp, J; Thornemo, M; Inerot, S et al. (1998) The helix-loop-helix transcription factors Id1 and Id3 have a functional role in control of cell division in human normal and neoplastic chondrocytes. FEBS Lett 438:85-90
Jagasia, A A; Block, J A; Qureshi, A et al. (1996) Chromosome 9 related aberrations and deletions of the CDKN2 and MTS2 putative tumor suppressor genes in human chondrosarcomas. Cancer Lett 105:91-103
Jagasia, A A; Block, J A; Diaz, M O et al. (1996) Partial deletions of the CDKN2 and MTS2 putative tumor suppressor genes in a myxoid chondrosarcoma. Cancer Lett 105:77-90
Schumacher, B L; Block, J A; Schmid, T M et al. (1994) A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys 311:144-52
Hauselmann, H J; Fernandes, R J; Mok, S S et al. (1994) Phenotypic stability of bovine articular chondrocytes after long-term culture in alginate beads. J Cell Sci 107 ( Pt 1):17-27
Caron, J P; Toppin, D S; Block, J A (1993) Effect of polysulfated glycosaminoglycan on osteoarthritic equine articular cartilage in explant culture. Am J Vet Res 54:1116-21