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Mechanisms of Age-Related Decline in Insulin-Like Growth Factor-I Dependent Proteoglycan Synthesis in Rat Intervertebral Disc Cells

Okuda, Shin’ya, MD; Myoui, Akira, MD; Ariga, Kenta, MD; Nakase, Takanobu, MD; Yonenobu, Kazuo, MD; Yoshikawa, Hideki, MD

Basic Science
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Study Design.  Age-related fluctuations in insulin-like growth factor-I dependent proteoglycan synthesis in rat intervertebral disc cells were investigated.

Objectives.  The purpose of this study was to determine whether synthetic responses to insulin-like growth factor-I decline with age and to explore the possibility that an age-related increase in the expression of insulin-like growth factor binding proteins suppresses matrix synthesis in intervertebral disc cells.

Summary and Background Data.  Several studies have reported that the responsiveness of chondrocytes to insulin-like growth factor-I decreases with age and furthermore that this phenomenon may be related to increased expression of insulin-like growth factor binding proteins by chondrocytes.

Materials and Methods.  Nucleus pulposus tissue and cells were obtained from the coccygeal vertebrae of 8-week-old, 40-week-old, and 120-week-old rats. Age-related changes in the expression of insulin-like growth factor-I and its receptor were assessed together with insulin-like growth factor-I dependent proteoglycan synthesis by the cultured nucleus pulposus cells. Also, western blot analysis of insulin-like growth factor binding protein-1 was carried out, and further examination was performed of insulin-like growth factor-I signal transduction through tyrosine phosphorylation of insulin receptor substrate-1, which is a signal transducer of insulin-like growth factor-I.

Results.  Semiquantitative reverse transcription polymerase chain reaction analysis indicated that the expression of insulin-like growth factor-I receptor in 120-week cells decreased clearly in comparison with the cells of younger animals. By contrast, insulin-like growth factor-I dependent proteoglycan synthesis decreased with age, and the sharpest decline of synthesis was found between 8-week and 40-week cells, although the level of insulin-like growth factor-I/insulin-like growth factor-I receptor gene expression was maintained in 40-week-old animals. Consistent with the results of proteoglycan synthesis, the expression of phosphorylated insulin receptor substrate-1 decreased with age. Thus, the expression of insulin-like growth factor binding protein-1 and proteoglycan synthesis was investigated by use of Long R3 insulin-like growth factor-I, which was not influenced by insulin-like growth factor binding proteins. Insulin-like growthfactor binding protein-1 was strongly expressed in 40-week cells in comparison withthe expression in 8-week cells. Furthermore, proteoglycan synthesis in 40-week cells supplemented with Long R3 insulin-like growth factor-I was upregulated in comparison with that in 40-week cells supplemented with insulin-like growth factor-I.

Conclusion.  The present findings indicate that the age-related decline in insulin-like growth factor-I dependent proteoglycan synthesis in nucleus pulposus is caused, at least in part, by the increase in insulin-like growth factor binding proteins at the early stages of aging, and further suggest that a loss of proteoglycan synthesis during the late stages of aging is caused by the downregulation of insulin-like growth factor-I receptor in addition to an increase in insulin-like growth factor binding proteins.

From the Department of Orthopaedic Surgery (E3), Osaka University Medical School, Osaka, Japan.

Supported by a grant from the Organization for Pharmaceutical Safety and Research and a grant-in-aid for Developmental Science Research from the Ministry of Education, Science, and Culture of Japan (11671431).

Acknowledgment date: January 1, 2001.

Acceptance date: April 13, 2001.

Device status category: 1.

Conflict of interest category: 12.

Address reprint requests to

Shin’ya Okuda, MD

Department of Orthopaedic Surgery (E3)

Osaka University Medical School

2-2 Yamadaoka

Suita

Osaka, 565-0871, Japan

E-mail: okuda@orh.go.jp

© 2001 Lippincott Williams & Wilkins, Inc.