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Home / Equine Research Bank / J Orthop Res / Signaling through the small G-protein Cdc42 is involved in i...
Journal of orthopaedic research : official publication of the Orthopaedic Research Society2006; 24(8); 1765-1772; doi: 10.1002/jor.20185

Signaling through the small G-protein Cdc42 is involved in insulin-like growth factor-I resistance in aging articular chondrocytes.

Abstract: During aging, chondrocytes become unresponsive to insulin-like growth factor-I (IGF-I). This study examined the role of Cdc42 (cell-division-cycle 42) in IGF-I signaling during aging. Experiments were performed using cartilage and chondrocytes isolated from horses ages 1 day-25 years. Northern analysis was used to examine expression of the small GTPases Cdc42, Rac, and RhoA. Western analysis was utilized to assess total Cdc42 (GTP + GDP-bound); active, GTP-Cdc42 was assessed using a pulldown assay with Western analysis. GTP-Cdc42 was also measured following IGF-I treatment. Gene expression for Cdc42 and Rac were decreased in mature samples, but there was no difference in total Cdc42 (GTP + GDP-bound) protein expression due to age. GTP-Cdc42 was significantly greater in prepubescent samples compared to other age groups. IGF-I diminished the GTP-bound state of Cdc42 in prepubescent chondrocytes; however, this effect was lost during aging. No differences in results were observed due to sample type; that is, cartilage tissues versus isolated chondrocytes. These studies suggest that loss of IGF-I-mediated regulation of Cdc42 activation may be a mechanism for the chondrocyte unresponsive state during aging. Further, the activation state of Cdc42, measured in native and IGF-I-treated cartilage tissue for the first time, is similar to that of isolated chondrocytes, indicating that the activation state of small G-proteins is not affected by isolation of chondrocytes from the extracellular matrix. Continued studies will identify the upstream regulators of Cdc42, which will further elucidate the molecular mechanism of IGF-I resistance during aging thereby providing insight into targeted strategies for age-related osteoarthritis.
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Publication Date: 2006-06-17 PubMed ID: 16779831PubMed Central: PMC4154065DOI: 10.1002/jor.20185Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research examines the role of the protein Cdc42 in the decreased responsiveness of old chondrocytes or cartilage cells to the insulin-like growth factor-I (IGF-I). The study suggests that an inefficient regulation of Cdc42 by IGF-I could explain the age-related imperviousness of chondrocytes.

About the Research

  • Chondrocytes, or cartilage cells, normally respond to a substance called insulin-like growth factor-I (IGF-I). However, as these cells age, their response to IGF-I weakens. This research explores why this happens.
  • The researchers are investigating the role of a small protein called Cdc42. Our cells use this protein to signal various cellular processes. The focus of this study is to understand the impact of Cdc42 on IGF-I signaling during aging.

Experimental Details

  • The study was carried out using cartilage and chondrocytes isolated from horses of various ages, ranging from 1 day to 25 years old.
  • The research team used northern analysis and western analysis techniques to explore the role of the small GTPases Cdc42, Rac, and RhoA – all proteins involved in cell signaling – and the expression of these proteins during aging.
  • The researchers specifically studied how IGF-I treatment affected the level of an active form of Cdc42 (GTP-Cdc42).

Findings

  • Gene expressions for Cdc42 and Rac were found to lessen in mature samples. However, when it came to the protein expression of total Cdc42 (GTP + GDP-bound), the researchers found no significant change associated with aging.
  • Interestingly, levels of activated Cdc42 (GTP-Cdc42) were significantly higher before puberty compared to other age groups.
  • When the young chondrocytes were treated with IGF-I, there was a reduction in the GTP-Cdc42 levels. However, this effect was lost as the chondrocytes aged, implying those older cells had become resistant to the IGF-I treatment.

Implications

  • The study suggests that Cdc42’s deregulation in response to IGF-I may underlie the cause of cartilage cells’ insensitivity during aging. In other words, the lack of response to IGF-I may be due to how the protein Cdc42 is activated, or not, as cells age.
  • The nature of Cdc42 activation (both natural and post-IGF-I treatment) was found to be identical in samples taken from cartilage tissue or isolated chondrocytes. This suggests that isolation doesn’t affect the active state of small G-proteins like Cdc42.
  • This research could help understand the molecular mechanics of IGF-I resistance during aging and provide valuable insights for future research focused on treating age-related osteoarthritis.

Cite This Article

APA
Fortier LA, Miller BJ. (2006). Signaling through the small G-protein Cdc42 is involved in insulin-like growth factor-I resistance in aging articular chondrocytes. J Orthop Res, 24(8), 1765-1772. https://doi.org/10.1002/jor.20185

Publication

Journal of orthopaedic research : official publication of the Orthopaedic Research Society
ISSN: 0736-0266
NlmUniqueID: 8404726
Country: United States
Language: English
Volume: 24
Issue: 8
Pages: 1765-1772

Researcher Affiliations

Fortier, Lisa A
  • Department of Clinical Sciences, VMC C3-181, Cornell University, Ithaca, New York 14853, USA. laf4@cornell.edu
Miller, Brian J

    MeSH Terms

    • Aging / physiology
    • Animals
    • Cartilage / cytology
    • Cartilage / physiology
    • Chondrocytes / cytology
    • Chondrocytes / drug effects
    • Chondrocytes / metabolism
    • Down-Regulation / physiology
    • Horses
    • Insulin-Like Growth Factor I / metabolism
    • Insulin-Like Growth Factor I / pharmacology
    • RNA, Messenger / metabolism
    • Signal Transduction / drug effects
    • Signal Transduction / physiology
    • cdc42 GTP-Binding Protein / genetics
    • cdc42 GTP-Binding Protein / metabolism

    Grant Funding

    • K08 AG000905 / NIA NIH HHS
    • Z01 AG000905 / Intramural NIH HHS
    • ZIA AG000905-13 / Intramural NIH HHS

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    This article has been cited 9 times.
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